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Intraadrenal Interactions in the Regulation of Adrenocortical Steroidogenesis

Department of Internal Medicine III (M.E.-B.), University of Leipzig, 04103 Leipzig, Germany; Department of Biochemistry (J.P.H., G.P.V.), Queen Mary and Westfield College, London E14NS, England; National Institute of Child Health and Human Development (S.R.B.), National Institutes of Health, Bethesda, Maryland 20892; and Diabetes Research Institute at the Heinrich Heine University (W.A.S.), 40225 Düsseldorf, Germany

	Abstract

Top Abstract I. Introduction: The Adrenal... II. Interaction Between Adrenal... III. Innervation of the... IV. The Vascular System... V. The Intraadrenal CRH/ACTH... VI. Immune Cells and... VII. Peptide Growth Factors... VIII. The Intraadrenal Renin... IX. Clinical Implications X. Conclusions References

 

I. Introduction: The Adrenal Functional Unit

II. Interaction Between Adrenal Medulla and Adrenal Cortex

A. Relationship between medullary and cortical cells

B. Paracrine control of adrenocortical function by the adrenal medulla

C. Gap junctions in the adrenal cortex

D. Summary

III. Innervation of the Adrenal Cortex

A. Evidence for a nerve supply to the adrenal cortex

B. The source of adrenocortical innervation

C. Regulation of adrenocortical innervation

D. Role of the splanchnic nerve in regulating adrenocortical neural function

E. Influence of adrenal innervation on adrenocortical function

F. Effects of neurotransmitter substances on adrenocortical function

G. Summary

IV. The Vascular System of the Adrenal Gland

A. Regulation of blood flow

B. Relationship between blood flow and steroid secretion

C. Effects of vascular endothelial cell products on steroid secretion

D. Summary

V. The Intraadrenal CRH/ACTH System

A. Extrapituitary effect of CRH

B. Intraadrenal ACTH

C. Intraadrenal CRH and CRH receptors

D. Feedback mechanisms

E. Summary

VI. Immune Cells and Cytokines in the Adrenal Gland

A. Source of cytokines within the adrenal

B. Cytokines that influence the adrenal cortex

C. Summary

VII. Peptide Growth Factors and the Adrenal Cortex

A. FGFs

B. IGFs

C. TGFß

D. Summary

VIII. The Intraadrenal Renin-Angiotensin System (RAS)

A. The role of the RAS in adrenocortical function

B. Renin

C. Angiotensinogen

D. Angiotensin-converting enzyme and the production of angiotensin II

E. What is the functional significance of the intraadrenal RAS?

F. How can the angiotensin II produced by the tissue RAS be distinguished from the systemic system?

G. Summary

IX. Clinical Implications

A. Cortisol

B. Aldosterone

C. Adrenal androgens

D. Summary

X. Conclusions

	I. Introduction: The Adrenal Functional Unit

Top Abstract I. Introduction: The Adrenal... II. Interaction Between Adrenal... III. Innervation of the... IV. The Vascular System... V. The Intraadrenal CRH/ACTH... VI. Immune Cells and... VII. Peptide Growth Factors... VIII. The Intraadrenal Renin... IX. Clinical Implications X. Conclusions References

 
OVER the past few years, considerable evidence has accumulated to challenge the accepted view of the regulation of adrenocortical function. Conventionally, the cortex and medulla have been viewed as distinct functional units, with cortical function regulated primarily by the circulating hormones, ACTH and angiotensin II, acting mainly on the inner adrenocortical zones and the glomerulosa, respectively. However, it has become clear that certain aspects of adrenocortical function cannot be explained in this simplistic manner. Certainly there are discrepancies between the concentrations of these regulatory hormones and the secretion of the corticosteroids, suggesting that other factors may also be involved.

As a result of intensive study in recent years, we now know that the regulatory mechanisms that account for such discrepancies are mainly located within the adrenal itself, and that several different components of the gland contribute to these functions. The adrenal produces a wide variety of hormones, neuropeptides, neurotransmitters, and cytokines, and it is evident that the colocalization of these different systems has a profound functional significance. The cells within the adrenal thus communicate with each other and adapt the function of the gland to different situations. The integrated control of adrenocortical function involves cortico-medullary interactions, the gland’s vascular supply, its neural input, the immune system, growth factors, and the intraglandular renin-angiotensin and CRH-ACTH systems. As well as directly regulating adrenocortical function, these systems influence each other and form complex intraadrenal regulatory circuits.

We here survey the mechanisms involved in the intra-glandular regulation of adrenocortical function and show how they combine to ensure that the gland functions as a unit.

	II. Interaction Between Adrenal Medulla and Adrenal Cortex

Top Abstract I. Introduction: The Adrenal... II. Interaction Between Adrenal... III. Innervation of the... IV. The Vascular System... V. The Intraadrenal CRH/ACTH... VI. Immune Cells and... VII. Peptide Growth Factors... VIII. The Intraadrenal Renin... IX. Clinical Implications X. Conclusions References

 
The adrenal gland consists of two endocrine tissues of different embryological origin: the primarily steroid-producing adrenocortical tissue and the catecholamine-producing chromaffin cells. During embryogenesis, the adrenal primordium is formed as a condensation of celomic epithelium at the cranial end of the kidney. This adrenal primordium consists of mesodermally derived fetal adrenal cells, which later become steroid-producing cells. In most mammals the adrenal cortex consists of three zones, varying in both their morphological features and the steroid hormones they produce. The zona glomerulosa is the unique source of the mineralocorticoid, aldosterone. The zona fasciculata and the zona reticularis produce the glucocorticoids, cortisol and corticosterone, and the androgens [predominantly dehydroepiandrostenedione (DHEA) and DHEA sulfate in human], which may be relatively more abundant in the zona reticularis.

Adrenomedullary chromaffin cells originate from neural crest precursor cells that migrate into the adrenal "anlagen" and later differentiate into chromaffin cells in the adrenal medulla under the influence of adrenocortical steroids (1, 2). The main secretory products of these differentiated cells are the catecholamines epinephrine and norepinephrine. In addition, chromaffin vesicles contain numerous transmitters, neuropeptides, and proteins, which may be released together with the catecholamines (3).

A. Relationship between medullary and cortical cells
Within the adult tetrapod adrenal, cortical and chromaffin cells are united in one gland. The organization of these two cell types varies among different species. In nonmammalian species chromaffin cells may be distributed in islets, as in amphibia and birds, or concentrated toward one pole of the gland, as in reptiles (4). In mammals, the conventional view holds that the two different endocrine tissues are clearly separated into an outer steroid-producing cortex and a central medulla (4, 5, 6, 7). However, this is an oversimplification, and the distribution of these cells may not be so clearly demarcated, but may instead involve closer contact than previously thought.

The occurrence of medullary cells in the zona glomerulosa of adult rats was first observed nearly 30 yr ago (8, 9). Although slow to receive general acceptance, it is now widely acknowledged that chromaffin cells can be found in all zones of the adult adrenal cortex, either radiating through the cortex from the medulla (8, 9, 10, 11, 12) or distributed as islets or single cells. Medullary cells may also spread into the subcapsular region, where they form larger nests of chromaffin cells (8, 11, 12, 13). Conversely, cortical cells are also located in the medulla, where they may form islets either surrounded by chromaffin tissue or retaining some contact to the rest of the cortex. The adrenal medulla appears, in part, to be peppered with cortical cells (12, 14) (Fig. 1). This intimate intermingling of the two cell types allows extensive contact zones for paracrine interaction.

View larger version (127K): [in this window] [in a new window]   Figure 1. Cross-section of a human adrenal. Adrenocortical cells are immunostained for 17-hydroxylase using diaminobenzidin (COR), and medullary cells are immunostained for chromogranin A using AEC (Dianova, Hamburg, Germany) (MED). Especially in the medulla, medullary and cortical tissues are highly intermingled with islets of cortical tissue (C) surrounded by medullary cells.

View larger version (124K): [in this window] [in a new window]   Figure 2. Electron micrograph of rat adrenal cortex. The exact moment of an exocytosis from a chromaffin cell (arrow) in direct apposition to an adrenocortical cell in the zona glomerulosa is shown. [Reproduced with permission from S. R. Bornstein and M. Ehrhart-Bornstein: Endocrinology 131:3126–3128, 1992 (15). © The Endocrine Society.]

1. Epinephrine, norepinephrine, and serotonin (5-HT). Neuroendocrine regulation of this type may depend on neurotransmitters released from nerve endings in the adrenal cortex (see Section III) or on the chromaffin cell products, epinephrine and norepinephrine. These catecholamines are secreted in response to splanchnic nerve stimulation and may influence adrenocortical function (references in Table 1). For example, the secretion of cortisol, aldosterone, and androstenedione was found to be stimulated by perfusion of the isolated porcine adrenal glands with epinephrine or norepinephrine (22, 24). In addition to this acute effect, catecholamines have a long-term effect on corticosteroid release from isolated adrenocortical cells, involving transcriptional regulation of steroid enzymes (27, 28). Interestingly, epinephrine and norepinephrine had the opposite effect in the frog adrenal, inhibiting steroid secretion (29). These data provide evidence for a direct influence of medullary products on cortical function.

2. Neuropeptides. However, in addition to catecholamines, adrenomedullary chromaffin cells produce, store, and secrete a whole series of neuropeptides (Table 2). The first neuropeptides to be discovered in the adrenal medulla were the enkephalins (37), which are by number the most prominent neuropeptides in the chromaffin vesicles (3). In addition, many other neuropeptides are costored with adrenomedullary catecholamines (Table 2; for review, see Refs. 3, and 38–40).

Coculture systems of bovine adrenomedullary chromaffin cells with bovine adrenocortical cells have now supplied evidence for the paracrine influence of chromaffin cells on adrenocortical cells. The secretory products of chromaffin cells stimulate steroidogenesis both when they are in direct contact with adrenocortical cells (Fig. 3) and also in a system in which the cell types are separated by a semipermeable membrane (49).

View larger version (86K): [in this window] [in a new window]   Figure 3. Primary cultures of bovine adrenocortical cells (A and C) and of bovine adrenocortical cells cultured together with chromaffin cells (B and D). Cells were kept in vitro for 3 days (DMEM/F12 + 10% FCS). Cortical cells were immunostained for 17-hydroxylase in panel A, chromaffin cells were immunostained for chromogranin A in panel B (COR, adrenocortical cell; MED, adrenomedullary cell). Isolated cortical cells (2 x 105/well) released 5% of the cortisol released by cortical cells (2 x 105/well) cultured together with chromaffin cells (2 x 105/well); 8.6 ± 2.1 nmol/liter/24 h (C) vs. 186.5 ± 34.9 nmol/liter/24 h (D) (mean ± SEM, n = 4).

C. Gap junctions in the adrenal cortex
Although the adrenal cortex and medulla are highly interwoven, only a subpopulation of adrenocortical cells lies in direct contact with adrenomedullary cells and therefore under the influence of adrenomedullary secretory products. A prompt adrenocortical response to stimulation (or inhibition), however, requires an effective cellular communication system. Gap junctions occur within all zones of the mammalian adrenal cortex (61, 65, 671, 672, 673), and active gap junctions have been shown to form between adrenocortical cells in primary culture (65, 66). Furthermore, gap junctions are induced relatively rapidly after ACTH stimulation, suggesting their pivotal role in hormone response. Gap junctions allow small, water-soluble molecules to pass directly from the cytoplasm of one cell to the cytoplasm of the other, and the intracellular signal may thus be propagated from stimulated to unstimulated cells, as observed in dispersed rat adrenocortical cells (67). Thereby, gap junctions could couple the cells both electrically and metabolically and may help to coordinate the function of the gland, especially in response to locally restricted stimulation.

D. Summary
In conclusion, the data presented in this chapter show that the medulla and cortex are interdispersed to various degrees in mammalian adrenals much as in nonmammalian vertebrates. In addition, these two different tissues interact by complex regulatory circuits. Increasing evidence exists that the close colocalization is the prerequisite for paracrine interactions within the adrenal. Various adrenomedullary secretory products, such as catecholamines, 5-HT, and a whole series of neuropeptides, are involved in the regulation of adrenocortical steroidogenesis, by either stimulating or inhibiting adrenocortical function. Under basal conditions, stimulatory influences seem to be dominant. However, the influence of adrenomedullary secretory products on adrenocortical functions is complex and probably varies in different physiological situations. The complexity in the intraadrenal regulation of steroid secretion is increased by the fact that several factors may interact by addition, potentiation, or antagonism of their effects. In turn, adrenocortical secretory products, the steroid hormones and cytokines released by the cortex, influence the neuropeptide, protein, and catecholamine expression in medullary chromaffin cells. It remains to be elucidated how the different adrenomedullary secretory products are involved in the adjustment of adrenocortical functions to the needs of the body and to the maintenance of homeostasis under different conditions.

	III. Innervation of the Adrenal Cortex

Top Abstract I. Introduction: The Adrenal... II. Interaction Between Adrenal... III. Innervation of the... IV. The Vascular System... V. The Intraadrenal CRH/ACTH... VI. Immune Cells and... VII. Peptide Growth Factors... VIII. The Intraadrenal Renin... IX. Clinical Implications X. Conclusions References

 
A. Evidence for a nerve supply to the adrenal cortex
The classic view of adrenal anatomy is that the nerve supply to the adrenal medulla passes directly through the cortex without branching or synapsing with any adrenocortical cells. The early descriptions of the microanatomy of the adrenal cortex concluded, therefore, that the adrenal cortex is not directly innervated (68, 69, 70, 71, 72). Only one of the early studies differed from this view, and in 1931 Alpert (73) described a "rich, intimate nerve supply to the cortex." It was 40 yr before this observation was confirmed by Unsicker’s report (74) of nerve fibers in the rat and pig adrenal glands, apparently synapsing with adrenocortical cells. This was followed in 1977, by similar observations in sheep adrenals (75). It is now the generally accepted view that the mammalian adrenal cortex receives a rich nerve supply, and there is strong evidence to suggest that nerve terminals may directly contact the steroid-secreting cells of the adrenal cortex (38, 76, 77, 78). Vesicle-containing nerve endings have been observed in direct contact with cortical cells in the frog adrenal (79) and zona glomerulosa cells in the rat adrenal (80), and similar observations have been made in the zona fasciculata of the human adrenal (81).

In addition to the well described afferent innervation of the adrenal cortex, there is also a less well documented efferent innervation. The presence of both chemoreceptors and baroreceptors in the adrenal gland has been reported (82, 83). This efferent innervation has been implicated in the contralateral hypertrophic response to adrenal damage (84).

B. The source of adrenocortical innervation
There is evidence that the afferent innervation of the adrenal cortex derives from two distinct sources (85): one source is the adrenal medulla, and it has been suggested that the adrenal cortex may originally have been a target organ for adrenomedullary postganglionic nerves. During evolution, as the cortex and medulla became more closely associated, the postganglionic fibers terminated entirely within the adrenal gland, forming the chromaffin tissue and innervating the cortical cells (86). The second source of nerves supplying the adrenal cortex is not clear, but these nerves appear to have their cell bodies outside the adrenal gland and enter the gland along blood vessels (85). It has been demonstrated that the adrenal nerves entering the gland contain both pre- and postganglionic fibers (87, 88), and presumably these postganglionic fibers supply the adrenal cortex.

Intraadrenal nerve fibers, originating in the medulla and innervating the outer layers of the cortex, have been described in the rat adrenal gland in particular. The most extensively studied neuropeptide has been VIP. Hökfelt and co-workers (89) described an intrinsic adrenal VIP-ergic neural system with cell bodies in the medulla and varicose fibers in the zona glomerulosa. This finding has been confirmed by others (90) and extended to include reports of other intrinsic adrenal peptidergic nerves, including CGRP-, substance P-, and neuropeptide Y-containing nerves (91, 92, 93). In addition to a wide range of neuropeptides, catecholamines (85, 94) and acetylcholine (95) have been identified as transmitters in nerves supplying the adrenal cortex of different mammalian species (Table 3; for reviews see Refs. 38 and 96), although the source of this innervation is often not clear. The term ‘intrinsic’ is frequently used to describe nerve fibers innervating the adrenal gland. This term is most properly used to describe neurons that are wholly contained within the adrenal gland, whose cell bodies can be clearly identified, and should not be extended to include other, less defined, forms of innervation. Unfortunately, it is not always clear in reports of adrenocortical innervation whether the innervation is intrinsic.

D. Role of the splanchnic nerve in regulating adrenocortical neural function
It is not clear to what extent the splanchnic nerve regulates adrenocortical nerve activity. Although it has been found that stimulation of the splanchnic nerve causes the release of several neuropeptides into the adrenal venous effluent, it is not possible to determine what proportion might be contributed by the cortical innervation, compared with the adrenal medulla. As may be seen in Section I, the same neurotransmitters found in nerve fibers innervating the cortex (Table 3) are also present in the chromaffin cells of the adrenal medulla (Table 2). There have been, however, studies that have directly addressed the question of the role of the splanchnic nerve in regulating cortical innervation, although the results are difficult to interpret.

Hökfelt and colleagues (89) found that the VIP-ergic intraadrenal nerves were independent of splanchnic nerve activity: after extrinsic adrenal denervation (achieved by cutting the splanchnic nerve and periarterial nerves and removing the celiac ganglion) VIP-immunoreactive fibers persisted in the rat adrenal cortex, and indeed no difference was reported in levels of immunoreactive VIP between control and adrenal denervated rats. Holzwarth (90), on the other hand, found that the VIP immunoreactive adrenal nerves with cell bodies in the medulla were regulated by splanchnic nerve activity, with an increase in VIP immunostaining after splanchnic nerve ligation. After adrenal enucleation and cortical regeneration, however, the number of VIP-ergic fibers in the cortex was greatly reduced. A recent study, in which immunoreactive cortical and medullary VIP were measured, reported that, while medullary VIP content was significantly decreased after splanchnic nerve section, there was no effect on cortical VIP (98). The problem with all of these studies is that in each, neuropeptide content is measured at a single point in time since dynamic studies of this type of system are not accessible using current methodology. The question that is posed by these data is: What does a change in neuropeptide content signify? If cytochemical studies can demonstrate a population of neurons that disappears after splanchnic nerve section, then it seems reasonable to conclude that those neurons are regulated by the splanchnic nerve. However, when the amount of a transmitter present increases after nerve ligation, it is questionable whether this reflects increased synthesis or decreased release of the transmitter (85). The converse is also true: if the amount of neuropeptide present decreases, is it because the nerve has degenerated or has its activity increased?

It is difficult to distinguish between intrinsic and extrinsic adrenocortical nerves and equally difficult to determine the influence of the splanchnic nerve on adrenocortical innervation. Most of our understanding of the role of the adrenocortical innervation in regulating adrenocortical function has, therefore, come from functional studies.

E. Influence of adrenal innervation on adrenocortical function
Several aspects of adrenocortical function have been shown to be influenced by adrenal innervation. Adrenal growth in response to damage of the contralateral adrenal gland (or in response to unilateral adrenalectomy), termed ‘compensatory adrenal hypertrophy,’ has been shown to be mediated by both adrenal afferent and efferent nerves, via the hypothalamus (84). This effect is independent of splanchnic nerve activity (84) and is not associated with an increase in adrenal neuropeptide content (98).

Most functional studies, however, have investigated the effects of splanchnic nerve section on adrenal responses. An account of the role of the splanchnic nerve in the regulation of adrenal blood flow is given in Section IV. Several studies in different species, including dog, calf, and sheep, suggest that splanchnic nerve activity regulates adrenocortical sensitivity to ACTH stimulation: sectioning the splanchnic nerve decreases the adrenal response to ACTH (21, 99), while stimulation enhances it (20, 100). In the pig, isolated perfused adrenal, splanchnic nerve stimulation increases the secretion of aldosterone, cortisol (22), and androstenedione (24). It is likely that the effects of stimulating the nerves supplying the adrenal gland are mediated by the local release of neurotransmitters, either from nerve endings or from medullary cells.

Adrenal innervation has also been implicated in regulating the diurnal variation in cortisol secretion (16, 17).

F. Effects of transmitter substances on adrenocortical function
Many studies have directly addressed the question of the functional role of the different neurotransmitters identified in neurons supplying the adrenal cortex. The results of these studies have implicated the various neurotransmitters in a wide range of effects. Many have been shown to directly stimulate steroidogenesis by dispersed adrenal cells, or by the intact perfused rat adrenal preparation. Others appear to stimulate the growth of the adrenal cortex, or to modulate the adrenocortical response to humoral stimulation. This subject has been recently reviewed by several groups (38, 76, 96, 101, 102, 103, 104). Clearly it is difficult to distinguish between the effects of medullary chromaffin cells and direct adrenal innervation, as the same transmitters may be produced by both. The effects of different transmitters are summarized in Table 1.

G. Summary
It is clear that the adrenal cortex receives a direct innervation, at least partly derived from the splanchnic nerve. The neurotransmitters identified in nerves supplying the cortex have a variety of actions, from direct effects on growth and steroidogenesis, to modulation of the actions of humoral stimuli on the adrenal cortex. This innervation also has a role in regulating the vasculature (see Section IV). It would appear that adrenocortical innervation has a role in fine tuning the functions of the adrenal cortex.

	IV. The Vascular System of the Adrenal Gland

Top Abstract I. Introduction: The Adrenal... II. Interaction Between Adrenal... III. Innervation of the... IV. The Vascular System... V. The Intraadrenal CRH/ACTH... VI. Immune Cells and... VII. Peptide Growth Factors... VIII. The Intraadrenal Renin... IX. Clinical Implications X. Conclusions References

 
The adrenal gland is a highly vascular tissue (Fig. 4) and receives a high proportion of the cardiac output relative to its size. The rat adrenal, for example, comprises approximately 0.02% of the total body weight, but receives around 0.14% of the cardiac output (105). The vascular supply to the adrenal gland has been described in several species, and while the general arrangement of blood vessels is similar, it is clear that there are some important variations between species, particularly in relation to the degree of independence of cortical and medullary blood supply (43, 106, 107, 108). In general, the adrenal gland is supplied by small arterioles that arise from the aorta, and from the renal and inferior phrenic arteries. Blood is supplied to a network of arterioles in the connective tissue capsule, referred to as the subcapsular arteriolar plexus, from which it is distributed into two types of vessel: the thin-walled sinusoids that supply the cortex and the medullary arteries that convey blood directly to the adrenal medulla. The numbers of these medullary arteries vary greatly among species (63), with the dog having a relatively large number and the rat very few (109). This is likely to be the reason for differences in the regulation of adrenal cortical and medullary blood flow (43).

View larger version (107K): [in this window] [in a new window]   Figure 4. Relationship of the noradrenergic innervation of the rat adrenal gland to the vasculature. Most of the nerve fibers are located in the capsular (c) and subcapsular region where they form arborizations around the vasculature and, to a lesser extent, around the zona glomerulosa cells. In addition, there is a sparse distribution of ganglionic cells and chromaffin cells (tyrosine hydroxylase and dopamine-ß-hydroxylase positive) among the cortical cells. zg, Zona glomerulosa; zf, zona fasciculata; zr, zona reticularis; m, medulla; n, nerve fibers; a, arteriole; ma, medullary artery; s, sinusoids; i, isolated islets of chromaffin cells; gc, ganglionic cells. [Modified and reproduced with permission from G. P. Vinson et al.: J Neuroendocrinol 6:235–246, 1994 (76).]

ACTH is well known to stimulate increases in adrenal blood flow (105, 116, 117, 118). Although it has been suggested that ACTH exerts its effects by constricting medullary arteries and diverting blood into the cortical sinusoids (106), studies in the perfused rat adrenal preparation have suggested that this is not the case: ACTH administration results in an overall increase in the flow of perfusion medium, suggesting a decreased vascular resistance within the gland (62). A mechanism has been proposed to account for the adrenal vascular effects of ACTH: mast cells are known to be present within the adrenal capsule, particularly where it is penetrated by the adrenal arteries. Mast cells contain histamine and 5-HT, both potent vasoactive compounds, which are released by the action of ACTH and cause adrenal vasodilatation. Evidence in support of this hypothesis was obtained by using disodium cromoglycate, an inhibitor of mast cell degranulation. This agent abolishes the vascular effects of ACTH, suggesting that mast cell degranulation is an essential step in the adrenal vascular response to ACTH (119, 120).

The recently identified secretory products of the vascular endothelium—nitric oxide, endothelin-1, and adrenomedullin—have also been implicated in the local regulation of adrenal blood flow. Decreasing endogenous nitric oxide production by administration of an inhibitor of nitric oxide synthase, such as L-NAME causes a decrease in the rate of blood flow through both the adrenal cortex and medulla in the dog (121) and a decrease in perfusion medium flow rate through the perfused rat adrenal gland (122). Perfusing the rat adrenal gland with medium lacking L-arginine, the substrate for nitric oxide synthesis, has a similar vasoconstrictive effect, which is reversed by administration of L-arginine (122), suggesting that nitric oxide exerts a tonic vasodilatory effect in this tissue. The presence or absence of nitric oxide does not significantly affect the vascular action of ACTH (122).

Endothelin also appears to regulate adrenal vascular tone. Administration of an endothelin receptor (ET_A) antagonist causes adrenal vasodilation, suggesting that endothelin-1 exerts a tonic vasoconstrictor effect on the adrenal vasculature (122). Adrenomedullin stimulates perfusion medium flow in the intact perfused rat adrenal model (47). The interactions between these agents, which produce an integrated control of adrenal blood flow, remain to be elucidated.

B. Relationship between blood flow and steroid secretion
A relationship between the rate of blood flow through the adrenal gland and the rate of glucocorticoid secretion was proposed in the early 1950s by Hechter and co-workers (123). Further studies in dogs, rats, and calves have shown that, in the presence of submaximal concentrations of ACTH, there is a clear relationship between adrenal blood flow and steroid secretion (123, 124, 125, 126). It has been shown that, under these conditions, increased blood flow causes an increase in the rate of presentation of ACTH to the adrenal gland, and it has been suggested that it is the rate of ACTH presentation, rather than the absolute concentration of ACTH present, that is the major determinant in the adrenocortical response (124). However, a relationship between adrenal blood flow and steroid secretion exists even in the absence of ACTH (62, 127). In the isolated perfused rat adrenal preparation, which has been used to address this question, there is a significant correlation between perfusion medium flow rate and corticosterone secretion that is seen in the absence of ACTH and is found when flow rate is changed either mechanically or by the use of vasodilators. Clearly, increased flow rates in this preparation have implications for the delivery of oxygen and the removal of steroid products, but this is an effect that is unique to the intact adrenal gland: collagenase-dispersed cells superfused on a column simply do not respond in the same way to changes in flow (62). This suggests that the effect of changes in blood (or perfusion medium) flow on steroid secretion are mediated by an element present in the intact gland that is lost when cells are dispersed. This factor is most likely to be one of the secretory products of the cells of the vascular endothelium.

C. Effects of vascular endothelial cell products on steroid secretion
Within the adrenal cortex the arrangement of blood vessels is such that nearly every adrenocortical cell is directly adjacent to a vascular endothelial cell (Fig. 4). In addition to their actions on the adrenal vasculature, the secretory products of endothelial cells exert significant effects on adrenal function, which appear to be independent of their vascular effects (Table 4). Endothelin-1 has been shown to stimulate aldosterone secretion in several species, including frog (128), cow (129, 130), rabbit (131), rat (132, 133), and human (132). In the calf it appears that endothelin acts through the ET_A receptor subtype to stimulate aldosterone secretion (130). In the rat, however, it is not clear which receptor subtype is involved in aldosterone secretion since both subtypes are present in the zona glomerulosa (134, 135, 136, 137); some authors report no effect of ET_A antagonists (135), while others have found that both receptor subtypes are involved (137, 138) or that ET_A receptors mediate most of the effect of endothelin (137). In the human adrenal cortex, both endothelin receptor subtypes are present in the zona glomerulosa (139, 140) while only ET_B receptors are present in the inner zones (139, 140).

Endothelin-1 also stimulates glucocorticoid secretion by inner zone cells from rat and human adrenals (132, 136) by interacting with ET_B receptors (134, 136). There is evidence that endothelin-1 is released from vascular endothelial cells in response to shear stress and increased perfusion pressure (144, 145). Since the rat adrenal gland releases endothelin-1 in response to increased perfusion medium flow rates, and also in response to ACTH, which is a vasodilator in this tissue (146), it may be concluded that endothelin-1 mediates at least some of the effects of increased blood flow on steroid secretion (63, 132).

It has been suggested that nitric oxide also has effects on adrenal steroid secretion. The presence or absence of L-arginine, the substrate for nitric oxide synthesis, does not alter rat adrenal glucocorticoid responsiveness to ACTH stimulation, although the basal rate of steroid output is much lower in the absence of endogenous nitric oxide synthesis (122). More recently it has been reported that the nitric oxide synthase inhibitor, L-NMMA (L-N^G monomethyl arginine), inhibits the aldosterone response to ACTH stimulation in rat capsular tissue (147), although L-NAME does not have this effect in the perfused rat adrenal (122). In intact rats the administration of inhibitors of nitric oxide synthesis attenuated the adrenal response to angiotensin II in anephric rats but did not affect basal aldosterone secretion (148).

There is some disagreement in the literature as to whether adrenomedullin stimulates (47, 149, 150) or inhibits (151, 152) aldosterone secretion. Nussdorfer and co-workers (47, 151) reported inhibition of stimulated aldosterone secretion using collagenase-dispersed adrenal cells but stimulation of basal aldosterone using an intact adrenal preparation. It has been reported, however, that adrenomedullin stimulates aldosterone and cAMP production by rat adrenal capsular tissue and zona glomerulosa cells (149, 153). The stimulatory effect of adrenomedullin appears to be mediated by specific adrenomedullin receptors (153), while its inhibitory actions appear to be mediated by the CGRP receptor (151). Differential expression of adrenomedullin and CGRP receptor may explain the discrepancies between the findings of different research groups. The related peptide PAMP (proadrenomedullin N-terminal 20 peptide) may have more potent inhibitory effects (154), although stimulatory actions have also been reported (153). It has also been shown that adrenomedullin inhibits angiotensin-stimulated aldosterone secretion in human adrenal cells (155) but stimulates inner zone function in the rat adrenal (47), although this effect may be secondary to vascular actions.

It has been established that adrenomedullin is produced within the adrenal gland, by both zona glomerulosa and chromaffin cells (153), although it is not yet clear how its secretion is regulated. Like endothelin-1, adrenomedullin may also have a role in mediating the steroid response to vascular events.

D. Summary
The regulation of adrenal blood flow is complex and probably involves a range of humoral and local mediators. There is clearly a close relationship between vascular events and steroid secretion, which may be mediated by the vascular endothelium in a paracrine manner. At present, the most likely agent is endothelin-1, which appears to satisfy the criteria for such a mediator. The evidence regarding adrenomedullin remains unclear at present, although that which is currently available suggests that the effects of this peptide differ according to the receptor subtype it activates.

	V. The Intraadrenal CRH/ACTH System

Top Abstract I. Introduction: The Adrenal... II. Interaction Between Adrenal... III. Innervation of the... IV. The Vascular System... V. The Intraadrenal CRH/ACTH... VI. Immune Cells and... VII. Peptide Growth Factors... VIII. The Intraadrenal Renin... IX. Clinical Implications X. Conclusions References

 
Cushing’s syndrome may be caused by ectopic ACTH production in a pheochromocytoma (Ref. 156 and literature herein). In addition, CRH-releasing pheochromocytomas causing Cushing’s syndrome have also been described (157, 158). Therefore, local CRH/ACTH production within the adrenal is of relevance in adrenal diseases. However, a local CRH/ACTH system may also be relevant in the regulation of adrenocortical function under physiological conditions.

A. Extrapituitary effect of CRH
The release of glucocorticoids is regulated via the hypothalamo-pituitary-adrenocortical axis, with CRH and ACTH as the respective secretagogues. Ovine CRH was purified and sequenced in 1981 (159, 160), and initial data on a dexamethasone-nonsuppressible, probably extrapituitary effect of CRH on adrenocortical steroidogenesis were published by De Souza and Van Loon in 1984 (161). Data from different experimental models have verified that CRH influences adrenocortical steroidogenesis independently from the HPA-axis. High doses of CRH had a trophic effect on the adrenal cortex of hypophysectomized rats (162), and CRH exerted a substantial steroidogenic effect on the adrenals in functionally hypophysectomized calves (163). In addition, CRH enhances the adrenal response to ACTH. When CRH was combined with a subeffective dose of ACTH, a marked dose-dependent increase in corticosterone release was observed from rat adrenals (164). In healthy humans, cortisol secretion was stimulated either by insulin or CRH. Interestingly, the ratio between the cortisol increment and the ACTH increment was higher after stimulation with CRH than with insulin (165), indicating a direct effect of CRH on the adrenal or via other factors that stimulate cortisol release.

Experiments in which the effect of CRH was neutralized also gave some evidence for the extrapituitary influence of CRH on the adrenal cortex. Immunoneutralization of CRH reduced resting corticosterone levels in rats without inducing concomitant reduction in plasma ACTH (166), and an antibody to CRH reduced the adrenal response to ACTH in dexamethasone-treated rats (164). In hypophysectomized rats, a subcutaneous infusion of -helical-CRH or corticotropin-inhibiting peptide, competitive inhibitors of CRH and ACTH, respectively, evoked a further significant lowering of plasma corticosterone concentration and markedly enhanced adrenal atrophy (167).

Is the influence of CRH due to its direct effect of this peptide on the adrenal cortex, or is it mediated by ACTH or another peptide? A direct effect of CRH on adrenocortical steroidogenesis seems unlikely, as CRH had no effect on either isolated, dispersed adrenocortical cells (164) or on adrenocortical autotransplants deprived of chromaffin tissue (168, 169). However, in isolated perfused adrenal glands in situ, the perfusion rate was increased when CRH and a substimulatory dose of ACTH were given together, although neither CRH nor ACTH alone had an effect on the flow rate (164). Thus, the CRH-enhanced adrenal response to ACTH may result from their synergistic action on adrenal blood flow. In another experimental model, CRH enhanced corticosterone secretion in rat adrenal slices containing both cortex and medulla but had no effect on adrenocortical autotransplants that lack chromaffin tissue (168, 169). Although the exact mechanism is not yet clear, the effect is indirect rather than direct, and the intact architecture of the adrenal seems to be mandatory for the stimulatory action of CRH on the adrenal cortex. In this context, two possibilities suggest themselves. First, CRH may act with ACTH directly on intraadrenal blood vessels, and second, the medulla may respond to CRH by releasing a secretagogue that stimulates adrenocortical function.

B. Intraadrenal ACTH
Given that the adrenal medulla is necessary for the action of CRH on the adrenal cortex, which medullary product mediates the effects of CRH? The stimulatory effect of CRH on corticosterone secretion by rat adrenal slices, containing both cortex and medulla, was annulled by corticotropin-inhibiting peptide (168, 169), indicating the involvement of intraadrenal ACTH. Indeed, ACTH immunoreactivity was found in extracts of rat (170) and human (171, 172, 173) adrenal medulla, and in the adrenal venous effluent of hypophysectomized calves in response to splanchnic stimulation (174). In addition, adrenal fragments composed mainly of chromaffin cells released ACTH in response to high concentrations of CRH (168, 169). In patients with proven pituitary ACTH deficiency who received ACTH replacement therapy, subsequent CRH administration induced a significant increase in plasma cortisol that was preceded by a rise in plasma ACTH (175). Taken together, these data suggest that the adrenal medulla is a source of extrapituitary ACTH that can be stimulated by CRH.

C. Intraadrenal CRH and CRH receptors
Plasma levels of CRH are probably too low to stimulate a significant release of ACTH from the adrenal medullary. Within the adrenal itself, CRH-like immunoreactivity with ACTH-releasing activity has been detected in the medulla of cattle (176, 177), dogs (178), humans (171, 172, 173), and rats (170, 179, 180). This adrenal CRH has proved to be identical to the hypothalamic CRH (171, 173) and to be released in response to physiological stimuli, such as hemorrhage (181), splanchnic nerve stimulation (182), K⁺-induced depolarization, nicotine (180), neurotensin (183), vasopressin (184), neuropeptide K and neurokinin A (185), and IL-1ß (170, 180, 186). The immunohistochemical localization of CRH revealed a distinct CRH-immunoreactive subpopulation of medullary cells in canine, with dense clusters of these cells located at the boundary between the medulla and cortex (178, 181). In sheep, immunostaining revealed a network of CRH-containing cells and varicose fibers in the adrenal cortex. Mono- and bipolar cells were found throughout the cortex, most densely at the corticomedullary junction (187). These nerves were found to be associated with medullary cells at the medullary-cortical interface, islands of medullary cells in the cortex, or with rays of medullary cells extending into the cortex (188). This provides strong morphological evidence for a local intraadrenal CRH/ACTH system that is involved in the regulation of adrenocortical function.

The adrenal CRH/ACTH system is completed by the demonstration of CRH receptors in the monkey adrenal where they were located exclusively in the adrenal medulla with no staining of adrenocortical cells (189, 190). These receptors are coupled to adenylate cyclase and stimulate the secretion of catecholamines and Met-enkephalin (189).

D. Feedback mechanisms
The central CRH/ACTH system is regulated via feedback mechanisms. Similar feedback mechanisms have also been described for the adrenal CRH/ACTH system. In rats, cortisol treatment lowered adrenal ACTH secretion after 2 days of treatment, and adrenal CRH content after 7 days (179). In contrast, the intraadrenal content of CRH and ACTH immunoreactivity increased in hypophysectomized rats in direct relation to the number of days after hypophysectomy. ACTH infusion, at a rate that restored its normal blood concentration, prevented the effect of hypophysectomy on intraadrenal ACTH and CRH concentrations (191), and in hypophysectomized calves, ACTH reduced adrenal CRH output (182). These findings suggest that the elimination of the central CRH/ACTH system induces a marked increase in the activity of the intraadrenal system, and that regulation of adrenal CRH and ACTH is achieved through feedback inhibition through the end products ACTH and glucocorticoids. Evidence exists that some neuropeptides [e.g., PACAP (192, 193) and neuromedin U8 (194)] may stimulate adrenocortical steroid secretion by activating the intraadrenal CRH/ACTH system.

E. Summary
In conclusion, a complete CRH/ACTH system exists within the adrenal, with the adrenal medulla and/or intraadrenal nerves as a source of CRH and adrenal medullary chromaffin cells as the target for this local releasing hormone and the source of ACTH. It is possible that the adrenal CRH/ACTH system is important in the overall function of the gland, and it would seem that as for other products of the medulla (see Section I) the close interrelationship of adrenocortical and chromaffin cells is of great importance.

	VI. Immune Cells and Cytokines in the Adrenal Gland

Top Abstract I. Introduction: The Adrenal... II. Interaction Between Adrenal... III. Innervation of the... IV. The Vascular System... V. The Intraadrenal CRH/ACTH... VI. Immune Cells and... VII. Peptide Growth Factors... VIII. The Intraadrenal Renin... IX. Clinical Implications X. Conclusions References

 
The interaction between the immune system and the HPA axis has been extensively studied since the pioneering work of Besedovsky and Sorkin (195), and it is now generally accepted that the immune system influences the activity of the HPA axis by stimulating the secretion of CRH and ACTH. These interactions have recently been reviewed in some excellent articles (196, 197, 198, 199, 200, 201, 202, 203, 204). However, increasing evidence exists for a local regulatory effect of the immune system within the adrenal itself.

A. Source of cytokines within the adrenal
It is generally accepted that plasma levels of immune-derived cytokines are too low to account for a direct effect on adrenal function. If secretory products of the immune system influence adrenal function, these factors should therefore be produced within the adrenal itself. The two main sources of cytokines within the adrenal are the local immune cells and the adrenal cells themselves.

1. Immune cells. The adrenal cortex is extensively infiltrated by macrophages under normal conditions (205, 206). Macrophages, shown immunohistochemically to be phagocytic, are found primarily in the zona reticularis close to the medulla (206). In addition to their phagocytotic functions, stimulated macrophages are able to secrete a variety of products, such as cytokines, including IL-1, IL-6, and TNF (207), or peptides, such as VIP (208) and transforming growth factor-ß (TGFß) (209, 210), that can influence adrenocortical function. In the adrenal, macrophages have been shown to produce IL-1 (211), IL-6 (212), and TNF (213). Since different cytokines may be stimulatory or inhibitory, the regulation of adrenocortical function by monocytes/macrophages may depend on their differential release, although how this is controlled is unclear. Supporting this view, monocytes may stimulate cortisol production by human cells through a non-ACTH factor (214), whereas lipopolysaccharide-stimulated murine macrophages produce a factor(s) that inhibit the action of ACTH on rabbit adrenocortical cells in vitro (215, 216).

The intraadrenal regulatory loop may be completed by the sympathetic regulation of macrophages, through their high numbers of ß-receptors (217) and the inhibition of cytokine secretion by cortisol (218). The macrophage seems to be a key player in the bidirectional immune-adrenocortical communication within the adrenal.

Lymphocytes have also been reported to produce and secrete ACTH-like substances (219), although the levels of extrapituitary, lymphocyte-derived ACTH are probably too low to account for a significant stimulation of adrenal steroidogenesis, even in response to viral infection (220). However, at least one case has been reported in which ectopic ACTH production by a granulomatous mass led to Cushing’s syndrome (221). In adrenals from elderly patients, T lymphocyte infiltration seems to be a regular phenomenon (222), thus making T lymphocyte-derived ACTH more relevant to the regulation of adrenal function. Thus, lymphocytes may also exert a paracrine influence on adrenocortical function during aging or in pathological situations.

2. Cytokines produced by adrenal cells. Adrenal cells themselves are also able to produce cytokines (Table 5), and although there is some conflicting evidence, there is agreement that several cytokines are produced, predominantly by adrenocortical cells.

Interferon--inducing factor (IGIF, also called IL-1 or IL-18) is a recently identified cytokine with pleiotropic functions. This cytokine is also produced by rat adrenocortical cells, specifically in the zona reticularis and fasciculata, and its gene expression is induced by cold stress (234). Although no effect of this cytokine on adrenocortical function has yet been shown, it may well turn out to be an additional intra-adrenal cytokine that modulates adrenocortical steroido-genesis.

B. Cytokines that influence the adrenal cortex
There is considerable evidence that cytokines directly influence adrenocortical function (summarized in Table 6).

2. IL-2. Like IL-1, IL-2 also stimulates the release of corticosterone from isolated rat adrenal cells (239). This effect is accompanied by increased cAMP and prostaglandin E₂ accumulation. The occurrence of IL-2 receptors was immunohistochemically demonstrated in rat adrenal cells in culture (244), and in this study the expression of the IL-2 receptor was enhanced by incubation with IL-2, but attenuated by dexamethasone.

3. IL-6. IL-6 alone and in synergism with ACTH stimulates the release of corticosterone from rat adrenocortical cells (245), an effect that may be mediated by prostaglandins (239). In humans, IL-6 activates the HPA axis by stimulating the release of cortisol and ACTH. Interestingly, in these studies plasma levels of ACTH decreased after long-term application of IL-6, whereas cortisol remained elevated, suggesting a direct effect of IL-6 on the adrenal cortex (246, 247). The IL-6 receptor is located on human adrenocortical cells, predominantly in the zona reticularis and inner zona fasciculata, and IL-6 stimulates corticosteroid release from human adrenal cells in primary culture, with a prominent effect on the release of adrenal androgens (248, 249). The effect of IL-6 on adrenal androgen production is of interest for two reasons. First, in view of the discrepancy in plasma ACTH levels and androgen release at adrenarche, and in several other clinical situations (250), IL-6 may be a local factor in the production of C₁₉-steroids. Second, as IL-6 is expressed in the zona reticularis and stimulates DHEA secretion, it may be involved in local immune functions of the adrenal.

4. TNF. TNF is a 17-kDa polypeptide hormone that is produced by a wide variety of tissues (251). Together with IL-1 and IL-6, TNF accounts for most of the HPA-axis-stimulating activity in plasma (203). In the adrenal, however, TNF inhibits the angiotensin II- and ACTH-induced release of aldosterone from rat adrenal cells (243) as well as basal and ACTH-stimulated cortisol production. TNF also influences P450 enzyme expression in human fetal adrenals (233, 252) with a consequent shift to androgen production (233). In contrast to its inhibitory action on isolated adrenal cells, TNF had a direct, ACTH-independent, stimulatory effect on corticosterone secretion in rats with cholestasis due to bile duct resection (253). In cultured human fetal adrenal cells, TNF inhibits basal and ACTH-induced insulin-like growth factor (IGF) expression (254, 255), indicating its involvement in growth and differentiation of the fetal adrenal (see Section VII). The direct, intraadrenal inhibitory effect of TNF therefore contrasts with its effects in the intact animal, indicating a role of local, intraadrenal produced TNF, which is different from the role of circulating inflammatory TNF.

5. Interferons. Interferons are a family of polypeptides that disrupt viral replication in infected cells. In addition, they have a wide variety of effects in immunological processes (256). Two members of this family have been shown to influence adrenal steroidogenesis. Interferon- stimulates corticosterone secretion from rat adrenal cells in primary culture (257). In contrast, interferon- inhibits basal and ACTH-induced IGF-II gene expression in human fetal adrenal cells (254, 255), suggesting its involvement in growth and differentiation of the fetal adrenal.

C. Summary
Cytokines produced either by immune cells that regularly infiltrate the adrenal or by adrenal cells themselves are able to directly influence adrenocortical function. They may, like IL-1, IL-2, and IL-6, stimulate steroidogenesis or, like TNF or interferon-, exert a regulatory influence on adrenal growth. The immune system and the endocrine system of the HPA axis have a crucial role in the complex adaptive response to the challenge of homeostasis by either stress or disease (for review, see Ref.258). It is therefore not surprising that both systems interact at different levels. In this context, it is of interest that the three cytokines located within the adrenal, namely IL-1, IL-6, and TNF (Table 4), are responsible for most of the immune-derived HPA axis-stimulating activity in plasma (203). Accordingly, these cytokines seem to play an important role in the regulation of the HPA axis. In this context an acute regulation at the level of the hypothalamus and a long-term regulation at the level of the adrenal have been suggested (203).

	VII. Peptide Growth Factors and the Adrenal Cortex

Top Abstract I. Introduction: The Adrenal... II. Interaction Between Adrenal... III. Innervation of the... IV. The Vascular System... V. The Intraadrenal CRH/ACTH... VI. Immune Cells and... VII. Peptide Growth Factors... VIII. The Intraadrenal Renin... IX. Clinical Implications X. Conclusions References

 
Although corticotropin and angiotensin II, the classic stimulants of the adrenal cortex, are known to have specific effects on adrenocortical growth and differentiation, their actions may be at least partially mediated via locally produced regulators. Various peptide growth factors may act as paracrine agents in this way and, in particular, basic fibroblast growth factor (bFGF), IGFs, and transforming growth factor-ß1 (TGF-ß1), have emerged in recent years as multifunctional molecules that typically play such regulatory roles and that are widely expressed in many mammalian tissues (259, 260, 261, 262). Characteristically, their actions on mitogenesis and tissue growth are mediated through receptor tyrosine kinases which, on activation, form stable complexes with tissue-signaling molecules, eventually leading to the regulation of protooncogene transcription factors, such as c-fos and c-jun, via the mitogen-activated protein kinase pathway (263, 264, 265, 266, 267). The formation of these and other growth factors has been demonstrated in the adrenal cortex using protein fractionation and immunological and molecular biological methods (268, 269, 270, 271, 272, 273, 274, 275). Clearly, the localized expression, release, and activation of such factors may moderate the actions of the circulating trophic hormones on the growth and differentiation of the zones of the adrenal cortex, and in recent years much evidence has accumulated in support of this hypothesis (259). Receptors for other growth factors, such as epidermal growth factor, may also be present in adrenocortical tissue, but thus far there is little evidence for their local production (274).

A. FGFs
First described in brain and pituitary (276, 277, 278), members of the FGF family have been shown to have a wide distribution (260). Two forms, acidic and basic FGF (aFGF and bFGF) have been studied intensively. These are closely related, with about 55% amino acid sequence identity (260, 279, 280). Both aFGF and bFGF are present in neural tissue, although only bFGF has been isolated from the bovine adrenal (281). Although bFGF cDNA predicts a polypeptide consisting of 155 amino acid residues, there is significant microheterogeneity (260), and various bFGF isoforms may be present in bovine or rat adrenals (282, 283).

bFGF is a multifunctional polypeptide with a wide range of biological activities on various target cells (260, 270). It has mitogenic actions on various mesoderm- and neuroectoderm-derived cells in culture (284, 285). In vivo, it may be associated with wound healing (286), angiogenesis (284), and reproductive function, as well as development and morphogenesis (260). bFGF is also an important neurotrophic factor (283, 285, 287).

Heparan sulfate proteoglycans of the extracellular matrix are important for the biological activity of bFGF by acting as a storage site (288, 289, 290, 291), from which they may be released by heparanase (291) or by plasminogen activator-associated proteolysis (290). Although bFGF is mainly associated with the extracellular matrix and with the basement membranes underlying epithelia, in many tissues, including the adrenal cortex, some may also be intracellular (269).

bFGF is expressed in many rat tissues (292) and has been purified and characterized from extracts of bovine adrenals (281) and cultured adrenocortical cells (286). Immunoblot analysis has shown bFGF-like immunoreactivity in rat adrenal glands (283). Its wide distribution, the low to undetectable mRNA level, and its high affinity for heparin are consistent with the view that bFGF is stored and stabilized in the extracellular matrix (260, 292), and that high levels of bFGF protein found in the adrenal tissues are attributable to storage of the mitogen and not continuous gene expression. Heparan sulfate proteoglycans may be regulated in adrenal tissue by ACTH or TGFß, thus controlling the bioavailability of bFGF (288). Another growth factor-binding protein, (2)-macroglobulin, which complexes with TGFß, is itself regulated by bFGF, as well as TGFß (293). Although, in bovine adrenal cells, bFGF release appears to be a prerequisite for its biological action (286), it is also possible that heparan sulfate binding facilitates bFGF interaction with its high-affinity receptor (294).

In studies on the mechanism of the compensatory hypertrophy after unilateral adrenalectomy, it was shown that bFGF receptors are concentrated in the capsule glomerulosa region of the rat adrenal cortex, and that bFGF itself is most abundant in the glomerulosa and in the medulla (289, 295). Compensatory hypertrophy was inhibited by suramin, a growth factor antagonist, and the proliferative actions of bFGF on glomerulosa cells in vitro were blocked by antisense techniques targeted against the bFGF receptor (282). These results are consistent with the concept that the capsule-glomerulosa region is the primary site for cellular proliferation in the adrenal. Although a great deal of evidence supports this view, there is also evidence that in other circumstances proliferation in the rat adrenal may be stimulated in other parts of the gland (296), depending on physiological demand, or during development. Thus, during the first week of postnatal development in rats, immunoreactive bFGF is found in the fasciculata as well as in the glomerulosa, although this declined at later stages: the reticularis expresses little at any stage (296). These changes are paralleled by decreases in the total bFGF mRNA content (297). Consistent with this, in situ hybridization studies showed that very small amounts of bFGF mRNA were detected, predominantly in the zona fasciculata of normal adult female rat adrenal cortex, but this distribution was affected by physiological manipulation. In particular, while a low sodium diet induced more bFGF gene transcription in the glomerulosa, corticotropin treatment resulted in increased message in the outer fasciculata as well as in the subcapsular region (275). In addition, transcription of mRNA coding for bFGF was enhanced by ACTH in human fetal adrenal cells in culture, suggesting that the increased growth induced by corticotropin may be mediated by this growth factor (298). Northern blot analysis also demonstrates the presence of bFGF mRNA in cultured bovine adrenocortical cells (286).

bFGF-binding sites have been detected in bovine adrenocortical cells (294) and in the capsule and zona glomerulosa of rat adrenal cortex (289) and may be directly induced by glucocorticoid in the cortex and medulla (299). bFGF is a potent mitogen in Y1 (300), bovine (286, 301, 302), and human fetal (259, 298) adrenocortical cells. It stimulates protooncogene mRNA expression in bovine adrenocortical cells (303) and increases the expression of 17-hydroxylase (303), angiotensin type I receptor, and -subunit of Gq and G11 proteins (304).

Thus the sites of bFGF gene transcription in the adrenal cortex, its regulation by ACTH, and its actions on mitosis and tissue growth are all consistent with its role in mediating the tropic actions of ACTH, and other tropic agents, since bFGF may also be involved in the proliferation of adrenocortical cells during the compensatory adrenal growth response (Ref. 295 and see below).

bFGF is also highly expressed in the medulla (283, 285, 297) and, like nerve growth factor it stimulates cell division and, perhaps more weakly, neurite outgrowth from cultured neonatal rat chromaffin cells (287). It also stimulates catecholamine storage (287). Neuronal differentiation, but not cell division, induced by bFGF is inhibited by glucocorticoids (285, 305), which increase FGF receptor mRNA transcription in the medulla as well as the cortex (299). Since the innervation of the cortex is partly derived from the medulla, bFGF may in this way also be involved in the development of adrenocortical innervation. In addition, since bFGF is a potent angiogenic factor (260, 281, 284, 291), it may also be involved in the organization of the adrenal vasculature.

B. IGFs
The IGF family consists of two closely related peptides, designated IGF-I and IGF-II. Both circulate in the plasma as hormones, and IGF-I is probably the principal blood-borne mediator of the actions of GH on bone elongation. These hormones are also widespread in tissues, with multiple actions as paracrine/autocrine agents (262). Of the two IGF receptor subtypes, the tetrameric type-1 IGF receptor structurally resembles the insulin receptor and has a higher affinity for IGF-I. The type-2 IGF receptor, which also binds mannose-6-phosphate, has no intrinsic tyrosine kinase activity, and in fact has an entirely different structure, with a short cytoplasmic domain and 15 cysteine-rich extracellar domains (262, 265). The IGF type-1 receptor mediates most of the effects of IGF-I and II (262).

A family of specific IGF-binding proteins (IGFBPs), with affinities for IGF-I equal to or higher than the high-affinity type-1 receptor, regulates its bioavailability (265).

Despite their similar chemical structures and in vitro activities, IGFs-I and II exhibit significant differences in their pattern of expression and activities in vivo. IGF-II is expressed predominantly in the embryonic stages of mammalian development in a wide variety of different tissues. Relatively higher amounts of IGF-II mRNA than IGF-I mRNA are present in multiple human fetal tissues (306, 307, 308). Both IGF-II mRNA and peptide are present in human (255, 306, 307, 308, 309, 310) and ovine (311) fetal adrenocortical cells, and transcription is induced by ACTH and cAMP as two components of complex multifactorial regulation (255, 309). In man, IGF-II expression is tightly linked to the H19 gene, which has an important role in embryogenesis and fetal development (255, 312). IGF-II may also be present in tumors (313). In contrast, IGF-I mRNA content of human fetal adrenocortical cells is low (310), although it is present in the capsule (309). On the other hand, IGF-I has been shown to maintain the differentiated function of fetal adrenal as well as bovine fasciculata cells in vitro (314, 315, 316), and IGF-I and II are equipotently mitogenic in cultured fetal adrenal cells, probably reflecting their common action through the IGF type-1 receptor (309). In contrast, IGF-I mRNA is present in cultured human adult adrenals (309). Thus, it is suggested that IGF-II is an important fetal growth factor, whereas IGF-I is more important postnatally (309, 311).

Both IGF-I mRNA and peptide are also detected in adult rat adrenal glands (310, 317), and using in situ hybridization, IGF-I mRNA was localized mainly in the zona fasciculata in normal adult female rat adrenal cortex. However, its expression in the glomerulosa was increased by ACTH pretreatment and by a low sodium diet (275).

Since the IGF peptides and their receptors have been detected in the adrenal cortex of various species, IGF-I appears to have an important regulatory role in adrenocortical growth and in the induction and maintenance of steroidogenic function (259, 316, 318, 319, 320, 321, 322, 323). Generally, IGF type-1 receptors have been studied, although in bovine adrenocortical cells, IGF type-2 receptors are in fact the more abundant (324). IGF-I stimulates DNA synthesis in primary cultures of bovine adrenal glomerulosa cells (319) and also acts as a mitogen for fetal rat (325) and ovine (314) adrenocortical cells in vitro, although apparently only weakly so in bovine adrenocortical cells (316). It also induces steroidogenesis in adrenocortical cells (316, 326). IGF formation and secretion is induced by FGF, ACTH, and by angiotensin II in bovine adrenocortical cells in vitro (315, 327). In contrast, both IGF-I and IGF-II mRNAs were reduced by ACTH in rat adrenals, despite significant growth and increased side chain cleavage P-450, while they were unchanged by compensatory hypertrophy (328).

The effect of IGF-I on ACTH-induced steroidogenesis in adrenocortical cells remains unresolved (316, 329, 330). Long-term treatment of bovine adrenocortical cells with IGF-I increases both angiotensin II and ACTH receptors and enhances the steroidogenic response to these hormones by increasing the activity of several steroid hydroxylases (316). In these cells, IGF-I potentiates the effect of ACTH on the expression of ACTH receptors and on the secretion of cortisol (331). The stimulatory effect of IGF-I on corticosteroidogenesis may also be ascribed to an increased expression of stimulatory G proteins (332). In contrast, the acute effect of IGF-I in ACTH-stimulated rat adrenocortical cells is inhibitory. IGF-I, acting through its specific receptor, reduces both cAMP production and corticosterone secretion (330). Neither insulin nor IGF-I was found to have any effect on steroidogenesis by guinea pig adrenocortical cells in vitro (329).

It has also been shown that IGFBPs are synthesized locally in the rat, as well as bovine adrenals (315, 333, 334, 335). It is probable that the IGFBPs play an important role in regulating IGF-I bioavailability. In one study, ACTH and angiotensin II were found to specifically induce a 38- to 42-kDa IGFBP, although other IGFBPs were inhibited or unaffected (315). In contrast, another study identified four IGFBPs in culture media from bovine adrenocortical cells, and all were increased by ACTH. Furthermore, IGF-II and a truncated form of IGF-I that does not bind to IGFBPs were both more potent than IGF-I in stimulating steroidogenesis (335).

C. TGFß
TGFß belongs to a large TGF superfamily that represents a family of low molecular mass (5–28 kDa) peptides with the ability to influence the phenotype and the growth characteristics of nontransformed cells (261). TGFß is a homodimeric, disulfide-bonded protein made up from two 12-kDa polypeptide chains: five different TGFß isoforms (TGFß 1–5) are found in vertebrates, and TGFß 1–3 are found during mammalian development (336).

TGFß protein has been detected in the bovine adrenal cortex by immunostaining, mainly in the zona fasciculata, with less staining in the glomerulosa, but with none in the adrenal medulla (337). TGFß mRNA was also found in adult mouse adrenal tissue, and the TGFß protein has been detected in the adult mouse adrenal inner cortex (338). Very small amounts of TGFß mRNA were detected in the zona fasciculata of the rat adrenal cortex and in the medulla, and these were not markedly affected by ACTH or a low-sodium diet (275). Bovine adrenocortical cells also secrete TGFß1, although in latent (activatable) forms, one of which is complexed with 2-macroglobulin (339). Latent TGFß can be activated by an ACTH-induced secreted protein (CISP), a member of the thrombospondin family (340).

In bovine adrenocortical cells, TGFß1 receptors have been characterized by RRAs and cross-linking techniques (341). Only type I and III receptors appear to be expressed in adrenocortical cells and are increased in number by ACTH stimulation (336, 341).

TGFß1 alone exhibits no detectable effect on DNA synthesis and has no effect on bovine adrenocortical cell proliferation (336, 342). In contrast, it is antimitogenic for cultured human fetal adrenocortical cells (343, 344), an action that is opposed by ACTH in the neocortex (344), although apparently not in the fetal zone (343).

TGFß is a potent modulator of differentiated adrenocortical cell functions, and it has recently been demonstrated that TGFß1 exerts an autocrine inhibitory effect on bovine adrenocortical cells (345). In this study, basal steroidogenic activity was increased through the suppression of TGFß1 expression by antisense nucleotides. TGFß exerts its inhibitory effect on different cellular levels. It has a significant inhibitory effect on the steroidogenic activities of bovine and ovine adrenocortical cells in culture in both basal and ACTH- or angiotensin II-stimulated conditions, though it has no effect on ACTH-stimulated adenylyl cyclase activity (342, 346). Cytochrome P-450₁₇ (CYP17, 17-hydroxylase) is a major target for this action, and its formation is inhibited at the mRNA transcriptional level (336, 347, 348).

TGFß also regulates receptor expression. Angiotensin II receptor expression is decreased in bovine adrenocortical cells (336, 349), as is the expression of low-density lipoprotein receptors (349). ACTH receptors are decreased in ovine adrenocortical cells (350). TGFß also stimulates the production of fibronectin (351, 352), heparan sulfate proteoglycans (288), and 2-macroglobulin in bovine adrenocortical cells (336, 353), thus contributing to an increased accumulation of growth factor-binding extracellular matrix. In fact, TGFß1 acts as an activator of 2-macroglobulin gene expression at the transcriptional level. TGFß2 and angiotensin II also appear able to stimulate 2-macroglobulin secretion in bovine cells, whereas ACTH is strongly inhibitory. Since 2-macroglobulin is a TGFß-binding protein, these observations suggest that it may play an important role in conjunction with hormones and growth factors in the homeostatic regulation of adrenocortical functions (336, 339, 353, 354).

The observed effects are different for the human adrenal and sometimes even in contrast to data from ovine and bovine adrenals. The most striking effect of TGFß on steroidogenesis in fetal (355, 356) as well as in adult (357) human adrenals seems to be the reduction of dehydroepiandrosterone sulfate. It had no effect on ACTH receptor mRNA levels and enhanced angiotensin-II type 1 receptor mRNA and binding sites (356, 357). TGFß had a differential effect on the expression of steroidogenic enzymes. It had no effect on cholesterol side-chain cleavage cytochrome P-450 mRNA, increased mRNA accumulation of 3ß-hydroxysteroid dehydrogenase mRNA (356, 357), and reduced those of cytochrome P-450 17-hydroxylase mRNA (355, 356, 357).

There is agreement that the inhibitory effect of TGFß action occurs distal to the formation of cAMP. TGFß did not influence cAMP levels in bovine adrenocortical cells (342) nor could the effect be overcome by the addition of (Bu)₂-cAMP (348, 358). In human fetal adrenals, TGFß inhibits (Bu)₂-cAMP-stimulated steroid secretion (342). However, in bovine adrenocortical cells, the effect could be completely reversed by the addition of 25-hydroxycholesterol, pregnenolone, or progesterone (342). These data suggest that TGFß induced inhibition of steroidogenesis at a site before the formation of cholesterol.

In a single report, TGF has also been identified in human adrenocortical tissue and tumors (274).

D. Summary
In summary, the development and maintenance of the adrenal cortex, like those of other tissues, appear, at least in part, to be mediated by the local production of growth factors. These include IGFs, TGFß, and ßFGF, which exert a variety of both stimulatory and inhibitory actions on the growth, differentiation, and differentiated functions of the gland. In these roles the growth factors may well mediate the growth-regulating effects of systemic factors, such as ACTH, and perhaps also contribute to their acute effects on steroid hormone secretion.

	VIII. The Intraadrenal Renin-Angiotensin System (RAS)

Top Abstract I. Introduction: The Adrenal... II. Interaction Between Adrenal... III. Innervation of the... IV. The Vascular System... V. The Intraadrenal CRH/ACTH... VI. Immune Cells and... VII. Peptide Growth Factors... VIII. The Intraadrenal Renin... IX. Clinical Implications X. Conclusions References

 
A. The role of the RAS in adrenocortical function
In 1958, Gross (359) first drew attention to the primary importance of the RAS in the regulation of aldosterone secretion. Since that time it has been demonstrated unequivocally that reduced sodium balance brings about rises in PRA, angiotensin II, and aldosterone concentrations, and that the increase in aldosterone can be blocked by use of a converting enzyme inhibitor, such as captopril (360, 361, 362). The ability of angiotensin II to stimulate aldosterone secretion has been shown directly in numerous species, including humans, rat, sheep, dog, and rabbit (363, 364, 365, 366, 367, 368), and, in general, this is unaccompanied by increases in glucocorticoid secretion by the inner adrenocortical zones (fasciculata and reticularis), although there is species variation in this respect (e.g., Refs. 369 and 370). The cells of the zona glomerulosa contain specific angiotensin receptors, mostly of the AT1 subtype (371, 372, 373, 374), and linkage to the synthesis and secretion of aldosterone is via the phosphatidyl inositol/ITP/intracellular calcium pathway (375, 376, 377, 378, 379, 380, 381). If anything, the action of angiotensin II on cAMP generation is inhibitory (377, 379, 382). In most species, concentrations of angiotensin II receptors are considerably lower in the inner adrenocortical zones than in the glomerulosa, and high concentrations of angiotensin II are required to stimulate steroid output in bovine fasciculata cells (370, 383, 384). Receptor subtypes in the adrenocortical inner zones have not been unequivocally identified but, since the signaling pathways in bovine cells are apparently the same as in the glomerulosa (385, 386), the AT1 subtype seems to be implicated here as well. The medulla also contains angiotensin receptors, though mostly of the AT2 subtype (372). In addition to its acute actions on aldosterone secretion, longer term treatment with angiotensin II also has a proliferative effect on the glomerulosa and on the maintenance of aldosterone synthase, and in this way it reproduces the chronic effects of a low-sodium diet (361, 387, 388, 389, 390, 391). In ovine adrenal cells, angiotensin II has also been shown to suppress 17-hydroxylase expression and to inhibit the response of cortisol to ACTH stimulation, in other words suppressing fasciculata-type function (392).

Most interpretations have been based on the premise that it is systemically generated angiotensin II that regulates aldosterone formation and secretion by the zona glomerulosa. However, the evidence has accumulated in recent years to suggest that, like other tissues, the adrenal gland contains its own tissue-localized RAS, and that angiotensin II is generated within the tissue, thus exercising paracrine regulation. This evidence consists of the identification of gene transcripts for prorenin, angiotensinogen, and angiotensin-converting enzyme in adrenal tissue, and of the proteins for which they code, both in the active (renin, angiotensin II) and inactive precursor forms. The evidence also suggests that these products are released in response to physiological demand. The specific role for the tissue system, as opposed to the systemic RAS, remains uncertain.

B. Renin
The presence of renin-like activity in the adrenal was shown by Ryan (393) and by Granzer (394), and subsequently by others in a variety of species, including rabbit, dog, rats, human, and mouse (395, 396, 397, 398). Its molecular mass, isoelectric point, and pH activation profile, as well as immunological similarity and the presence of the inactive prorenin form, proved the identity of the adrenal enzyme with that produced by the kidney in human and rat glands (397, 399). That the enzyme was locally formed within the adrenal was shown by its increased concentration in nephrectomized animals (in spontaneously hypertensive rats as well as in normal strains) and by the fact that in humans it has little correlation with PRA (397, 400, 401, 402, 403, 404).

The zona glomerulosa is the primary site of renin formation in the rat and human gland (403, 405, 406, 407, 408, 409, 410, 411, 412), where it is localized in particulate subcellular components, identified as the mitochondrial fraction in human and rat adrenals (397, 413), as lysosome-like dense bodies (401, 414, 415) or intramitochondrial dense bodies (416) in rats, or as lysosomal granules in fetal mice (417, 418, 419). There may be both glomerulosa and inner zone sources of renin in the mouse adrenal (398, 403), while transgenic rats bearing the mouse Ren-2 gene also express renin in inner zones (420). Medullary cells are also a source of renin (421).

Prorenin is also present in human and rat adrenals (400, 410, 421, 422) and is activated in the glomerulosa (400, 423); there are lower amounts of prorenin than renin in human normal tissue and adenomas (422). Transcription of prorenin mRNA has been shown in adrenal tissue and cells using Northern blot, PCR, and in situ hybridization techniques in rat glands and in normal human glands and adenomas (408, 411, 422, 424, 425, 426, 427).

Adrenal renin expression is regulated in accordance with apparent physiological requirement; thus prorenin mRNA transcription activity is increased in rats by a low-sodium diet or by potassium loading (428, 429, 430), and a high-sodium diet decreases it (430). Similarly, potassium, ACTH, or angiotensin II stimulation of cultured rat glomerulosa cells increased renin mRNA in vitro and also the formation both of active renin (which remained largely cellular) and prorenin, the predominant secreted form (408, 409, 431). In bovine glomerulosa cells, potassium, ACTH, and cAMP stimulated the secretion of active renin, whereas prorenin secretion was stimulated by catecholamines (432).

C. Angiotensinogen
The presence of angiotensinogen mRNA has been demonstrated in the adrenals of mouse, rat (424, 433, 434), and human (422), in capsular fibroblast-like cells rather than in adrenocortical cells in rats (433), and in normal and abnormal glomerulosa, fasciculata, and medullary cells in the human gland (422). While angiotensinogen was synthesized, it was apparently not stored, and there was no correlation between immunoassayable angiotensinogen and its mRNA (422, 426).

D. Angiotensin-converting enzyme and the production of angiotensin II
Direct evidence for angiotensin formation in the adrenal comes from several studies. Assay of HPLC-fractionated angiotensins I, II, and III and des-Asp angiotensin II shows that the rat adrenal zona glomerulosa contains higher concentrations of these than the inner zones. Tissue angiotensin content is unaffected by nephrectomy (402), is enhanced (particularly angiotensin II) by a low-sodium diet (402) or potassium loading (428), but is reduced in sodium-replete animals, as are renin- and angiotensin II-binding activities (407). Angiotensin II is secreted by superfused rat adrenal capsules and superfused human adrenal glands (426, 435), and secretion of both angiotensin I and II by rat tissue was stimulated by increased potassium ion concentrations (435). Superfused rat adrenal zona glomerulosa cells similarly respond to high potassium ion concentrations with increased angiotensin II secretion, although the source is only a subpopulation of cells. In chronic stimulation, by low dietary sodium, both output per cell and the number of cells involved in angiotensin II secretion are increased (436). Previous evidence suggested that formation of angiotensin II in the rat adrenal glomerulosa is extracellular (437), although there appears to be no direct evidence of the precise location of angiotensin-converting enzyme. Nevertheless, angiotensin II secretion by rat adrenal capsule/glomerulosa explants was attenuated by the addition of a converting enzyme inhibitor under control (unstimulated) conditions and also when stimulated by increased potassium ion concentration, as was aldosterone (410). Angiotensin I-stimulated aldosterone secretion was also inhibited by converting enzyme inhibition in superfused rat adrenal capsules, whereas angiotensin II-stimulated aldosterone secretion was not (438). In other experiments with human tissue, the addition of a converting enzyme inhibitor caused a concomitant decrease in angiotensin II/III and aldosterone in three normal samples, although it was without effect in two aldosteronomas (439).

Quite remarkably, in addition to the effect of converting enzyme inhibition on potassium-stimulated aldosterone synthesis, noted above, ACTH-stimulated aldosterone output is also attenuated (431), conveying the possibility that at least a part of the stimulatory action of ACTH on aldosterone may be modulated by the tissue RAS. This is difficult to reconcile with the literature, which shows that the action of exogeneously added angiotensin II and ACTH may be antagonistic.

E. What is the functional significance of the intraadrenal RAS?
To interpret this function correctly, two fundamental questions require resolution, viz 1) what specific roles of the tissue RAS are not or cannot be fulfilled by the systemic RAS? and 2) how are the systemic and tissue RAS separately maintained and independently distinguished by target organ receptors?

There are very few clues to suggest a specific role for the adrenal RAS, because it and the systemic RAS appear to respond broadly to the same stimuli. It is certainly possible that tissue-generated angiotensin II may be more effective than plasma angiotensin in mediating increases in aldosterone secretion, e.g., to a low-sodium diet, and this is suggested by the parallel kinetics of tissue angiotensin II and plasma aldosterone in rats, which may require 1–2 days to reach a plateau, in contrast to the relatively rapid peak in PRA, reached 8 h after onset of sodium restriction (440). In superfused rat glomerulosa tissue and in dispersed cells, the secretion of aldosterone and angiotensin II were highly significantly correlated, and secretion of both was oscillatory (435).

Nevertheless, it has also become apparent that the response of aldosterone secretion to stimulation by other factors may, in fact, depend on the adrenal RAS. Thus, both the effects of ACTH and of potassium ions are attenuated by converting enzyme inhibition in rat adrenal glomerulosa cells in monolayer culture (410, 431) and by the specific type 1 angiotensin II (AT1) receptor antagonist, losartan (441), In bovine adrenocortical cells, the aldosterone-secretory response to ouabain was inhibited by losartan (442). It may be, therefore, that the activity of the tissue RAS is required to maintain adrenocortical cells in an appropriate functional state to be able to respond to acute or chronic stimulation by other factors. One can only speculate what such effects of the RAS may be, and it might be worth studying, for example, its actions on the replenishment of steroid precursor pools, such as cellular cholesterol, or of calcium pools in the endoplasmic reticulum (cf. Ref.442).

The view that the local tissue RAS may be more concerned with the longer term purely tropic actions of angiotensin II, rather than with the acute response of aldosterone secretion, has been suggested by studies with rats transfected with the Ren-2 mouse renin gene, the hypertensive transgenic [TGR (mRen-2)27] animal (443). In these, there are high concentrations of adrenal renin, not only in the glomerulosa, but also in inner adrenocortical zones, whereas kidney renin content and renin gene expression are low (444). Aldosterone production was also found in the inner adrenocortical zones, prompting the view that one role of the adrenal RAS is to support aldosterone synthase expression (419, 420). The concept that chronic tropic actions, rather than the acute effects, are the characteristic response to the tissue rather than the systemic RAS accords with similar interpretations of the cardiac RAS (445). Certainly, angiotensin II infusions, like a low-sodium diet, promote cell division both in the glomerulosa and reticularis (446). The capacity of angiotensin II to model the tissue becomes more complex with the finding that, whereas the AT1 receptor modulates the mitotic response, the AT2 receptor may be specifically concerned with apoptosis (447). The precise action of angiotensin II on tissue structure may therefore depend in part on the relative abundance of the two receptor subtypes.

The possibility also exists that adrenal-generated angiotensin II may have systemic effects, at least in a spontaneously stroke-prone rat strain (402, 448), and the transgenic [TGR (mRen-2)27] rat (449, 450), through the secretion of prorenin, which may in this case have an intrinsic activity without the requirement for conversion to renin (451). The adrenal RAS may also have a role in the hypotensive response to angiotensin-converting enzyme (ACE) inhibition in normal rats (452). In both the transgenic rats and in normal animals, basal adrenal renin content is stimulated by angiotensin II, suggesting a remarkable positive feedback loop (409, 453), but in normal rats the ACTH-stimulated increase in renin is blocked by angiotensin II (409). Nevertheless, nephrectomy enhances adrenal renin content (450), as in nontransgenic animals (see above); thus, the regulation of adrenal renin production is complex.

Another possibility is that the adrenal tissue RAS is associated with regulation of the vasculature. It is clear that the function of the inner adrenocortical zones and the secretion of glucocorticoids are greatly influenced by vascular events. In particular, increased blood flow through the gland is associated with, and indeed stimulates, glucocorticoid secretion, presumably through changes in the secretion of factors originating in the vessels themselves, such as nitric oxide and the endothelins (Section IV). It is possible that tissue angiotensin II also has a role here, in view of its vasoactive properties and its known vasoconstrictive action in the rat adrenal (454). Together with other possible functions, a role in regulating regional blood flow has also been suggested for the local RAS in the heart (455). Further studies are required to establish the validity of any of these hypotheses (see also Refs. 412 and 456).

F. How can the angiotensin II produced by the tissue RAS be distinguished from the systemic system?
Precise data on the cellular localizations of the sites of production of the RAS components, their regulation, and their spatial relationship to the sites of angiotensin II receptors are an absolute requirement for the interpretation of these systems. In general, this has not been achieved because of a lack of monoclonal antibodies to the receptors (412, 434). Gross measurement of angiotensin II-binding activity and adrenal renin and angiotensin II concentrations in rat adrenals has suggested little overall relationship between these parameters (407), although, in view of the intimacy of sites of angiotensin production and action, resolution at the light microscope, if not the ultrastructural, level is required.

However, if both angiotensin II formation and angiotensin II receptors occur in the same cell type, what implications does this hold for receptor occupancy and the gland’s capacity to respond to physiological demand? One possibility is that angiotensin receptors are in some way sequestrated intracellularly so that their availability to locally generated angiotensin II can be regulated.

G. Summary
In summary, the evidence is very powerful that, as in certain other tissues, a complete RAS is present in the adrenal cortex, primarily in the glomerulosa. This system generates angiotensin II to act in a paracrine/autocrine fashion on the cells of the glomerulosa and responds to physiological demand as does the circulating system, e.g., its activity is enhanced in conditions of dietary sodium restriction. It can be conjectured that this system is concerned with various aspects of glomerulosa function, including the mediation of the effects of other stimulants, such as ACTH or potassium ions, and tissue differentiation and modeling.

	IX. Clinical Implications

Top Abstract I. Introduction: The Adrenal... II. Interaction Between Adrenal... III. Innervation of the... IV. The Vascular System... V. The Intraadrenal CRH/ACTH... VI. Immune Cells and... VII. Peptide Growth Factors... VIII. The Intraadrenal Renin... IX. Clinical Implications X. Conclusions References

 
A. Cortisol
Why should a neuro-adrenocortical axis or other intraadrenal mechanism be relevant to clinical medicine? Is there evidence for extrapituitary, intraadrenal regulation of cortisol secretion? It is well established that glucocorticoids are mainly regulated by pituitary ACTH and that hypophysectomy leads to atrophy of the adrenal cortex. However, it has been known for many years that in individuals given dexamethasone in doses large enough to suppress pituitary function, plasma corticosteroids nevertheless increase in response to surgical stress (457, 458), although ACTH and CRH levels may fall below presurgical values (458). The rise in cortisol can, however, be abolished by interrupting the neural connection at the operative site (6). This elevation of cortisol levels after surgery is not attributable to changes in cortisol metabolism (459), and it therefore presumably arises through direct stimulation of the adrenal cortex. TNF and IL-6 concentrations are elevated during major surgery and may remain elevated for an additional 48–72 h, corresponding to the period of increased levels of cortisol (460).

There is further evidence of the dissociation between plasma ACTH concentrations and cortisol secretion. In patients with bacterial sepsis (461, 462) and in the chronic severe illness of late-stage human immunodeficiency virus disease, persistently elevated cortisol levels are accompanied by suppressed ACTH values (463). In this context, cytokines such as IL-6 may be relevant, since this cytokine is a potent activator of the HPA axis (246, 247) and may exceed in potency the action of CRH (464). While the effect of IL-6 on the pituitary appears to be acute, IL-6 has a long-term direct action on the adrenal cortex at concentrations that may occur in critical illness (246, 249). Ten to 20% of patients with critical illness, however, develop adrenocortical insufficiency (465). In these cases cytokines such as TGFß, which are elevated in sepsis, may directly block adrenal function.

Corticosteroids are essential for survival during periods of critical illness. It is obvious that during severe stress, the neuroendocrine systems and the immune system need to interact at multiple levels in an attempt to provide a coordinated response that meets the challenge to homeostasis with minimal damage to the organism as a whole (464, 466).

The disturbance of the peripheral immune-adrenal axis may lead to adrenal disease. For example, a case of Cushing’s syndrome that disappeared after removal of inflammatory tissue has been described (221). We treated a patient with Cushing’s syndrome due to an adrenal adenoma with aberrant expression of IL-1 receptor. Adrenocortical cells from this patient demonstrated a marked release of cortisol after incubation with IL-1 with no response to ACTH (H. Willenberg, C. A. Stratakis, C. Marx, M. Ehrhart-Bornstein, G. P. Chrousos, and S. R. Bornstein, unpublished observation).

Extrapituitary mechanisms may also be relevant in clinical situations other than severe illness. In patients with proven pituitary ACTH deficiency, CRH induced a significant increase in plasma cortisol, preceded by a rise in plasma ACTH (175), indicating the involvement of an extrapituitary, perhaps intraadrenal, CRH/ACTH-system. It is also of interest that the mechanism of adrenal stimulation in diabetic patients is apparently not solely mediated through the pituitary since there is a diminished pituitary response to metyrapone (467).

Depressed patients may have enlarged adrenals and cortisol hypersecretion (468), although the ACTH response to CRH may be blunted (469). It is possible that stressors acting directly on the adrenal cortex may contribute to the stimulation of the adrenals in these patients. Indeed, a number of neurotransmitters and neuropeptides secreted from the adrenal medulla that are able to stimulate the adrenal cortex in a paracrine manner have been postulated to play a role in the development of psychiatric and other idiopathic syndromes (470).

In human adrenals, adrenomedullary and adrenocortical tissue are particularly extensively intermingled within the normal adrenal medulla (14). Interestingly, cells of all three zones of the cortex occur in the human adrenal medulla (471). This provides the basis for a close cellular interaction, allowing a fine tuning of the two stress systems. The occurrence of adrenocortical cells within the medulla has direct consequences during isolation of adrenomedullary tissue for autologous transplantation to the caudate nucleus as a treatment in patients suffering from Parkinson’s disease. As pointed out by Carmichael et al. (472), it is especially important to minimize the percentage of cortical cells and to remove these islets in these preparations since cortical steroids would stimulate the conversion of dopamine to epinephrine.

Another important observation is that adrenal nodules and adenomata frequently appear to originate from cortical islets in the medulla (471). It seems that these islets, which are under direct stimulatory influence of the surrounding adrenomedullary tissue, bear a higher risk for a pathological development compared with cortical cells located within the adrenal cortex.

There are case descriptions in the literature reporting patients with the clinical signs of pheochromocytoma with elevated catecholamine levels and the histological features of adrenocortical adenoma or carcinoma (473, 474, 475, 476, 477). In many of these patients, steroid levels were found to be elevated. Therefore, it was suggested that adrenal cortical neoplasm may be added to the list of pathological entities (pseudopheochromocytoma) that may occasionally be associated with the clinical picture of pheochromocytoma.

On the other hand, patients have been described with the clinical signs of Cushing’s syndrome and the pathological finding of a pheochromocytoma (478, 479, 480, 481, 482, 483, 484). This may be due to production of CRH or ectopic ACTH production in the pheochromocytoma, although the diagnosis of ectopic ACTH production was made preoperatively in only three of the 46 cases reported in the literature (for review, see Ref.482). A wide variety of both eutopic and ectopic neurotransmitters and neuropeptides expressed in pheochromocytoma are able to stimulate cortisol secretion and may be involved in causing Cushing’s syndrome (485).

There has been some speculation that adrenocortical tumor cells may produce catecholamines or that chromaffin-derived tumor cells produce steroids, but this may be less likely than the possibility that interactions between the two distinct cell types that are adjacent to each other in these conditions give rise to correlated medullary and cortical hyperactivity.

It is possible that corticotropin-independent Cushing’s syndrome could arise from the aberrant expression in the cortex of receptors, such as ß-receptors (486) or vasopressin receptors (487, 488), for secretagogues released from the adrenal medulla. In addition, patients have been described in whom Cushing’s syndrome was caused by a member of the glucagon/VIP peptide family, gastric inhibitory polypeptide (489, 490).

B. Aldosterone
Are there any clinical implications for intraadrenal aldosterone regulation?

In acute stress, activation of the RAS may depend, not on volume and blood pressure changes alone, but also on stimulation of renin and aldosterone release via neural pathways (491). Interestingly, the adrenal RAS can be activated via the sympathoadrenal system (432). Evidently, the neural and intraadrenal regulation of adrenal aldosterone production and the adrenal RAS has important clinical implications. It has been suggested that the differences in adrenal responses to angiotensin II with high, normal, and low sodium balance may be at least partially if not completely accounted for by a decreased dopaminergic inhibition of aldosterone secretion (for review see Ref.492). In addition, in idiopathic hyperaldosteronism and low renin essential hypertension, there is increased adrenocortical sensitivity to angiotensin (493, 494) with low circulating levels of angiotensin. The pathogenesis of these disorders could be related to a primary reduction of dopaminergic activity, which would result in an increased secretion of aldosterone in response to low levels of angiotensin. In idiopathic cyclic edema, orthostatic weight gain is associated with an increased secretion of aldosterone and antinatriuresis in the upright position (495). In these patients, the increase in PRA does not sufficiently explain the marked increase of aldosterone secretion with erect posture, and evidence suggests that reduced dopaminergic or increased adrenergic activity may be responsible for the increased aldosterone secretion in some of these cases (495).

Since arginine vasopressin is a potent stimulator of aldosterone production in human glomerulosa cells (496) and since it is also formed in the adrenal medulla, it is clear that, together with the products of the adrenal RAS and other factors from the endothelium and chromaffin tissue, including ANF (497), there are numerous possibilities for intra-adrenal regulation of aldosterone production in humans. This local regulation may provide an explanation for the continued normal secretion of aldosterone under conditions where peripheral angiotensin II is altered and for the increases observed in aldosterone secretion when the circulating angiotensin II concentration remains unchanged.

Another intriguing finding is that in patients with primary hyperaldosteronism (Conn’s syndrome) due to an adrenal adenoma, the remaining cortex may demonstrate morphological features of stimulation (498). This suggests that there is a paracrine interaction between the adenoma and the remnant cortex.

The fact that adrenocortical cells express a large array of receptors for various neurotransmitters also has pharmacological implications: drugs administered for the treatment of various disorders may exert unwanted effects on the adrenal cortex. For instance, 5-HT₄ receptor agonists that are used as antiemetic agents will also stimulate aldosterone secretion (499). Similarly, the neuroleptic drug metoclopramide exhibits 5-HT₄ agonistic activity and can thus stimulate aldosterone secretion (500, 501).

C. Adrenal androgens
Finally, intraadrenal regulation of adrenal androgen secretion may have several clinical implications. First, considering the fact that there is a discrepancy in ACTH levels in plasma and androgen release in the time of adrenarche and in several other clinical situations (250), the regulation of adrenal androgen production by the sympatho-adrenal system may be particularily important during that time. Also, IL-6 appears to be a local factor in the production of C19-steroids. Interestingly, IL-6 receptor is expressed with high density in the zona reticularis, and IL-6 stimulates DHEA secretion (249). DHEA influences the immune system at various levels, and the interaction with cytokines may be of relevance for the process of adrenal senescence and autoimmunity. Cytokines produced by the inner zones of the human adrenal cortex, such as TNF (213), may participate in the constitutive expression of MHC class II molecules in the inner cortical zone, which is related to differentiation and programmed cell death in the adrenal cortex (502, 503). On the basis of these findings, MHC class II was found to be a reliable tumor marker for adrenocortical carcinoma, with its presence excluding malignancy (504).

D. Summary
In conclusion, cellular proximity and functional coordination between the different cellular systems may explain several of the discrepancies between cortisol secretion and its main regulatory hormones, ACTH and angiotensin II, in many physiological and pathophysiological states, including adrenarche, severe stress, depression, and others. The notion of a potent endocrine and paracrine interaction between the immune and endocrine systems at the level of the adrenal gland is supported by the number of reports showing strong interdependence of cytokine and adrenal hormone levels in clinical states, such as sepsis, exercise, and inflammation.

	X. Conclusions

Top Abstract I. Introduction: The Adrenal... II. Interaction Between Adrenal... III. Innervation of the... IV. The Vascular System... V. The Intraadrenal CRH/ACTH... VI. Immune Cells and... VII. Peptide Growth Factors... VIII. The Intraadrenal Renin... IX. Clinical Implications X. Conclusions References

 
The complexity of adrenocortical function is only now becoming apparent (Fig. 5). Clearly, the gland is capable of responding to physiological demand with infinite flexibility and subtlety in a manner that depends on the interactions of numerous cell types, each contributing its own signals to the system and each responding in varied ways to the signals from the cells around it. In addition to the regulation of adrenal steroidogenesis through the pituitary, intraadrenal mechanisms play a role during development, differentiation, physiological, and pathophysiological processes of the adrenal gland. The concept that adrenocortical function can be adequately interpreted by studying the functions of individual cells in isolation, if it was ever seriously believed, is certainly unreliable. The clear requirement for future research is to establish new methods in which integrated functions of the adrenal gland can be successfully studied in physiological settings. This constitutes a major challenge.

View larger version (80K): [in this window] [in a new window]   Figure 5. Numerous cell types and numerous systems with their specific signals interact in the intraadrenal regulation of adrenocortical steroidogenesis.

	Footnotes

 
Address reprint requests to: Monika Ehrhart-Bornstein, Ph.D., NIH, NIMH, Building 10, Room 2D46, 10 Center Drive, MSC 1284, Bethesda, Maryland 20892.

	References

Top Abstract I. Introduction: The Adrenal... II. Interaction Between Adrenal... III. Innervation of the... IV. The Vascular System... V. The Intraadrenal CRH/ACTH... VI. Immune Cells and... VII. Peptide Growth Factors... VIII. The Intraadrenal Renin... IX. Clinical Implications X. Conclusions References

 

1. Pohorecky LA, Wurtman RJ 1971 Adrenocortical control of epinephrine synthesis. Pharmacol Rev 23:1–35[Free Full Text]
2. Axelrod J, Reisine TD 1984 Stress hormones: their interaction and regulation. Science 224:452–459[Abstract/Free Full Text]
3. Winkler H, Apps DK, Fischer-Colbrie R 1986 The molecular function of adrenal chromaffin granules: established facts and unresolved topics. Neuroscience 18:261–290[CrossRef][Medline]
4. Deane HW 1962 The anatomy, chemistry and physiology of adrenocortical tissue. In: Deane HW (ed) Handbuch der experimentellen Pharmakologie, Vol. 14, Part 1. The Adrenocortical Hormones. Their Origin, Chemistry, and Pharmacology. Springer, Berlin, pp 1–185
5. Landsberg L, Young JB 1992 Williams Textbook of Endocrinology. Saunders Company, Philadelphia, p 624
6. Orth DN, Kovacs WJ, DeBold CR 1992 The adrenal cortex. In: Wilson JD, Foster DW (eds) Williams Textbook of Endocrinology. Saunders Company, Philadelphia, pp 489–619
7. Rittmaster RS, Cutler GBj 1990 Morphology of the adrenal cortex and medulla. In: Becker KL (ed) Principles and Practice of Endocrinology and Metabolism. Lippincott Company, Philadelphia, pp 572–579
8. Fortak W, Kmiec B 1968 [About occurrence of the chromophilic cells in the adrenal cortex of white rats]. Endokrynol Pol 19:117–128[Medline]
9. Kmiec B 1968 Histologic and histochemical observations on regeneration of the adrenal medulla after enucleation in white rats. Folia Morphol (Warsz) 27:238–245
10. Palacios G, Lafraga M 1975 Chromaffin cells in the glomerular zone of adult rat adrenal cortex. Cell Tissue Res 164:275–278[Medline]
11. Gallo-Payet N, Pothier P, Isler H 1987 On the presence of chromaffin cells in the adrenal cortex: their possible role in adrenocortical function. Biochem Cell Biol 65:588–592[Medline]
12. Bornstein SR, Ehrhart-Bornstein M, Usadel H, Böckmann M, Scherbaum WA 1991 Morphological evidence for a close interaction of chromaffin cells with cortical cells within the adrenal gland. Cell Tissue Res 265:1–9[CrossRef][Medline]
13. Berka JL, Kelly DJ, Robinson DB, Alcorn D, Marley PD, Fernley RT, Skinner SL 1996 Adrenaline cells of the rat adrenal cortex and medulla contain renin and prorenin. Mol Cell Endocrinol 119:175–184[CrossRef][Medline]
14. Bornstein SR, González-Hernández JA, Ehrhart-Bornstein M, Adler G, Scherbaum WA 1994 Intimate contact of chromaffin and cortical cells within the human adrenal gland forms the cellular basis for important intraadrenal interactions. J Clin Endocrinol Metab 78:225–232[Abstract]
15. Bornstein SR, Ehrhart-Bornstein M 1992 Ultrastructural evidence for a paracrine regulation of the rat adrenal cortex mediated by the local release of catecholamines from chromaffin cells. Endocrinology 131:3126–3128[Abstract/Free Full Text]
16. Ottenweller JE, Meier AH 1982 Adrenal innervation may be an extrapituitary mechanism able to regulate adrenocortical rhythmicity in rats. Endocrinology 111:1334–1338[Abstract/Free Full Text]
17. Dijkstra I, Binnekade R, Tilders FJH 1996 Diurnal variation in resting levels of corticosterone is not mediated by variation in adrenal responsiveness to adrenocorticotropin but involves splanchnic nerve integrity. Endocrinology 137:540–547[Abstract]
18. Muglia LJ, Jacobson L, Weninger SC, Luedeke CE, Bae DS, Jeong KH, Majzoub JA 1997 Impaired diurnal adrenal rhythmicity restored by constant infusion of corticotropin-releasing hormone in corticotropin-releasing hormone-deficient mice. J Clin Invest 99:2923–2929[Medline]
19. Dallman MF 1984 Control of adrenocortical growth in vivo. Endocr Res 10:213–242[Medline]
20. Edwards AV, Jones CT 1987 The effect of splanchnic nerve stimulation on adrenocortical activity in conscious calves. J Physiol 382:385–396[Abstract/Free Full Text]
21. Edwards AV, Jones CT, Bloom SR 1986 Reduced adrenal cortical sensitivity to ACTH in lambs with cut splanchnic nerves. J Endocrinol 110:81–85[Abstract/Free Full Text]
22. Bornstein SR, Ehrhart-Bornstein M, Scherbaum WA, Pfeiffer EF, Holst JJ 1990 Effects of splanchnic nerve stimulation on the adrenal cortex may be mediated by chromaffin cells in a paracrine manner. Endocrinology 127:900–906[Abstract/Free Full Text]
23. Ehrhart-Bornstein M, Bornstein SR, Scherbaum WA, Pfeiffer EF, Holst JJ 1991 The role of the vasoactive intestinal peptide in a neuroendocrine regulation of the adrenal cortex. Neuroendocrinology 54:623–628[Medline]
24. Ehrhart-Bornstein M, Bornstein SR, Güse-Behling H, Stromeyer H, Scherbaum WA, Adler G, Holst JJ 1994 Sympathoadrenal regulation of adrenal androstenedione release. Neuroendocrinology 59:406–412[Medline]
25. Ehrhart-Bornstein M, Bornstein SR, González-Hernández JA, Holst JJ, Waterman MR, Scherbaum WA 1995 Sympathoadrenal regulation of adrenocortical steroidogenesis. Endocr Res 21:13–24[Medline]
26. Dupont W, Leboulenger F, Vaudry H, Vaillant R 1976 Regulation of the aldosterone secretion in the frog Rana esculenta L. Gen Comp Endocrinol 29:51–60[CrossRef][Medline]
27. Ehrhart-Bornstein M, Bornstein SR, Trzeciak WH, Usadel H, Güse-Behling H, Waterman MR, Scherbaum WA 1991 Adrenaline stimulates cholesterol side chain cleavage cytochrome P450 mRNA accumulation in bovine adrenocortical cells. J Endocrinol 131:R5–R8
28. Güse-Behling H, Ehrhart-Bornstein M, Bornstein SR, Waterman MR, Scherbaum WA, Adler G 1992 Regulation of adrenal steroidogenesis by adrenaline: expression of cytochrome P450 genes. J Endocrinol 135:229–237[Abstract/Free Full Text]
29. Morra M, Leboulenger F, Vaudry H 1990 Dopamine inhibits corticosteroid secretion from frog adrenal gland, in vitro. Endocrinology 127:218–226[Abstract/Free Full Text]
30. Ritzén M, Hammerström L, Ullberg S 1965 Autoradiographic distribution of 5-hydroxytryptamine and 5-hydroxytryptophan in the mouse. Biochem Pharmacol 14:313–383
31. Holzwarth MA, Brownfield MS 1985 Serotonin coexists with epinephrine in rat adrenal medulla. Neuroendocrinology 41:230–236[Medline]
32. Verhofstad AAJ, Jonsson G 1983 Immunohistochemical and neurochemical evidence for the presence of serotonin in the adrenal medulla of the rat. Neuroscience 10:1443–1453[CrossRef][Medline]
33. Delarue C, Leboulenger F, Morra M, Héry F, Verhofstad AAJ, Bérod A, Denoroy L, Pelletier G, Vaudry H 1988 Immunohistochemical and biochemical evidence for the presence of serotonin in amphibian adrenal chromaffin cells. Brain Res 459:17–26[CrossRef][Medline]
34. Contesse V, Delarue C, Leboulenger F, Lefebvre H, Héry F, Vaudry H 1993 Serotonin produced in the adrenal gland regulates corticosteroid secretion through a paracrine mode of communication. In: Facchinetti F, Henderson IW, Pieratoni R, Polzonetti-Magni A (eds) Cellular Communication in Reproduction. Journal of Endocrinology Ltd. Bristol, pp 187–198
35. Lefebvre H, Contesse V, Delarue C, Feuilloley M, Hery F, Grise P, Raynaud G, Verhofstad AAJ, Wolf LM, Vaudry H 1992 Serotonin-induced stimulation of cortisol secretion from human adrenocortical tissue is mediated through activation of a serotonin-4 receptor subtype. Neuroscience 47:999–1007[CrossRef][Medline]
36. Lefebvre H, Compagnon P, Contesse V, Hamel C, Delarue C, Thuillez C, Vaudry H, Kuhn JM 1996 Production and metabolism of serotonin (5-HT) by the human adrenal gland. Endocr Res 22:851–853[Medline]
37. Schultzberg M, Lundberg JM, Hökfelt T, Terenius L, Brandt J, Elde RP, Goldstein M 1978 Enkephalin-like immunoreactivity in gland cells and nerve terminals of the adrenal medulla. Neuroscience 3:1169–1186[CrossRef][Medline]
38. Toth IE, Hinson JP 1995 Neuropeptides in the adrenal gland: distribution, localization of receptors, and effects on steroid hormone synthesis. Endocr Res 21:39–51[Medline]
39. Reinecke M, Heym C, Forssmann WG 1992 Distribution patterns and coexistence of neurohormonal peptides (ANP, BNP, NPY, SP, CGRP, enkephalins) in chromaffin cells and nerve fibers of the anuran adrenal organ. Cell Tissue Res 268:247–256[CrossRef][Medline]
40. Pelto-Huikko M 1989 Immunocytochemical localization of neuropepides in the adrenal medulla. J Electron Microsc Tech 12:364–379[CrossRef][Medline]
41. Yon L, Contesse V, Leboulenger F, Feuilloley M, Esneu M, Kodjo MK, Lesouhaitier O, Pelletier G, Delarue C, Vaudry H 1994 New concepts concerning the regulation of corticosteroid secretion in amphibians. In: Davey KG, Peter RE, Tobe SS (eds) Perspectives in Comparative Endocrinology. National Research Council of Canada, Ottawa, pp 539–547
42. Gallo-Payet N 1993 Nouveaux concepts sur la régulation de la sécrétion d’aldostérone; interactions endocrine, paracrines, autocrines et neurocrines. Med Sci 9:943–951
43. Breslow MJ 1992 Regulation of adrenal medullary and cortical blood flow. Am J Physiol 262:H1317–H1330
44. Neri G, Andreis PG, Prayer-Galetti T, Rossi GP, Malendowicz LK, Nussdorfer GG 1996 Pituitary adenylate-cyclase activating peptide enhances aldosterone secretion of human adrenal gland: evidence for an indirect mechanism, probably involving the local release of catecholamines. J Clin Endocrinol Metab 81:169–173[Abstract]
45. Hinson JP, Kapas S, Orford CD, Vinson GP 1992 Vasoactive intestinal peptide stimulation of aldosterone secretion by the rat adrenal cortex may be mediated by the local release of catecholamines. J Endocrinol 133:253–258[Abstract/Free Full Text]
46. Mazzocchi G, Malendowicz LK, Belloni AS, Nussdorfer GG 1995 Adrenal medulla is involved in the aldosterone secretagogue effect of substance P. Peptides 16:351–355[CrossRef][Medline]
47. Mazzocchi G, Musajo F, Neri G, Gottardo G, Nussdorfer GG 1996 Adrenomedullin stimulates steroid secretion by the isolated perfused rat adrenal gland in situ: comparison with calcitonin gene-related peptide effects. Peptides 17:853–857[CrossRef][Medline]
48. Bernet F, Bernard J, Laborie C, Montel V, Maubert E, Dupouy JP 1994 Neuropeptide Y (NPY)- and vasoactive intestinal peptide (VIP)-induced aldosterone secretion by rat capsule/glomerulosa zone could be mediated by catecholamine via ß1 adrenergic receptors. Neurosci Lett 166:109–112[CrossRef][Medline]
49. Haidan A, Bornstein SR, Glasow A, Uhlmann K, Lübke C, Ehrhart-Bornstein M 1998 Basal steroidogenic activity of adrenocortical cells is increased tenfold by co-culture with chromaffin cells. Endocrinology 139:772–780[Abstract/Free Full Text]
50. Bauerfeind R, Huttner WB 1993 Biogenesis of constitutive secretory vesicles, secretory granules and synaptic vesicles. Curr Opin Cell Biol 5:628–635 [Published erratum appears in Curr Opin Cell Biol 1993; 5:1106.]
51. Siegel RE, Eiden LE, Pruss RM 1985 Multiple populations of neuropeptide-containing cells in cultures of the bovine adrenal medulla. Brain Res 349:267–270[Medline]
52. Linnoila RI, Diaugustine RP, Hervonen A, Miller RJ 1980 Distribution of [Met⁵]- and [Leu⁵]- enkephalin-, vasoactive intestinal polypeptide- and substance P-like immunoreactivities in human adrenal glands. Neuroscience 5:2247–2259[CrossRef][Medline]
53. Dumont M, Day R, Lemaire S 1983 Distinct distribution of immunoreactive dynorphin and leucine enkephalin in various populations of isolated adrenal chromaffin cells. Life Sci 32:287–294[CrossRef][Medline]
54. Fischer-Colbrie R, Eskay RL, Eiden LE, Maas D 1992 Transsynaptic regulation of galanin, neurotensin, and substance P in the adrenal medulla: combinatorial control by second-messenger signaling pathways. J Neurochem 59:780–783[CrossRef][Medline]
55. Tschernitz C, Laslop A, Eiter C, Kroesen S, Winkler H 1995 Biosynthesis of large dense-core vesicles in PC12 cells: effects of depolarization and second messengers on the mRNA levels of their constituents. Brain Res Mol Brain Res 31:131–140[Medline]
56. Pruss RM, Mezey E, Forman DS, Eiden LE, Hotchkiss AJ, Di Maggio DA, O’Donohue TL 1986 Enkephalin and neuropeptide Y: two colocalized neuropeptides are independently regulated in primary cultures of bovine chromaffin cells. Neuropeptides 7:315–327[CrossRef][Medline]
57. Fischer-Colbrie R, Iacangelo A, Eiden LE 1988 Neural and humoral factors separately regulate neuropeptide Y, enkephalin, and chromogranin A and B mRNA levels in rat adrenal medulla. Proc Natl Acad Sci USA 85:3240–3244[Abstract/Free Full Text]
58. Eskay RL, Eiden LE 1992 Interleukin-1 and tumor necrosis factor- differentially regulate enkephalin, vasoactive intestinal polypeptide, neurotensin, and substance P biosynthesis in chromaffin cells. Endocrinology 130:2252–2258[Abstract/Free Full Text]
59. Beinfeld MC, Brick PL, Howlett AC, Holt IL, Pruss RM, Moskal JR, Eiden LE 1988 The regulation of vasoactive intestinal peptide synthesis in neuroblastoma and chromaffin cells. Ann NY Acad Sci 527:68–76[CrossRef][Medline]
60. Vaupel R, Jarry H, Schlomer HT, Wuttke W 1988 Differential response of substance P-containing subtypes of adrenomedullary cells to different stressors. Endocrinology 123:2140–2145[Abstract/Free Full Text]
61. Black VH, Robbins E, McNamara N, Huima T 1979 A correlated thin-section and freeze-fracture analysis of Guinea pig adrenocortical cells. Am J Anat 156:453–503[CrossRef][Medline]
62. Hinson JP, Vinson GP, Whitehouse BJ 1986 The relationship between perfusion medium flow rate and steroid secretion in the isolated perfused rat adrenal gland in situ. J Endocrinol 111:391–396[Abstract/Free Full Text]
63. Vinson GP, Hinson JP 1992 Blood flow and hormone secretion in the adrenal gland. In: James VHT (ed) The Adrenal Gland. Raven Press, New York, pp 71–86
64. Nussdorfer GG 1986 Cytophysiology of the adrenal cortex. Int Rev Cytol 98:1–395[Medline]
65. Usadel H, Bornstein SR, Ehrhart-Bornstein M, Kreysch HG, Scherbaum WA 1993 Gap junctions in the adrenal cortex. Horm Metab Res 25:653–654[Medline]
66. Munari-Silem Y, Lebrethon MC, Morand I, Rousset B, Saez JM 1995 Gap junction-mediated cell-to-cell communication in bovine and human adrenal cells. A process whereby cells increase their responsiveness to physiological corticotropin concentrations. J Clin Invest 95:1429–1439
67. Warchol JB, Filipiak K, Ignaszak E, Nussdorfer GG, Malendowicz LK 1993 Oxytocin directly stimulates corticosterone secretion by dispersed rat adrenal zonae fasciculata and reticularis cells: evidence for the spreading of the oxytocin-evoked signal from responsive to unresponsive cells. Biomed Res 14:261–264
68. Elliot TR 1913 The innervation of the adrenal glands. J Physiol 46:285–290
69. Hollingshead WH 1936 The innervation of the adrenal glands. J Comp Neurol 64:449–468[CrossRef]
70. Bennett HS 1940 The life history and secretion of the cells of the adrenal cortex of the cat. Am J Anat 67:151–227[CrossRef]
71. MacFarland WE, Davenport HA 1941 Adrenal innervation. J Comp Neurol 75:219–234[CrossRef]
72. Swinyard CA 1937 The innervation of the suprarenal glands. Anat Rec 68:417–429[CrossRef]
73. Alpert LK 1931 The innervation of the suprarenal glands. Anat Rec 50:221–233[CrossRef]
74. Unsicker K 1971 On the innervation of the rat and pig adrenal cortex. Z Zellforsch 116:151–156[CrossRef][Medline]
75. Robinson PM, Perry RA, Hardy KJ, Coghlan JP, Scoggins BA 1977 The innervation of the adrenal cortex in sheep, Ovis ovis. J Anat 124:117–129[Medline]
76. Vinson GP, Hinson JP, Tóth IE 1994 The neuroendocrinology of the adrenal cortex. J Neuroendocrinol 6:235–246[CrossRef][Medline]
77. Parker TL, Kesse WK, Mohamed AA, Afework M 1993 The innervation of the mammalian adrenal gland. J Anat 183:265–276
78. Kondo H 1985 Immunohistochemical analysis of the localization of neuropeptides in the adrenal gland. Arch Histol Jpn 48:453–481[Medline]
79. Yon L, Chartel N, Feuilloley M, De Marchis S, Fournier A, De Rijk E, Pelletier G, Roubos E, Vaudry H 1994 Pituitary adenylate cyclase-activating polypeptide stimulates both adrenocortical cells and chromaffin cells in the frog adrenal gland. Endocrinology 135:2749–2758[Abstract]
80. Vizi ES, Toth IE, Szalay KS, Windisch K, Orso E, Szabo D, Vinson GP 1992 Catecholamines released from local adrenergic axon terminals are possibly involved in fine tuning of steroid secretion from zona glomerulosa cells: functional and morphological evidence. J Endocrinol 135:551–561[Abstract/Free Full Text]
81. Dorovini-Zis K, Zis AP 1991 Innervation of the zona fasciculata of the human adrenal cortex: a light and electron microscopic study. J Neural Transm 84:75–84[CrossRef][Medline]
82. Niijima A, Winter DL 1967 Chemosensitive receptors in the adrenal gland. Fed Proc 26:544
83. Niijima A, Winter DL 1968 Baroreceptors in the adrenal gland. Science 159:434–435[Abstract/Free Full Text]
84. Dallman MF, Engeland WC, McBride MH 1977 The neural regulation of compensatory adrenal growth. Ann NY Acad Sci 297:373–392
85. Holzwarth MA, Cunningham LA, Kleitman N 1987 The role of adrenal nerves in the regulation of adrenocortical functions. Ann NY Acad Sci 512:449–464[Medline]
86. Hinson JP 1990 Paracrine control of adrenocortical function: a new role for the medulla? J Endocrinol 124:7–9[Abstract/Free Full Text]
87. Kesse WK, Parker TL, Coupland RE 1988 The innervation of the adrenal gland. I. The source of pre- and postganglionic nerve fibers to the rat adrenal gland. J Anat 157:33–41[Medline]
88. Carlsson S, Skarphedinsson JO, Jennische E, Delle M, Thoren P 1990 Neurophysiological evidence for and characterization of the post-ganglionic innervation of the adrenal gland in the rat. Acta Physiol Scand 140:491–499[Medline]
89. Hökfelt T, Lundberg JM, Schultzberg M, Fahrenkrug J 1981 Immunohistochemical evidence for a local VIP-ergic neuron system in the adrenal gland of the rat. Acta Physiol Scand 113:575–576[Medline]
90. Holzwarth MA 1984 The distribution of vasoactive intestinal peptide in the rat adrenal cortex and medulla. J Auton Nerv Syst 11:269–283[CrossRef][Medline]
91. Kuramoto H, Kondo H, Fujita T 1987 Calcitonin gene-related peptide (CGRP)-like immunoreactivity in scattered chromaffin cells and nerve fibers in the adrenal gland of rats. Cell Tissue Res 247:309–315[Medline]
92. Kuramoto H, Kondo H, Fujita T 1986 Neuropeptide tyrosine (NPY)-like immunoreactivity in adrenal chromaffin cells and intraadrenal nerve fibers of rats. Anat Rec 214:321–328[CrossRef][Medline]
93. Kuramoto H, Kondo H, Fujita T 1985 Substance P-like immunoreactivity in adrenal chromaffin cells and intra-adrenal nerve fibers of rats. Histochemistry 82:507–512[CrossRef][Medline]
94. Vizi ES, Toth IE, Orso E, Szalay KS, Szabo D, Baranyi M, Vinson GP 1993 Dopamine is taken up from the circulation by, and released from, local noradrenergic varicose axon terminals in zona glomerulosa of the rat: a neurochemical and immunocytochemical study. J Endocrinol 139:213–226[Abstract/Free Full Text]
95. Charlton BG, Nkomazana OF, McGadey J, Neal DE 1991 A preliminary study of acetylcholinesterase-positive innervation in the human adrenal cortex. J Anat 176:99–104[Medline]
96. Nussdorfer GG 1996 Paracrine control of adrenal cortical function by medullary chromaffin cells. Pharmacol Rev 48:495–530[Medline]
97. Chua Jr SC, Leibel RL, Hirsch J 1991 Food deprivation and age modulate neuropeptide gene expression in murine hypothalamus and adrenal gland. Mol Brain Res 9:95–101[Medline]
98. Hinson JP, Kapas S 1996 Effect of splanchnic nerve section and compensatory adrenal hypertrophy on rat adrenal neuropeptide content. Regul Pept 61:105–109[CrossRef][Medline]
99. Edwards AV, Jones CT 1987 The effect of splanchnic nerve section on the sensitivity of the adrenal cortex to adrenocorticotrophin in the calf. J Physiol (Lond) 390:23–31[Abstract/Free Full Text]
100. Engeland WC, Gann DS 1989 Splanchnic nerve stimulation modulates steroid secretion in hypophysectomized dogs. Neuroendocrinology 50:124–131[Medline]
101. Malendowicz LK 1993 Involvement of neuropeptides in the regulation of growth, structure and function of the adrenal cortex. Histol Histopath 8:173–186[Medline]
102. Ehrhart-Bornstein M, Bornstein SR, Scherbaum WA 1996 Sympathoadrenal system and immune system in the regulation of adrenocortical function. Eur J Endocrinol 135:19–26[Abstract/Free Full Text]
103. Lesouhaitier O, Esneu M, Kodjo MK, Hamel C, Contesse V, Yon L, Remy-Jouet I, Fasolo A, Fournier A, Vandesande F, Pelletier G, Conlon JM, Roubos EW, Feuilloley M, Delarue C, Leboulenger F, Vaudry H 1995 Neuroendocrine communication in the frog adrenal gland. Zool Sci 12:255–264[Medline]
104. Edwards AV, Jones CT 1993 Autonomic control of adrenal function. J Anat 183:291–307
105. Sapirstein LA, Goldman HA 1959 Adrenal blood flow in the albino rat. Am J Physiol 196:159–162
106. Harrison RG, Hoey MJ 1960 The Adrenal Circulation. Blackwell, Oxford, U.K.
107. Idelman S 1978 The structure of the mammalian adrenal cortex. In: Chester Jones I, Henderson IW (eds) General, Comparative and Clinical Endocrinology of the Adrenal Cortex. Academic Press, New York, pp 2–199
108. Neville AM, O’Hare M 1982 The Human Adrenal Cortex. Springer Verlag, Berlin,
109. Vinson GP, Pudney JA, Whitehouse BJ 1985 The mammalian adrenal circulation and the relationship between adrenal blood flow and steroidogenesis. J Endocrinol 105:285–294[Abstract/Free Full Text]
110. Breslow MJ, Jordan DA, Thellman ST, Traystman RJ 1987 Neural control of adrenal medullary and cortical blood flow during hemorrhage. Am J Physiol 252:H521–8
111. Allen JM, Bircham PM, Bloom SR, Edwards AV 1984 Release of neuropeptide Y in response to splanchnic nerve stimulation in the conscious calf. J Physiol (Lond) 357:401–408[Abstract/Free Full Text]
112. Bloom SR, Edwards AV, Jones CT 1988 The adrenal contribution to the neuroendocrine responses to splanchnic nerve stimulation in conscious calves. J Physiol (Lond) 397:513–526[Abstract/Free Full Text]
113. Gaumann DM, Yaksh TL, Tyce GM, Stoddard SL 1989 Adrenal vein catecholamines and neuropeptides during splanchnic nerve stimulation in cats. Peptides 10:587–592[CrossRef][Medline]
114. Hinson JP, Vinson GP 1990 Calcitonin gene-related peptide stimulates adrenocortical function in the isolated perfused rat adrenal gland in situ. Neuropeptides 16:129–133[CrossRef][Medline]
115. Hinson JP, Cameron LA, Purbrick A, Kapas S 1994 The role of neuropeptides in the regulation of adrenal vascular tone: effects of vasoactive intestinal polypeptide, substance P, neuropeptide Y, neurotensin, Met-enkephalin, and Leu-enkephalin on perfusion medium flow rate in the intact perfused rat adrenal. Regul Pept 51:55–61[CrossRef][Medline]
116. Nichols J, Richardson AW 1960 Effect of DDD on steroid response and blood flow through the adrenal after ACTH. Proc Soc Exp Biol Med 104:539–542
117. Wright RD 1963 Blood flow through the adrenal gland. Endocrinology 72:418–428
118. Stark E, Varga B, Acs Z, Papp M 1965 Adrenal blood flow response to adrenocorticotropic hormone and other stimuli in the dog. Pflugers Arch 385:296–301[CrossRef]
119. Hinson JP, Vinson GP, Pudney J, Whitehouse BJ 1989 Adrenal mast cells modulate vascular and secretory responses in the intact adrenal gland of the rat. J Endocrinol 121:253–260[Abstract/Free Full Text]
120. Hinson JP, Vinson GP, Kapas S, Teja R 1991 The relationship between adrenal vascular events and steroid secretion: the role of mast cells and endothelin. J Steroid Biochem Mol Biol 40:381–389[CrossRef][Medline]
121. Breslow MJ, Tobin JR, Bredt DS, Ferris CD, Snyder SH, Traystman RJ 1993 Nitric oxide as a regulator of adrenal blood flow. Am J Physiol 264:H464–H469
122. Cameron LA, Hinson JP 1993 The role of nitric oxide derived from L-arginine in the control of steroidogenesis, and perfusion medium flow rate in the isolated perfused rat adrenal gland. J Endocrinol 139:415–423[Abstract/Free Full Text]
123. Frank HA, Frank ED, Korman H, Macchi IA, Hechter O 1955 Corticosteroid output and adrenal blood flow during hemorrhagic shock in the dog. Am J Physiol 182:24–28[Free Full Text]
124. Jones CT, Edwards AV, Bloom SR 1990 The effect of changes in adrenal blood flow on adrenal cortical responses to adrenocorticotrophin in conscious calves. J Physiol (Lond) 429:377–386[Abstract/Free Full Text]
125. Porter JC, Klaiber MS 1965 Corticosterone secretion in rats as a function of ACTH input and adrenal blood flow. Am J Physiol 209:811–814[Abstract/Free Full Text]
126. Urquhart J 1965 Adrenal blood flow and the response to corticotropin. Am J Physiol 209:1162–1168[Abstract/Free Full Text]
127. Sibley CP, Whitehouse BJ, Vinson GP, Goddard C, McCredie E 1981 Studies on the mechanism of secretion of corticosteroids by the isolated perfused adrenal of the rat. J Endocrinol 91:313–323[Abstract/Free Full Text]
128. Delarue C, Delton I, Fiorini F, Homo-Delarche F, Fasolo A, Braquet P, Vaudry H 1990 Endothelin stimulates steroid secretion by frog adrenal gland in vitro: evidence for the involvement of prostaglandins and extracellular calcium in the mechanism of actin of endothelin. Endocrinology 127:2001–2008[Abstract/Free Full Text]
129. Cozza EN, Gomez-Sanchez CE, Foecking MF, Chiou S 1989 Endothelin binding to cultured calf adrenal zona glomerulosa cells and stimulation of aldosterone secretion. J Clin Invest 84:1032–1035
130. Gomez-Sanchez CE, Cozza EN, Foecking MF, Chiou S, Ferris MW 1990 Endothelin receptor subtypes and stimulation of aldosterone secretion. Hypertension 15:744–747[Abstract/Free Full Text]
131. Morishita R, Higaki J, Ogihara T 1989 Endothelin stimulates aldosterone biosynthesis by dispersed rabbit adreno-capsular cells. Biochem Biophys Res Commun 160:628–632[CrossRef][Medline]
132. Hinson JP, Vinson GP, Kapas S, Teja R 1991 The role of endothelin in the control of adrenocortical function: stimulation of endothelin release by ACTH and the effects of endothelin-1 and endothelin-3 on steroidogenesis in rat and human adrenocortical cells. J Endocrinol 128:275–280[Abstract/Free Full Text]
133. Mazzocchi G, Malendowicz LK, Nussdorfer GG 1990 Endothelin-1 acutely stimulates the secretory activity of rat zona glomerulosa cells. Peptides 11:763–765[CrossRef][Medline]
134. Belloni AS, Rossi GP, Andreis PG, Neri G, Albertin G, Pessina AC, Nussdorfer GG 1996 Endothelin adrenocortical secretagogue effect is mediated by the B receptor in rats. Hypertension 27:1153–1159[Abstract/Free Full Text]
135. Belloni AS, Malendowicz LK, Gottardo G, Nussdorfer GG 1996 Endothelin-1 stimulates the proliferation of rat adrenal zona glomerulosa cells, acting via the ET(A) receptor subtype. Med Sci Res 24:393–394
136. Belloni AS, Rossi GP, Zanin L, Prayer-Galetti T, Pessina AC, Nussdorfer GG 1994 In vitro autoradiographic demonstration of endothelin-1 binding sites in the human adrenal cortex. Biomed Res 15:95–99
137. Kapas S, Cameron LA, Puddefoot JR, Hinson JP 1996 Studies on endothelin receptors in the zonae fasciculata/reticularis of the rat adrenal cortex: contrast with the zona glomerulosa. FEBS Lett 397:186–190[CrossRef][Medline]
138. Mazzocchi G, Rebuffat P, Gottardo G, Meneghelli V, Nussdorfer GG 1996 Evidence that both ET(A) and ET(B) receptor subtypes are involved in the in-vivo aldosterone secretagogue effect of endothelin-1 in rats. Res Exp Med 196:145–152[CrossRef][Medline]
139. Davenport AP, Hoskins SL, Kuc RE, Plumpton C 1996 Differential distribution of endothelin peptides and receptors in human adrenal-gland. Histochem J 28:779–789[CrossRef][Medline]
140. Rossi GP, Albertin G, Belloni A, Zanin L, Biasolo MA, Prayer-Galetti T, Bader M, Nussdorfer GG, Palu G, Pessina AC 1994 Gene expression, localisation and characterisation of endothelin A and B receptors in the human adrenal cortex. J Clin Invest 94:1226–1234
141. Cozza EN, Gomez-Sanchez CE 1993 Mechanisms of ET-1 potentiation of angiotensin-II stimulation of aldosterone production. Am J Physiol 265:E179–E 183
142. Rosolowsky LJ, Campbell WB 1990 Endothelin enhances adrenocorticotropin-stimulated aldosterone release from cultured bovine adrenal cells. Endocrinology 126:1860–1866[Abstract/Free Full Text]
143. Vierhapper H, Nowotny P, Waldhäusl W 1995 Effect of endothelin-1 in man: impact on basal and adrenocorticotropin-stimulated concentrations of aldosterone. J Clin Endocrinol Metab 80:948–951[Abstract]
144. Yanagisawa M, Masaki T 1989 Molecular biology and biochemistry of the endothelins. Trends Pharmacol Sci 10:374–378[CrossRef][Medline]
145. Yoshizumi M, Kurihara H, Sugiyama T, Takaku F, Yanagisawa M, Masaki T, Yazaki Y 1989 Hemodynamic shear stress stimulates endothelin production by cultured endothelial cells. Biochem Biophys Res Commun 161:859–864[CrossRef][Medline]
146. Cameron LA, Kapas S, Hinson JP 1994 Endothelin-1 release from the isolated perfused rat adrenal gland is elevated acutely in response to increasing flow rates and ACTH(1–24). Biochem Biophys Res Commun 202:873–879[CrossRef][Medline]
147. Nakayama T, Izumi Y, Soma M, Kanmatsuse K 1996 A nitric oxide synthesis inhibitor prevents the ACTH-stimulated production of aldosterone in rat adrenal gland. Endocr J 43:157–162[Medline]
148. Simmons JC, Freeman RH 1995 L-arginine analogues inhibit aldosterone secretion in rats. Am J Physiol 268:R1137–R1142
149. Kapas S, Hinson JP 1996 Actions of adrenomedullin on the rat adrenal cortex. Endocr Res 22:861–865[Medline]
150. Esneu M, Delarue C, Fournier A, Vaudry H 1996 Characterization of the receptor mediating the effect of calcitonin gene-related peptide in the frog adrenal gland. Eur J Pharmacol 308:187–193[CrossRef][Medline]
151. Mazzocchi G, Rebuffat P, Gottardo G, Nussdorfer GG 1996 Adrenomedullin and calcitonin gene-related peptide inhibit aldosterone secretion in rats, acting via a common receptor. Life Sci 58:839–844[CrossRef][Medline]
152. Yamaguchi T, Baba K, Doi Y, Yano K 1994 Effect of adrenomedullin on aldosterone secretion by dispersed rat adrenal zona glomerulosa cells. Life Sci 56:379–387[CrossRef]
153. Kapas S, Martinez A, Cuttitta F, Hinson JP 1997 Local production and action of adrenomedullin in the rat adrenal zona glomerulosa. J Endocrinol in press
154. Andreis PG, Mazzocchi G, Rebuffat P, Nussdorfer GG 1997 Effects on adrenomedullin and proadrenomedullin N-terminal 20 peptide on rat zona glomerulosa cells. Life Sci 60:1693–1697[CrossRef][Medline]
155. Andreis PG, Neri G, Prayer-Galetti T, Rossi GP, Gottardo G, Malendowicz LK, Nussdorfer GG 1997 Effects of adrenomedullin on the human adrenal glands: an in vitro study. J Clin Endocrinol Metab 82:1167–1170[Abstract/Free Full Text]
156. Wajchenberg BL, Mendonca BB, Liberman B, Pereira MAA, Kirschner MA 1995 Ectopic ACTH syndrome. J Steroid Biochem Mol Biol 53:139–151[CrossRef][Medline]
157. Jessop DS, Cunnah D, Millar JGB, Neville E, Coates P, Doniach I, Besser GM, Rees LH 1987 A phaeochromocytoma presenting with Cushing’s syndrome associated with increased concentrations of circulating corticotrophin-releasing factor. J Endocrinol 113:133–138[Abstract/Free Full Text]
158. O’Brien T, Young WFJ, Davila DG, Scheithauer BW, Kovacs K, Horvath E, Vale W, van Heerden JA 1992 Cushing‘s syndrome associated with ectopic production of corticotrophin-releasing hormone, corticotrophin and vasopressin by a pheochromocytoma. Clin Endocrinol (Oxf) 37:460–467[Medline]
159. Vale W, Spiess J, Rivier C, Rivier J 1981 Characterization of a 41 residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213:1394–1397[Free Full Text]
160. Spiess J, Rivier J, Rivier C, Vale W 1981 Primary structure of corticotropin-releasing factor from ovine hypothalamus. Proc Natl Acad Sci USA 78:6517–6521[Abstract/Free Full Text]
161. De Souza E, Van Loon GR 1984 Corticotropin releasing factor increases the adrenocortical responsiveness to adrenocorticotropin. Experentia 40:1004–1006[CrossRef][Medline]
162. Bornstein SR, Ehrhart M, Scherbaum WA, Pfeiffer EF 1990 Adrenocortical atrophy of hypophysectomized rats can be reduced by corticotropin releasing hormone (CRH). Cell Tissue Res 260:161–166[CrossRef][Medline]
163. Jones CT, Edwards AV 1992 The role of corticotrophin releasing factor in relation to the neural control of adrenal function in conscious calves. J Physiol (Lond) 447:489–500[Abstract/Free Full Text]
164. van Oers JWAM, Hinson JP, Binnekade R, Tilders FJH 1992 Physiological role of corticotropin-releasing factor in the control of adrenocorticotropin-mediated corticosterone release from the rat adrenal gland. Endocrinology 130:282–288[Abstract/Free Full Text]
165. Azar ST, Turner A, Melby JC 1992 Corticotropin-independent effect of ovine corticotropin-releasing hormone on cortisol release in man. Am J Med Sci 303:217–221[Medline]
166. van Oers JWAM, Tilders FJH 1991 Non-adrenocorticotropin mediated effects of endogenous corticotropin-releasing factor on the adrenocortical activity in the rat. J Neuroendocrinol 3:119–121
167. Markowska A, Rebuffat P, Rocco S, Gottardo G, Mazzocchi G, Nussdorfer GG 1993 Evidence that an extrahypothalamic pituitary corticotropin-releasing hormone (CRH)/adrenocorticotropin (ACTH) system controls adrenal growth and secretion in rats. Cell Tissue Res 272:439–445[CrossRef][Medline]
168. Andreis PG, Neri G, Nussdorfer GG 1991 Corticotropin-releasing hormone (CRH) directly stimulates corticosterone secretion by the rat adrenal gland. Endocrinology 128:1198–1200[Abstract/Free Full Text]
169. Andreis PG, Neri G, Mazzocchi G, Musajo FG, Nussdorfer GG 1992 Direct secretagogue effect of corticotropin-releasing factor on the rat adrenal cortex: the involvement of the zona medullaris. Endocrinology 131:69–72[Abstract/Free Full Text]
170. Mazzocchi G, Musajo FG, Malendowicz LK, Andreis PG, Nussdorfer GG 1993 Interleukin-1ß stimulates corticotropin-releasing hormone (CRH) and adrenocorticotropin (ACTH) release by rat adrenal gland in vitro. Mol Cell Neurosci 4:267–270[CrossRef]
171. Suda T, Tomori N, Tozawa F, Mouri T, Demura H, Shizume K 1984 Distribution and characterization of immunoreactive corticotropin-releasing factor in human tissues. J Clin Endocrinol Metab 59:861–866[Abstract/Free Full Text]
172. Suda T, Tomori N, Yajima F, Odagiri E, Demura H, Shizume K 1986 Characterization of immunoreactive corticotropin and corticotropin-releasing factor in human adrenal and ovarian tumors. Acta Endocrinol (Copenh) 111:546–552[Abstract/Free Full Text]
173. Suda T, Tomori N, Tozawa F, Demura H, Shizume K, Mouri T, Miura Y, Sasano N 1984 Immunoreactive corticotropin and corticotropin-releasing factor in human hypothalamus, adrenal, lung cancer, and pheochromocytoma. J Clin Endocrinol Metab 58:919–924[Abstract/Free Full Text]
174. Jones CT, Edwards AV 1990 Release of adrenocorticotrophin from the adrenal gland in the conscious calf. J Physiol (Lond) 426:397–407[Abstract/Free Full Text]
175. Fehm HL, Holl R, Späth-Schwalbe E, Born J, Voigt KH 1988 Ability of corticotropin releasing hormone to simulate cortisol secretion independent from pituitary adrenocorticotropin. Life Sci 42:679–686[CrossRef][Medline]
176. Hashimoto K, Murakami K, Hattori T, Nimi M, Fujino K, Ota Z 1984 Corticotropin-releasing factor (CRF)-like immunoreactivity in the adrenal medulla. Peptides 5:707–712[CrossRef][Medline]
177. Minamino N, Uehara A, Arimura A 1988 Biological and immunological characterization of corticotropin-releasing activity in the bovine adrenal medulla. Peptides 9:37–45[CrossRef][Medline]
178. Bruhn TO, Engeland WC, Anthony ELP, Gann DS, Jackson IMD 1987 Corticotropin-releasing factor in the adrenal medulla. Ann NY Acad Sci 512:115–128[Medline]
179. Bagdy G, Calogero AE, Szemeredi K, Chrousos GP, Gold PW 1990 Effects of cortisol treatment on brain and adrenal corticotropin- releasing hormone (CRH) content and other parameters regulated by CRH. Regul Pept 31:83–92[CrossRef][Medline]
180. Venihaki M, Gravanis A, Margioris AN 1997 Comparative study between normal rat chromaffin and PC12 rat pheochromocytoma cells: production and effects of corticotropin-releasing hormone. Endocrinology 138:698–704[Abstract/Free Full Text]
181. Bruhn TO, Engeland WC, Anthony ELP, Gann DS, Jackson IMD 1987 Corticotropin-releasing factor in the dog adrenal medulla is secreted in response to hemorrhage. Endocrinology 120:25–33[Abstract/Free Full Text]
182. Edwards AV, Jones CT 1988 Secretion of corticotropin releasing factor from the adrenal during splanchnic nerve stimulation in conscious calves. J Physiol 400:89–100[Abstract/Free Full Text]
183. Mazzocchi G, Malendowicz LK, Rebuffat P, Gottardo G, Nussdorfer GG 1997 Neurotensin stimulates CRH and ACTH release by rat adrenal medulla in vitro. Neuropeptides 31:8–11[CrossRef][Medline]
184. Mazzocchi G, Malendowicz LK, Rebuffat P, Tortorella C, Nussdorfer GG 1997 Arginine-vasopressin stimulates CRH and ACTH release by rat adrenal medulla, acting via the V1 receptor subtype and a protein kinase C-dependent pathway. Peptides 18:191–195[CrossRef][Medline]
185. Mazzocchi G, Malendowicz LK, Gottardo G, Nussdorfer GG 1997 Neuropeptide K and neurokinin A stimulate CRH and ACTH release by rat adrenal medulla in vitro. Peptides 18:487–490[CrossRef][Medline]
186. Andreis PG, Neri G, Belloni AS, Mazzocchi G, Kasprzak A, Nussdorfer GG 1991 Interleukin 1ß enhances corticosterone secretion by acting directly on the rat adrenal gland. Endocrinology 129:53–57[Abstract/Free Full Text]
187. Rundle SE, Benedict JC, Robinson PM, Funder JW 1988 Innervation of the sheep adrenal cortex: an immunohistochemical study with rat corticotropin-releasing factor antiserum. Neuroendocrinology 48:8–15[Medline]
188. Pomerantz JE, Li C, Nathanielsz PW, McDonald TJ 1996 Corticotropin-releasing hormone-like axons in the adrenal glands of fetal and postnatal sheep. J Auton Nerv Syst 59:87–90[CrossRef][Medline]
189. Udelsman R, Harwood JP, Millan MA, Chrousos GP, Goldstein DS, Zimlichman R, Catt KJ, Aguilera G 1986 Functional corticotropin releasing factor receptors in the primate peripheral sympathetic nervous system. Nature 319:147–150[CrossRef][Medline]
190. Aguilera G, Millan MA, Hauger RL, Catt KJ 1987 Corticotropin-releasing factor receptors: distribution and regulation in brain, pituitary, and peripheral tissues. Ann NY Acad Sci 512:48–66[Medline]
191. Mazzocchi G, Malendowicz LK, Markowska A, Nussdorfer GG 1994 Effect of hypophysectomy on corticotropin-releasing hormone and adrenocorticotropin immunoreactivities in the rat adrenal gland. Mol Cell Neurosci 5:345–349[CrossRef][Medline]
192. Edwards AV, Jones CT 1994 Adrenal responses to the peptide PACAP in conscious functionally hypophysectomized calves. Am J Physiol 266:E870–E876
193. Andreis PG, Malendowicz LK, Belloni AS, Nussdorfer GG 1995 Effects of pituitary adenylate-cyclase activating peptide (PACAP) on the rat adrenal secretory activity: preliminary in- vitro studies. Life Sci 56:135–142[CrossRef][Medline]
194. Malendowicz LK, Andreis PG, Markowska A, Nowak M, Warchol JB, Neri G, Nussdorfer GG 1994 Effects of neuromedin U-8 on the secretory activity of the rat adrenal cortex: evidence for an indirect action requiring the presence of the zona medullaris. Res Exp Med 194:69–79[Medline]
195. Besedovsky HO, Sorkin E 1977 Network of immune-neuroendocrine interactions. Clin Exp Immunol 27:1–12[Medline]
196. Bateman A, Singh A, Kral T, Solomon S 1989 The immune-hypothalamic-pituitary-adrenal axis. Endocr Rev 10:92–112[Abstract/Free Full Text]
197. Wick G, Hu Y, Schwarz S, Kroemer G 1993 Immunoendocrine communication via the hypothalamo-pituitary-adrenal axis in autoimmune diseases. Endocr Rev 14:539–563[Abstract/Free Full Text]
198. Reichlin S 1993 Neuroendocrine-immune interactions. N Engl J Med 329:1246–1253[Free Full Text]
199. Imura H, Fukata J 1994 Endocrine-paracrine interaction in communication between the immune and endocrine systems. Activation of the hypothalamic-pituitary-adrenal axis in inflammation. Eur J Endocrinol 130:32–37[Abstract/Free Full Text]
200. Blalock JE 1989 A molecular basis for bidirectional communication between the immune and neuroendocrine systems. Physiol Rev 69:1–32[Free Full Text]
201. Rivier C 1995 Influence of immune signals on the hypothalamic-pituitary axis of the rodent. Front Neuroendocrinol 16:151–182[CrossRef][Medline]
202. Turnbill AV, Rivier C 1995 Regulation of the HPA axis by cytokines. Brain Behav Immun 9:253–275[CrossRef][Medline]
203. Chrousos GP 1995 The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 332:1351–1362[Free Full Text]
204. Besedovsky HO, del Rey A 1996 Immune-neuro-endocrine interactions: facts and hypotheses. Endocr Rev 17:64–102[Abstract/Free Full Text]
205. Hume DA, Halpin D, Charlton H, Gordon S 1984 The mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80: macrophages of endocrine organs. Immunology 81:4174–4177
206. González-Hernández JA, Bornstein SR, Ehrhart-Bornstein M, Geschwend JE, Adler G, Scherbaum WA 1994 Macrophages within the human adrenal gland. Morphological data for a possible local immune-neuroendocrine interaction. Cell Tissue Res 278:201–205[Medline]
207. Dinarello CA 1992 The biology of interleukin 1. In: Kishimoto T (ed) Interleukins: Molecular Biology and Immunology. Karger, Basel, pp 1–32
208. Ottaway CA 1991 Vasoactive intestinal peptide and immune function. In: Ader R, Felten DL, Cohen N (eds) Psychoneuroimmunology. Academic Press, San Diego, CA, pp 225–262
209. Nathan CF 1987 Secretory products of macrophages. J Clin Invest 79:319–326
210. Assoian RK, Fleurdelys BE, Stevenson HC, Miller PJ, Madtes DK, Raines EW, Ross R, Sporn MB 1987 Expression and secretion of type ß transforming growth factor by activated human macrophages. Proc Natl Acad Sci USA 84:6020–6024[Abstract/Free Full Text]
211. González-Hernández JA, Bornstein SR, Ehrhart-Bornstein M, Geschwend JE, Gwosdow AR, Jirikowski GF, Scherbaum WA 1995 Interleukin 1 is expressed in human adrenal gland in vivo. Possible role in a local immune-adrenal axis. Clin Exp Immunol 99:137–141[Medline]
212. González-Hernández JA, Bornstein SR, Ehrhart-Bornstein M, Späth-Schwalbe E, Jirikowski GF, Scherbaum WA 1994 Interleukin-6 mRNA expression in human adrenal gland in vivo: new clue to a paracrine or autocrine regulation of adrenal function. J Clin Endocrinol Metab 79:1492–1497[Abstract]
213. González-Hernández JA, Ehrhart-Bornstein M, Späth-Schwalbe E, Scherbaum WA, Bornstein SR 1996 Human adrenal cells express TNF-mRNA: evidence for a paracrine control of adrenal function. J Clin Endocrinol Metab 81:807–813[Abstract]
214. Whitcomb RW, Linehan WM, Wahl LM, Knazek RA 1988 Monocytes stimulate cortisol production by cultured human adrenocortical cells. J Clin Endocrinol Metab 66:33–38[Abstract/Free Full Text]
215. Mathison JC, Schreiber RD, La Forest AC, Ulevitch RJ 1983 Suppression of ACTH-induced steroidogenesis by supernatants from LPS-treated peritoneal exudate macrophages. J Immunol 130:2757–2762[Abstract]
216. Mathison JC, La Forest AC, Ulevitch RJ 1984 Properties and requirements for production of a macrophage product which suppresses steroid production by adrenocortical cells. Infect Immun 45:360–366[Abstract/Free Full Text]
217. Maisel AS, Fowler P, Rearden A, Motulsky HJ, Michel MC 1989 A new method for isolation of human lymphocyte subsets reveals differential regulation of ß-adrenergic receptors by terbutaline treatment. Clin Pharmacol Ther 46:429–439[Medline]
218. Jones TH, Kennedy RL 1993 Cytokines and hypothalamic-pituitary function. Cytokine 5:531–538[CrossRef][Medline]
219. Woloski BMRNJ, Smith EM, Meyer III WJ, Fuller GM, Blalock JE 1985 Corticotropin-releasing activity of monokines. Science 230:1035–1037[Abstract/Free Full Text]
220. Olsen NJ, Nicholson WE, De Bold CR, Orth DN 1992 Lymphocyte-derived adrenocorticotropin is insufficient to stimulate adrenal steroidogenesis in hypophysectomized rats. Endocrinology 130:2113–2119[Abstract/Free Full Text]
221. DuPont AG, Somers G, Van Steirteghem AC, Warson F, Vanhaelst L 1984 Ectopic adrenocorticotropin production: disappearance after removal of inflammatory tissue. J Clin Endocrinol Metab 58:654–658[Abstract/Free Full Text]
222. Hayashi Y, Hiyoshi T, Takemura T, Kurashima C, Hirokawa K 1989 Focal lymphocytic infiltration in the adrenal cortex of the elderly: immunohistological analysis of infiltrating lymphocytes. Clin Exp Immunol 77:101–105[Medline]
223. Schultzberg M, Andersson C, Undén A, Troye-Blomberg M, Svenson SB, Bartfai T 1989 Interleukin-1 in adrenal chromaffin cells. Neuroscience 30:805–810[CrossRef][Medline]
224. Bartfai T, Andersson C, Bristluf J, Schultzberg M, Svenson S 1990 Interleukin-1 in the noradrenergic chromaffin cells in the rat adrenal medulla. Ann NY Acad Sci 594:207–213[CrossRef][Medline]
225. Bornstein SR, Ehrhart-Bornstein M, González-Hernández JA, Schröder S, Scherbaum WA 1996 Expression of interleukin-1 in pheochromocytoma (PCC). J Endocrinol Invest 19:693–698[Medline]
226. Alheim K, Andersson C, Tingsborg S, Ziolkowska M, Schultzberg M, Bartfai T 1991 Interleukin-1 expression is inducible by nerve growth factor in PC-12 pheochromocytoma cells. Proc Natl Acad Sci USA 88:9302–9306[Abstract/Free Full Text]
227. Judd AM, Spangelo BL, Mac Leod RM 1990 Rat adrenal zona glomerulosa cells produce interleukin-6. Prog Neuro Endocrin Immunol 3:282–292
228. Judd AM, Mac Leod RM 1995 Differential release of tumor necrosis factor and Il-6 from adrenal zona glomerulosa cells in vitro. Am J Physiol 268:E114–E120
229. Judd AM, Mac Leod RM 1991 Angiotensin II increases interleukin 6 release from rat adrenal zona glomerulosa cells. Prog Neuro Endocrin Immunol 4:240–247
230. Judd AM, MacLeod RM 1992 Adrenocorticotropin increases interleukin-6 release from rat adrenal zona glomerulosa cells. Endocrinology 130:1245–1254[Abstract/Free Full Text]
231. Muramami N, Fukata J, Tsukada T, Kobayashi H, Ebisui O, Segawa H, Muro S, Imura H, Nakao K 1993 Bacterial lipopolysaccharide-induced expression of interleukin-6 messenger ribonucleic acid in the rat hypothalamus, pituitary, adrenal gland, and spleen. Endocrinology 133:2574–2578[Abstract/Free Full Text]
232. Ritchie PK, Knight HH, Ashby M, Judd AM 1996 Serotonin increases interleukin-6 release and decreases tumor necrosis factor release from rat adrenal zona glomerulosa cells in vitro. Endocrine 5:291–297[CrossRef]
233. Jäättelä M, Carpén O, Stenman U-H, Saksela E 1990 Regulation of ACTH-induced steroidogenesis in human fetal adrenals by rTNF-. Mol Cell Endocrinol 68:R31–R36
234. Conti B, Jahng JW, Tinti C, Son JH, Joh TH 1997 Induction of interferon-gamma inducing factor in the adrenal cortex. J Biol Chem 272:2035–2037[Abstract/Free Full Text]
235. Kapcala LP, He JR, Gao Y, Pieper JO, DeTolla LJ 1996 Subdiaphragmatic vagotomy inhibits intra-abdominal interleukin-1ß stimulation of adrenocorticotropin secretion. Brain Res 728:247–254[CrossRef][Medline]
236. Roh MS, Drazenovich KA, Barbose JJ, Dinarello CA, Cobb CF 1987 Direct stimulation of the adrenal cortex by interleukin-1. Surgery 102:140–146[Medline]
237. Gwosdow AR, O’Connell NA, Spencer JA, Kumar MSA, Agarwal RK, Bode HH, Abou-Samra AB 1992 Interleukin-1-induced corticosterone release occurs by an adrenergic mechanism from rat adrenal gland. Am J Physiol Endocrinol Metab 263:E461–E466
238. O’Connell NA, Kumar A, Chatzipanteli K, Mohan A, Agarwal RK, Head C, Bornstein SR, Abou-Samra AB, Gwosdow AR 1994 Interleukin-1 regulates corticosterone secretion from the rat adrenal gland through a catecholamine-dependent and prostaglandin E₂-independent mechanism. Endocrinology 135:460–467[Abstract]
239. Tominaga T, Fukata J, Naito Y, Usui T, Murakami N, Fukushima M, Hirai Y, Imura H 1991 Prostaglandin dependent in vitro stimulation of adrenal steroidogenesis by interleukins. Endocrinology 128:526–531[Abstract/Free Full Text]
240. Winter JSD, Gow KW, Perry YS, Greenberg HA 1990 A stimulatory effect of interleukin 1 on adrenocortical cortisol secretion mediated by prostaglandins. Endocrinology 127:1904–1909[Abstract/Free Full Text]
241. Cunningham Jr ET, Wada E, Carter DB, Tracey DE, Battey JF, De Souza EB 1992 In situ histochemical localization of type I interleukin-1 receptor messenger RNA in the central nervous system, pituitary, and adrenal gland of the mouse. J Neurosci 12:1101–1114[Abstract]
242. Andreis PG, Neri G, Meneghelli V, Mazzocchi G, Nussdorfer GG 1992 Effects of interleukin-1 beta on the renin-angiotensin-aldosterone system in rats. Res Exp Med 192:1–6[Medline]
243. Natarajan R, Ploszaj S, Horton R, Nadler J 1989 Tumor necrosis factor and interleukin-1 are potent inhibitors of angiotensin II-induced aldosterone synthesis. Endocrinology 125:3084–3089[Abstract/Free Full Text]
244. Tominaga T, Fukata J, Fujimoto T, Ogawa K, Diamanstein T, Imura H, Nakao K 1996 Immunocytochemical evidence for interleukin-2 receptor regulation on rat anterior pituitary and adrenal cells. Acta Histochem Cytochem 29:255–260
245. Salas MA, Evans SW, Levell MJ, Whicher JT 1990 Interleukin-6 and ACTH act synergistically to stimulate the release of corticosterone from adrenal gland cells. Clin Exp Immunol 79:470–473[Medline]
246. Mastorakos G, Chrousos GP, Weber JS 1993 Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab 77:1690–1694[Abstract]
247. Späth-Schwalbe E, Born J, Schrezenmeier H, Bornstein SR, Stromeyer P, Drechsler S, Fehm HL, Porzsolt F 1994 Interleukin-6 stimulates the hypothalamus-pituitary-adrenocortical axis in man. J Clin Endocrinol Metab 79:1212–1214[Abstract]
248. Päth G, Bornstein SR, Späth-Schwalbe E, Scherbaum WA 1996 Direct effects of interleukin-6 on human adrenal cells. Endocr Res 22:867–873[Medline]
249. Päth G, Bornstein SR, Ehrhart-Bornstein M, Scherbaum WA 1997 Interleukin-6 and the interleukin-6 receptor in the human adrenal gland: expression and effects on steroidogenesis. J Clin Endocrinol Metab 82:2343–2349[Abstract/Free Full Text]
250. Parker LN, Odell WD 1980 Control of adrenal androgen secretion. Endocr Rev 1:392–410[Abstract/Free Full Text]
251. Tracey KJ, Vlassara H, Cerami A 1989 Cachectin/tumor necrosis factor. Lancet 1:1122–1126[Medline]
252. Jäättelä M, Ilvesmäki V, Voutilainen R, Ulf-Hakan S, Saksela E 1991 Tumor necrosis factor as a potent inhibitor of adrenocorticotropin-induced cortisol production and steroidogenic P 450 enzyme gene expression in cultured human fetal adrenal cells. Endocrinology 128:623–629[Abstract/Free Full Text]
253. Swain MG, Maric M 1996 Tumor necrosis factor- stimulates adrenal glucocorticoid secretion in cholestatic rats. Am J Physiol 270:G987–G991
254. Ilvesmaki V, Jaattela M, Saksela E, Voutilainen R 1993 Tumor necrosis factor-alpha and interferon-gamma inhibit insulin-like growth factor II gene expression in human fetal adrenal cell cultures. Mol Cell Endocrinol 91:59–65[CrossRef][Medline]
255. Voutilainen R, Ilvesmaki V, Ariel I, Rachmilewitz J, de Groot N, Hochberg A 1994 Parallel regulation of parentally imprinted H19 and insulin-like growth factor-II genes in cultured human fetal adrenal cells. Endocrinology 134:2051–2056[Abstract/Free Full Text]
256. Lengyel P 1982 Biochemistry of interferons and their actions. Annu Rev Biochem 51:251–282[CrossRef][Medline]
257. Gisslinger H, Svoboda T, Clodi M, Gilly B, Ludwig H, Havelec L, Luger A 1993 Interferon- stimulates the hypothalamic-pituitary-adrenal axis in vivo and in vitro. Neuroendocrinology 57:489–495[Medline]
258. Chrousos GP 1996 Organization and integration of the endocrine system. In: Sperling M (ed) Pediatric Endocrinology. Saunders Co. Philadelphia, pp 1–14
259. Feige JJ, Baird A 1991 Growth factor regulation of adrenal cortex growth and function. Prog Growth Factor Res 3:103–113[Medline]
260. Baird A, Bohlen A 1990 Fibroblast growth factors. In: Sporn MB, Roberts AB (eds) Peptide Growth Factors and Their Receptors. Springer-Verlag, Berlin, vol 1:369–418
261. Roberts AB, Sporn MB 1990 The transforming growth factors-ß. In: Sporn MB, Roberts AB (eds) Peptide Growth Factors and Their Receptors. Springer-Verlag, Berlin, vol 1:419–472
262. Rechler MM, Nissley SP 1990 Insulin-like growth factors. In: Sporn MB, Roberts AB (eds) Peptide Growth Factors and Their Receptors. Springer-Verlag, Berlin, vol 1:263–367
263. Panayotou G, Waterfield MD 1993 The assembly of signaling complexes by receptor tyrosine kinases. Bioessays 15:171–177[CrossRef][Medline]
264. Lee JS, Pilch PF 1994 The insulin-receptor—structure, function, and signaling. Am J Physiol 266:C319–C334
265. Leroith D, Sampson PC, Roberts CT 1994 How does the mitogenic insulin-like growth-factor-i receptor differ from the metabolic insulin-receptor. Horm Res 41:74–79
266. Avruch J, Zhang X, Kyriakis JM 1994 Raf meets Ras: the framework of a signal transduction pathway. Trends Biochem Sci 19:279–283[CrossRef][Medline]
267. Johnson GL, Vaillancourt RR 1994 Sequential protein kinase reactions controlling cell growth and differentiation. Curr Opin Cell Biol 6:230–238[CrossRef][Medline]
268. Berse B, Brown LF, Vandewater L, Dvorak HF, Senger DR 1992 Vascular-permeability factor (vascular endothelial growth-factor) gene is expressed differentially in normal-tissues, macrophages, and tumors. Mol Biol Cell 3:211–220[Abstract]
269. Gonzalez AM, Buscaglia M, Ong M, Baird A 1990 Distribution of basic fibroblast growth factor in the 18-day rat fetus: localization in the basement membranes of diverse tissues. J Cell Biol 110:753–765[Abstract/Free Full Text]
270. Gospodarowicz D, Neufeld G, Schweigerer L 1986 Fibroblast growth factor. Mol Cell Endocrinol 46:187–204[CrossRef][Medline]
271. Gospodarowicz D 1975 Purification of a fibroblast growth factor from bovine pituitary. J Biol Chem 250:2515–2520[Abstract/Free Full Text]
272. Grothe C, Unsicker K 1990 Immunocytochemical mapping of basic fibroblast growth factor in the developing and adult rat adrenal gland. Histochemistry 94:141–147[CrossRef][Medline]
273. Shweiki D, Itin A, Neufeld G, Gitaygoren H, Keshet E 1993 Patterns of expression of vascular endothelial growth-factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J Clin Invest 91:2235–2243
274. Sasano H, Suzuki T, Shizawa S, Kato K, Nagura H 1994 Transforming growth factor alpha, epidermal growth factor, and epidermal growth factor receptor expression in normal and diseased human adrenal cortex by immunohistochemistry and in situ hybridization. Mod Pathol 7:741–746[Medline]
275. Ho MM, Vinson GP 1995 Endocrine control of the distribution of basic fibroblast growth factor, insulin-like growth factor-I and transforming growth factor-beta 1 mRNAs in adult rat adrenals using non-radioactive in situ hybridization. J Endocrinol 144:379–387[Abstract/Free Full Text]
276. Trowell OA, Chir B, Willmer EN 1939 Growth of tissues in vitro. VI. The effects of some tissue extracts on the growth of periosteal fibroblasts. J Exp Biol 16:60–70[Abstract]
277. Hoffman RS 1940 The growth-activating effect of extracts of adult and embryonic tissues of the rat on fibroblast colonies in culture. Growth 4:361–376
278. Armelin HA 1973 Pituitary extracts and steroid hormones in the control of 3T3 cell growth. Proc Natl Acad Sci USA 70:2702–2706[Abstract/Free Full Text]
279. Abraham JA, Whang JL, Tumolo A, Mergia A, Friedman J, Gospodarowicz D, Fiddes JC 1986 Human basic fibroblast growth factor: nucleotide sequence and genomic organization. EMBO J 5:2523–2528[Medline]
280. Jaye M, Howk R, Burgess W, Ricca GA, Chiu IM, Ravera MW, O’Brien SJ, Modi WS, Maciag T, Drohan WN 1986 Human endothelial cell growth factors: cloning, nucleotide sequence, and chromosome localization. Science 233:541–545[Abstract/Free Full Text]
281. Gospodarowicz D, Baird A, Cheng J, Lui GM, Esch F, Böhlen P 1986 Isolation of FGF from bovine adrenal gland: physicochemical and biological characterization. Endocrinology 118:82–90[Abstract/Free Full Text]
282. Holzwarth MA 1995 Evidence for fibroblast growth-factor mediation of compensatory adrenocortical proliferation. Endocr Res 21:115–119[Medline]
283. Westermann R, Johannsen M, Unsicker K, Grothe C 1990 Basic fibroblast growth factor (bFGF) immunoreactivity is present in chromaffin granules. J Neurochem 55:285–292[CrossRef][Medline]
284. Gospodarowicz D, Neufeld G, Schweigerer L 1986 Molecular and biological characterisation of fibroblast growth factor, an angiogenic factor which controls the proliferation and differentiation of mesoderm and neuroectodermal derived cells. Cell Differ 19:1–17[CrossRef][Medline]
285. Stemple DL, Mahanthappa NK, Anderson DJ 1988 Basic FGF induces neuronal differentiation, cell division, and NGF dependence in chromaffin cells: a sequence of events in sympathetic development. Neuron 1:517–525[CrossRef][Medline]
286. Schweigerer L, Neufeld G, Friedman J, Abraham JA, Fiddes JC, Gospodarowicz D 1987 Basic fibroblast growth factor: production and growth stimulation in cultured adrenal cortex cells. Endocrinology 120:796–800[Abstract/Free Full Text]
287. Unsicker K, Westermann R 1992 Basic fibroblast growth factor promotes transmitter storage and synthesis in cultured chromaffin cells. Dev Brain Res 65:211–216[CrossRef][Medline]
288. Jiang Z, Savona C, Chambaz EM, Feige JJ 1992 Transforming growth factor ß1 and adrenocorticotropin differentially regulate the synthesis of adrenocortical cell heparan sulfate proteoglycans and their binding of basic fibroblast growth factor. J Cell Physiol 153:266–276[CrossRef][Medline]
289. Basile DP, Holzwarth MA 1994 Basic fibroblast growth-factor receptor in the rat adrenal-cortex—effects of suramin and unilateral adrenalectomy on receptor numbers. Endocrinology 134:2482–2489[Abstract/Free Full Text]
290. Saksela O, Rifkin DB 1990 Release of basic fibroblast growth factor-heparan sulfate complexes from endothelial cells by plasminogen activator-mediated proteolytic activity. J Cell Biol 110:767–775[Abstract/Free Full Text]
291. Vlodavsky I, Bar Shavit R, Ishai Michaeli R, Bashkin P, Fuks Z 1991 Extracellular sequestration and release of fibroblast growth factor: a regulatory mechanism? Trends Biochem Sci 16:268–271[CrossRef][Medline]
292. Shimasaki S, Emoto N, Koba A, Mercado M, Shibata F, Cooksey K, Baird A, Ling N 1988 Complementary DNA cloning and sequencing of rat ovarian basic fibroblast growth factor and tissue distribution study of its mRNA. Biochem Biophys Res Commun 157:256–263[CrossRef][Medline]
293. Savona C, Keramidas M, Chambaz EM, Feige JJ 1994 Synergistic induction of alpha(2)-macroglobulin synthesis by fibroblast growth factor-II and transforming growth-factor beta(1) in bovine adrenocortical-cells. Growth Factors 10:197–205[Medline]
294. Savona C, Chambaz EM, Feige JJ 1991 Proteoheparan sulfates contribute to the binding of basic FGF to its high affinity receptors on bovine adrenocortical cells. Growth Factors 5:273–282[Medline]
295. Basile DP, Holzwarth MA 1993 Basic fibroblast growth-factor may mediate proliferation in the compensatory adrenal growth-response. Am J Physiol 265:R1253–R1261
296. McEwan PC, Lindop GB, Kenyon CJ 1996 Control of cell-proliferation in the rat adrenal-gland in-vivo by the renin-angiotensin system. Am J Physiol 34:E192–E198
297. Meisinger C, Hertenstein A, Grothe C 1996 Fibroblast growth factor receptor 1 in the adrenal gland and PC12 cells: developmental expression and regulation by extrinsic molecules. Mol Brain Res 36:70–78[Medline]
298. Mesiano S, Mellon SH, Gospodarowicz D, Di Blasio AM, Jaffe RB 1991 Basic fibroblast growth factor expression is regulated by corticotropin in the human fetal adrenal: a model for adrenal growth regulation. Proc Natl Acad Sci USA 88:5428–5432[Abstract/Free Full Text]
299. Meisinger C, Zeschnigk C, Grothe C 1996 In-vivo and in-vitro effect of glucocorticoids on fibroblast growth-factor (FGF)-2 and FGF receptor-1 expression. J Biol Chem 271:16520–16525[Abstract/Free Full Text]
300. Gospodarowicz D, Handley HH 1975 Stimulation of division of Y1 adrenal cells by a growth factor isolated from bovine pituitary cells. Endocrinology 97:102–107[Abstract/Free Full Text]
301. Gospodarowicz D, Ill CR, Hornsby PJ, Gill GN 1977 Control of bovine adrenal cortical cell proliferation by fibroblast growth factor. Lack of effect of epidermal growth factor. Endocrinology 100:1080–1089[Abstract/Free Full Text]
302. Hornsby PJ, Gill GN 1977 Hormonal control of adrenocortical cell proliferation. Desensitization to ACTH and interaction between ACTH and fibroblast growth factor in bovine adrenocortical cell cultures. J Clin Invest 60:342–354
303. Viard I, Jaillard C, Saez JM 1993 Regulation by growth factors (IGF-I, b-FGF and TGF-beta) of proto-oncogene mRNA, growth and differentiation of bovine adrenocortical fasciculata cells. FEBS Lett 328:94–98[CrossRef][Medline]
304. Langlois D, Ouali R, Berthelon MC, Derrien A, Saez JM 1994 Regulation by growth factors of angiotensin II type-1 receptor and the subunit of Gq and G11 in bovine adrenal cells. Endocrinology 135:480–483[Abstract]
305. Wolf N, Krieglstein K 1995 Phenotypic development of neonatal rat chromaffin cells in response to adrenal growth-factors and glucocorticoids—focus on pituitary adenylate-cyclase activating polypeptide. Neurosci Lett 200:207–210[CrossRef][Medline]
306. Han VK, Hill DJ, Strain AJ, Towle AC, Lauder JM, Underwood LE, D’Ercole AJ 1987 Identification of somatomedin/insulin-like growth factor immunoreactive cells in the human fetus. Pediatr Res 22:245–249[Medline]
307. Han VK, Snouweart J, Towle AC, Lund PK, Lauder JM 1987 Cellular localization of tyrosine hydroxylase mRNA and its regulation in the rat adrenal medulla and brain by in situ hybridization with an oligodeoxyribonucleotide probe. J Neurosci Res 17:11–18[CrossRef][Medline]
308. Han VK, Lund PK, Lee DC, D’Ercole AJ 1988 Expression of somatomedin/insulin-like growth factor messenger ribonucleic acids in the human fetus: identification, characterization, and tissue distribution. J Clin Endocrinol Metab 66:422–429[Abstract/Free Full Text]
309. Mesiano S, Mellon SH, Jaffe RB 1993 Mitogenic action, regulation, and localization of insulin-like growth factors in the human fetal adrenal gland. J Clin Endocrinol Metab 76:968–976[Abstract]
310. Voutilainen R, Miller WL 1987 Coordinate tropic hormone regulation of mRNAs for insulin-like growth factor II and the cholesterol side-chain-cleavage enzyme, P450 scc, in human steroidogenic tissues. Proc Natl Acad Sci USA 84:1590–1594[Abstract/Free Full Text]
311. Han VK, Lu F, Bassett N, Yang KP, Delhanty PJ, Challis JR 1992 Insulin-like growth factor-II (IGF-II) messenger ribonucleic acid is expressed in steroidogenic cells of the developing ovine adrenal gland: evidence of an autocrine/paracrine role for IGF-II. Endocrinology 131:3100–3109[Abstract/Free Full Text]
312. Lustig O, Ariel I, Ilan J, Levlehman E, Degroot N, Hochberg A 1994 Expression of the imprinted gene H19 in the human fetus. Mol Reprod Dev 38:239–246[CrossRef][Medline]
313. Liu JQ, Kahri AI, Heikkila P, Ilvesmaki V, Voutilainen R 1995 H19 and insulin-like growth factor-II gene-expression in adrenal-tumors and cultured adrenal-cells. J Clin Endocrinol Metab 80:492–496[Abstract]
314. Naaman E, Chatelain P, Saez JM, Durand P 1989 In vitro effect of insulin and insulin-like growth factor-I on cell multiplication and adrenocorticotropin responsiveness of fetal adrenal cells. Biol Reprod 40:570–577[Abstract]
315. Penhoat A, Leduque P, Jaillard C, Chatelain PG, Dubois PM, Saez JM 1991 ACTH and angiotensin II regulation of IGF-I and its binding proteins in cultured bovine adrenal cells. J Mol Endocrinol 7:223–232[Abstract/Free Full Text]
316. Penhoat A, Chatelain PG, Jaillard C, Saez JM 1988 Characterization of insulin-like growth factor I and insulin receptors on cultured bovine adrenal fasciculata cells. Role of these peptides on adrenal cell function. Endocrinology 122:2518–2526[Abstract/Free Full Text]
317. Hansson HA, Nilsson A, Isgaard J, Billig H, Isaksson O, Skottner A, Andersson IK, Rozell B 1988 Immunohistochemical localization of insulin-like growth factor I in the adult rat. Histochemistry 89:403–410[CrossRef][Medline]
318. Pillion DJ, Arnold P, Yang M, Stockard CR, Grizzle WE 1989 Receptors for insulin and insulin-like growth factor-I in the human adrenal gland. Biochem Biophys Res Commun 165:204–211[CrossRef][Medline]
319. Horiba N, Nomura K, Hizuka N, Takano K, Demura H, Shizuma K 1987 Effects of IGF-I on proliferation and steroidogenesis of cultured adrenal zona glomerulosa cells. Endocrinol Jpn 34:611–614[Medline]
320. Ito Y, Yasuda K, Takeda N, Goto S, Hayashi M, Inoue H, Aoyama K, Miura K 1992 Characterization of insulin-receptors in the bovine adrenal-cortex and medulla. Endocrinol Jpn 39:217–222[Medline]
321. Backlin C, Rastad J, Skogseid B, Hellman P, Akerstrom G, Juhlin C 1995 Immunohistochemical expression of insulin-like-growth-factor-1 and its receptor in normal and neoplastic human adrenal-cortex. Anticancer Res 15:2453–2459[Medline]
322. Pillion DJ, Yang M, Grizzle WE 1988 Distribution of receptors for insulin and insulin-like growth factor I (somatomedin C) in the adrenal gland. Biochem Biophys Res Commun 154:138–145[CrossRef][Medline]
323. L’Allemand D, Penhoat A, Lebrethon MC, Ardèvol R, Baehr V, Oelkers W, Saez JM 1996 Insulin-like growth factors enhance steroidogenic enzyme and corticotropin receptor messenger ribonucleic acid levels and corticotropin steroidogenic responsiveness in cultured human adrenocortical cells. J Clin Endocrinol Metab 81:3892–3897[Abstract/Free Full Text]
324. Weber MM, Kiess W, Beikler T, Simmler P, Reichel M, Adelmann B, Kessler U, Engelhardt D 1994 Identification and characterization of insulin-like growth-factor-iI(IGF-I) and IGF-II/mannose-6-phosphate (IGF-II/m6p) receptors in bovine adrenal-cells. Eur J Endocrinol 130:265–270[Abstract/Free Full Text]
325. van Dijk JP, Tanswell AK, Challis JR 1988 Insulin-like growth factor (IGF)-II and insulin, but not IGF-I, are mitogenic for fetal rat adrenal cells in vitro. J Endocrinol 119:509–516[Abstract/Free Full Text]
326. Pham-Huu-Trung MT, Binoux M 1990 IGF-I induces cortisol production in bovine adrenocortical cells in primary culture. J Steroid Biochem 36:583–588[CrossRef][Medline]
327. Penhoat A, Naville D, Jaillard C, Chatelain PG, Saez JM 1989 Hormonal regulation of insulin-like growth factor I secretion by bovine adrenal cells. J Biol Chem 264:6858–6862[Abstract/Free Full Text]
328. Townsend SF, Dallman MF, Miller WL 1990 Rat insulin-like growth factor-I and -II mRNAs are unchanged during compensatory adrenal growth but decrease during ACTH-induced adrenal growth. J Biol Chem 265:22117–22122[Abstract/Free Full Text]
329. O’Connell Y, McKenna TJ, Cunningham SK 1994 The effect of prolactin, human chorionic-gonadotropin, insulin and insulin-like growth-factor I on adrenal steroidogenesis in isolated guinea-pig adrenal-cells. J Steroid Biochem Mol Biol 48:235–240[CrossRef][Medline]
330. Fujii H, Iida S, Tsugawa M, Gomi M, Moriwaki K, Tarui S 1990 Inhibitory effect of somatomedin C/insulin-like growth factor I on adrenocorticotropin- or forskolin-induced steroidogenesis in isolated rat adrenocortical cells. Endocrinology 126:26–30[Abstract/Free Full Text]
331. Penhoat A, Jaillard C, Saez JM 1989 Synergistic effects of corticotropin and insulin-like growth factor I on corticotropin receptors and corticotropin responsiveness in cultured bovine adrenocortical cells. Biochem Biophys Res Commun 165:355–359[CrossRef][Medline]
332. Begeot M, Langlois D, Saez JM 1989 Insulin-like growth factor-I and insulin increase the stimulatory guanine nucleotide binding protein (Gs) in cultured bovine adrenal cells. Mol Cell Endocrinol 66:53–57[CrossRef][Medline]
333. Shimasaki S, Gao L, Shimonaka M, Ling N 1991 Isolation and molecular cloning of insulin-like growth factor-binding protein-6. Mol Endocrinol 5:938–948[Abstract/Free Full Text]
334. Shimasaki S, Uchiyama F, Shimonaka M, Ling N 1990 Molecular cloning of the cDNAs encoding a novel insulin-like growth factor-binding protein from rat and human. Mol Endocrinol 4:1451–1458[Abstract/Free Full Text]
335. Weber MM, Simmler P, Fottner C, Engelhardt D 1995 Insulin-like-growth-factor-II (IGF-II) is more potent than IGF-I in stimulating cortisol secretion from cultured bovine adrenocortical-cells—interaction with the IGF-I receptor and IGF-binding proteins. Endocrinology 136:3714–3720[Abstract]
336. Feige JJ, Cochet C, Savona C, Shi DL, Keramidas M, Defaye G, Chambaz EM 1991 Transforming growth factor ß1: an autocrine regulator of adrenocortical steroidogenesis. Endocr Res 17:267–279[Medline]
337. Keramidas M, Bourgarit JJ, Tabone E, Corticelli P, Chambaz EM, Feige JJ 1991 Immunolocalization of transforming growth factor-ß₁ in the bovine adrenal cortex using antipeptide antibodies. Endocrinology 129:517–526[Abstract/Free Full Text]
338. Thompson NL, Flanders KC, Smith JM, Ellingsworth LR, Roberts AB, Sporn MB 1989 Expression of transforming growth factor-beta 1 in specific cells and tissues of adult and neonatal mice. J Cell Biol 108:661–669[Abstract/Free Full Text]
339. Feige JJ, Negoescu A, Keramidas M, Souchelnitskiy S, Chambaz EM 1996 Alpha(2)-macroglobulin—a binding-protein for transforming growth-factor-beta and various cytokines. Horm Res 45:227–232[Medline]
340. Chambaz EM, Souchelnitskiy S, Pellerin S, Defaye G, Cochet C, Feige JJ 1996 Transforming growth factor-ßs—a multifunctional cytokine family—implication in the regulation of adrenocortical cell endocrine functions. Horm Res 45:222–226[Medline]
341. Cochet C, Feige JJ, Chambaz EM 1988 Bovine adrenocortical cells exhibit high affinity transforming growth factor-ß receptors which are regulated by adrenocorticotropin. J Biol Chem 263:5707–5713[Abstract/Free Full Text]
342. Hotta M, Baird A 1986 Differential effects of transforming growth factor type ß on the growth and function of adrenocortical cells in vitro. Proc Natl Acad Sci USA 83:7795–7799[Abstract/Free Full Text]
343. Riopel L, Branchaud CL, Goddyer CG, Adkar V, Lefebvre Y 1989 Growth-inhibitory effect of TGF-ß on human fetal adrenal cells in primary monolayer culture. J Cell Physiol 140:233–238[CrossRef][Medline]
344. Parker Jr CR, Stankovic AK, Harlin C, Carden L 1992 Adrenocorticotropin interferes with transforming growth factor-ß-induced growth inhibition of neocortical cells from the human fetal adrenal gland. J Clin Endocrinol Metab 75:1519–1521[Abstract]
345. Le Roy C, Leduque P, Dubois PM, Saez JM, Langlois D 1996 Repression of transforming growth factor beta 1 protein by antisense oligonucleotide-induced increase of adrenal cell differentiated functions. J Biol Chem 271:11027–11033[Abstract/Free Full Text]
346. Rainey WE, Viard I, Mason JI, Cochet C, Chambaz EM, Saez JM 1988 Effects of transforming growth factor beta on ovine adrenocortical cells. Mol Cell Endocrinol 60:189–198[CrossRef][Medline]
347. Perrin A, Pascal O, Defaye G, Feige JJ, Chambaz EM 1990 Transforming growth factos ß₁ is a negative regulator of steroid 17-hydroxylase in bovine adrenocortical cells. Endocrinology 128:357–362[Abstract/Free Full Text]
348. Rainey WE, Naville D, Saez JM, Carr BR, Byrd W, Magness RR, Mason JI 1990 Transforming growth factor-ß inhibits steroid 17-hydroxylase cytochrome P-450 expression in ovine adrenocortical cells. Endocrinology 127:1910–1915[Abstract/Free Full Text]
349. Feige JJ, Lafeuillade B, Cochet C, Chambaz EM 1991 Autocrine regulation of adrenal steroidogenesis by growth factor transforming TGF-beta 1 [Regulation autocrine de la steroidogenese corticosurrenalienne par le facteur de croissance transformant TGF beta 1]. Ann Endocrinol (Paris) 52:451–455[Medline]
350. Rainey WE, Viard I, Saez JM 1989 Transforming growth factor ß treatment decreases ACTH receptors on ovine adrenocortical cells. J Biol Chem 264:21474–21477[Abstract/Free Full Text]
351. Shi DL, Savona C, Chambaz EM, Feige JJ 1990 Stimulation of fibronectin production by TGF-beta 1 is independent of effects on cell proliferation: the example of bovine adrenocortical cells. J Cell Physiol 145:60–68[CrossRef][Medline]
352. Williams CA, Allen Hoffmann BL 1990 Transforming growth factor-ß1 stimulates fibronectin production in bovine adrenocortical cells in culture. J Biol Chem 265:6467–6472[Abstract/Free Full Text]
353. Shi DL, Savona C, Gagnon J, Cochet C, Chambaz EM, Feige JJ 1990 Transforming growth factor-beta stimulates the expression of 2-macroglobulin by cultured bovine adrenocortical cells. J Biol Chem 265:2881–2887[Abstract/Free Full Text]
354. Keramidas M, Chambaz EM, Feige JJ 1992 Inhibition of adrenocortical steroidogenesis by alpha 2-macroglobulin is caused by associated transforming growth factor beta. Mol Cell Endocrinol 84:243–251[CrossRef][Medline]
355. Stankovic AK, Dion LD, Parker Jr CR 1994 Effects of transforming growth factor-beta on human fetal adrenal steroid production. Mol Cell Endocrinol 99:145–151[CrossRef][Medline]
356. Lebrethon MC, Jaillard C, Naville D, Begeot M, Saez JM 1994 Regulation of corticotropin and steroidogenic enzyme mRNAs in human fetal adrenal cells by corticotropin, angiotensin-II and transforming growth factor ß₁. Mol Cell Endocrinol 106:137–143[CrossRef][Medline]
357. Lebrethon MC, Jaillard C, Naville D, Begeot M, Saez JM 1994 Effects of transforming growth factor-ß1 on human adrenocortical fasciculata-reticularis cell differentiated functions. J Clin Endocrinol Metab 79:1033–1039[Abstract]
358. Rainey WE, Naville D, Mason JI 1991 Regulation of 3ß-hydroxysteroid dehydrogenase in adrenocortical cells: effects of angiotensin II and transforming growth factor beta. Endocr Res 17:281–296[Medline]
359. Gross F 1958 Renin und Hypertensin, physiologische oder pathologische Wirkstoffe? Klin Wochenschr 36:693–706
360. Aguilera G, Hauger RL, Catt KJ 1978 Control of aldosterone secretion during sodium restriction: adrenal receptor regulation and increased adrenal sensitivity to angiotensin II. Proc Natl Acad Sci USA 75:975–979[Abstract/Free Full Text]
361. Aguilera G, Catt KJ 1983 Regulation of aldosterone secretion during altered sodium intake. J Steroid Biochem 19:525–530[CrossRef][Medline]
362. Swartz SL, Williams GH, Hollenberg NK, Dluhy RG, Moore TJ 1980 Primacy of the renin-angiotensin system in mediating the aldosterone response to sodium restriction. J Clin Endocrinol Metab 50:1071–1074[Abstract/Free Full Text]
363. Tait JF, Tait SAS 1979 Recent perspectives on the history of the adrenal cortex. J Endocrinol 83:3P–24P
364. Ganong WF, Mulrow PJ, Boryczka A, Cera G 1962 Evidence for a direct effect of angiotensin II on adrenal cortex of the dog. Proc Soc Exp Biol Med 109:381–384
365. Urquhart J, Davis JO, Higgins JT 1963 Effects of prolonged infusion of angiotensin II in normal dogs. Am J Physiol 205:1241–1246[Abstract/Free Full Text]
366. Blair-West JR, Coghlan JP, Denton DA, Goding JR, Munro JA, Peterson RE, Wintour M 1962 Humoral stimulation of adrenocortical secretion. J Clin Invest 41:1606–1627
367. Mason PA, Fraser J, Morton JJ, Semple PF, Wilson A 1976 The effect of angiotensin II infusion on plasma corticosteroid concentrations in normal man. J Steroid Biochem 7:859–861[CrossRef][Medline]
368. Braverman B, Davis JO 1973 Adrenal steroid secretion in the rabbit: sodium depletion, angiotensin II and ACTH. Am J Physiol 225:1306–1310[Free Full Text]
369. Hinson JP, Vinson GP, Whitehouse BJ 1988 Effects of dietary sodium restriction on peptide stimulation of aldosterone secretion by isolated perfused rat adrenal gland in situ: a report of exceptional sensitivity to angiotensin II amide. J Endocrinol 119:83–88[Abstract/Free Full Text]
370. Finn FM, Stehle C, Ricci P, Hofmann K 1988 Angiotensin stimulation of adrenal fasciculata cells. Arch Biochem Biophys 264:160–167[CrossRef][Medline]
371. Chang RS, Lotti VJ 1990 Two distinct angiotensin II receptor binding sites in rat adrenal revealed by new selective nonpeptide ligands. Mol Pharmacol 37:347–351[Abstract]
372. Balla T, Baukal AJ, Eng S, Catt KJ 1991 Angiotensin II receptor subtypes and biological responses in the adrenal cortex and medulla. Mol Pharmacol 40:401–406[Abstract]
373. Hajnoczky G, Csordas G, Bago A, Chiu AT, Spat A 1992 Angiotensin II exerts its effect on aldosterone production and potassium permeability through receptor subtype AT1 in rat adrenal glomerulosa cells. Biochem Pharmacol 43:1009–1012[CrossRef][Medline]
374. Timmermans PBMWM, Wong PC, Chui AT, Herblin WF, Benfield P, Carini PJ, Lee RJ, Wexler RR, Saye JAM, Smith RD 1993 Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 45:205–251[Medline]
375. Balla T, Baukal AJ, Guillemette G, Morgan RO, Catt KJ 1986 Angiotensin-stimulated production of inositol trisphosphate isomers and rapid metabolism through inositol 4-monophosphate in adrenal glomerulosa cells. Proc Natl Acad Sci USA 83:9323–9327[Abstract/Free Full Text]
376. Braley L, Menachery A, Brown E, Williams G 1984 The effects of extracellular K⁺ and angiotensin II on cytosolic Ca⁺⁺ and steroidogenesis in adrenal glomerulosa cells. Biochem Biophys Res Commun 123:810–815[CrossRef][Medline]
377. Catt KJ, Balla T, Baukal AJ, Hausdorff WP, Aguilera G 1988 Control of glomerulosa cell function by angiotensin. Clin Exp Pharmacol Physiol 15:501–515[Medline]
378. Kojima I, Kojima K, Rasmussen H 1985 Characteristics of angiotensin II-, K⁺- and ACTH-induced calcium influx in adrenal glomerulosa cells. Evidence that angiotensin II, K⁺, and ACTH may open a common calcium channel. J Biol Chem 260:9171–9176[Abstract/Free Full Text]
379. Ohnishi J, Ishido M, Shibata T, Inagami T, Murakami K, Miyazaki H 1992 The rat angiotensin II AT1A receptor couples with three different signal transduction pathways. Biochem Biophys Res Commun 186:1094–1101[CrossRef][Medline]
380. Rossier MF, Capponi AM, Vallotton MB 1988 Inositol trisphosphate isomers in angiotensin II-stimulated adrenal glomerulosa cells. Mol Cell Endocrinol 57:163–168[CrossRef][Medline]
381. Woodcock EA, Smith AI, White LB 1988 Angiotensin II-stimulated phosphatidylinositol turnover in rat adrenal glomerulosa cells has a complex dependence on calcium. Endocrinology 122:1053–1059[Abstract/Free Full Text]
382. Woodcock EA, Johnston CI 1984 Inhibition of adenylate cyclase in rat adrenal glomerulosa cells by angiotensin II. Endocrinology 115:337–341[Abstract/Free Full Text]
383. Douglas JG, Brown GP, White C 1984 Angiotensin II receptors of human and primates adrenal fasciculata and glomerulosa. Metabolism 33:685–688[CrossRef][Medline]
384. Douglas J, Aguilera G, Kondo T, Catt KJ 1978 Angiotensin II receptors and aldosterone production in rat adrenal glomerulosa cells. Endocrinology 102:685–696[Abstract/Free Full Text]
385. Bird IM, Meikle I, Williams BC, Walker SW 1989 Angiotensin II-stimulated cortisol secretion is mediated by a hormone-sensitive phospholipase C in bovine adrenal fasciculata/reticularis cells. Mol Cell Endocrinol 64:45–53[CrossRef][Medline]
386. Williams BC, Lightly ER, Ross AR, Bird IM, Walker SW 1989 Characterization of the steroidogenic responsiveness and ultrastructure of purified zona fasciculata/reticularis cells from bovine adrenal cortex before and after primary culture. J Endocrinol 121:317–324[Abstract/Free Full Text]
387. Du Y, Guo DF, Inagami T, Speth RC, Wang DH 1996 Regulation of Ang-II-receptor subtype and its gene-expression in adrenal-gland. Physiology 40:H440–H446
388. Robba C, Rebuffat P, Mazzocchi G, Nussdorfer GG 1988 Long-term trophic effect of sodium restriction on the rat adrenal zona glomerulosa .1. its partial independence of the renin-angiotensin system. Exp Clin Endocrinol 91:43–50[Medline]
389. Tremblay A, Lehoux JG 1992 Influence of captopril on adrenal cytochrome P-450 s and adrenodoxin expression in high potassium or low sodium intake. J Steroid Biochem Mol Biol 41:799–808IS[CrossRef][Medline]
390. Ogishima T, Suzuki H, Hata J, Mitani F, Ishimura Y 1992 Zone-specific expression of aldosterone synthase cytochrome P-450 and cytochrome P-45011ß in rat adrenal cortex: histochemical basis for the functional zonation. Endocrinology 130:2971–2977[Abstract/Free Full Text]
391. Markowska A, Nussdorfer GG, Malendowicz LK 1994 Proliferogenic effect of neurotensin (NT) and neuromedin-N (NMN) on the rat adrenal-cortex—evidence that angiotensin-II mediates the effect of NMN, but not of NT. Neuropeptides 27:91–94[CrossRef][Medline]
392. Bird IM, Magness RR, Mason JI, Rainey WE 1992 Angiotensin-II acts via the type 1 receptor to inhibit 17-hydroxylase cytochrome P450 expression in ovine adrenocortical cells. Endocrinology 130:3113–3121[Abstract/Free Full Text]
393. Ryan JW 1967 Renin-like activity in the adrenal gland. Science 158:1589–1590[Abstract/Free Full Text]
394. Granzer E 1952 Über die Wirkung von Hormonextrakten des Hypophysenhinterlappens auf die Serumproteinzusammensetzung sowie ihre Beziehungen zum Renin. Naturwissenschaften 39:400–405
395. Hayduk K, Boucher R, Genest J 1970 Renin activity content in various tissues of dogs under different physiological states. Proc Soc Exp Biol Med 134:352–350
396. Ganten D, Ganten U, Kubo S, Granger P, Nowaczinski W, Bousher R, Genest J 1974 Influence of sodium, potassium, and pituitary hormones on iso-renin in rat adrenal glands. Am J Physiol 227:224–229[Free Full Text]
397. Naruse M, Sussman CR, Naruse K, Jackson RV 1983 Renin exists in human adrenal tissue. J Clin Endocrinol Metab 57:482–487[Abstract/Free Full Text]
398. Naruse M, Naruse K, Inagaki T, Inagami T 1984 Immunoreactive renin in mouse adrenal gland: localisation in the inner cortical region. Hypertension 6:275–280[Abstract/Free Full Text]
399. Naruse M, Takii Y, Inagami T 1981 Renin exists in high concentration in the adrenal of the rat. Biomed Res 2:583–580
400. Baba K, Doi Y, Yamaguchi T, Yano K, Hashiba K 1992 Production of active and inactive renin by adrenal explant cultures and the existence of a prorenin activating enzyme in the adrenal gland. Jpn Heart J 33:465–476[Medline]
401. Inagami T, Mizuno K, Naruse M, Nakamaru M, Naruse K, Hoffman LH, McKenzie JC 1989 Active and inactive renin in the adrenal. Am J Hypertens 2:311–319[Medline]
402. Kim S, Tokuyama M, Hosoi M, Yamamoto K 1992 Adrenal and circulating renin-angiotensin system in stroke-prone hypertensive rats. Hypertension 20:280–291[Abstract/Free Full Text]
403. Mizuno K 1991 Renin in adrenal: an overview of its synthesis, subcellular localization, and functions. Fukushima J Med Sci 37:41–57[Medline]
404. Naruse M, Inagami T 1982 Markedly elevated specific renin level in the adrenal in genetically hypertensive rats. Proc Natl Acad Sci USA 79:3295–3299[Abstract/Free Full Text]
405. Doi Y, Baba K, Yamaguchi T, Hashiba K, Mulrow PJ 1986 Evidence of release and production of inactive renin from adrenal zona glomerulosa cells. J Hypertens 4:S6
406. Doi Y, Atarashi K, Franco-Saenz R, Mulrow PJ 1983 Adrenal renin: a possible regulator of aldosterone production. Clin Exp Hypertens [A] 5:1119–1126[Medline]
407. Husain A, DeSilva P, Speth RC, Bumpus FM 1987 Regulation of angiotensin II in rat adrenal gland. Circ Res 60:640–648[Abstract/Free Full Text]
408. Wang Y, Yamaguchi T, Franco Saenz R, Mulrow PJ 1992 Regulation of renin gene expression in rat adrenal zona glomerulosa cells. Hypertension 20:776–781[Abstract/Free Full Text]
409. Yamaguchi T, Franco Saenz R, Mulrow PJ 1992 Effect of angiotensin II on renin production by rat adrenal glomerulosa cells in culture. Hypertension 19:263–269[Abstract/Free Full Text]
410. Shier DN, Kusano E, Stoner GD, Franco-Saenz R, Mulrow PJ 1989 Production of renin, angiotensin II, and aldosterone by adrenal explant cultures: response to potassium and converting enzyme inhibition. Endocrinology 125:486–491[Abstract/Free Full Text]
411. Deschepper CF, Mellon SH, Cumin F, Baxter JD, Ganong WF 1986 Analysis by immunocytochemistry and in situ hybridization of renin and its mRNA in kidney, testis, adrenal, and pituitary of the rat. Proc Natl Acad Sci USA 83:7552–7556[Abstract/Free Full Text]
412. Mulrow PJ 1992 Adrenal renin: regulation and function. Front Neuroendocrinol 13:47–60[Medline]
413. Mizuno K, Fukuchi S, Inagami T 1991 Distinct localization of renin and angiotensins in separate subcellular fractions of the rat adrenal cortex. Endocrinol Jpn 38:655–660[Medline]
414. Rebuffat P, Malendowicz LK, Kasprzak A, Mazzocchi G, Gottardo G, Nussdorfer GG 1991 A coupled morphological and biochemical study on the cellular localisation of the intra-adrenal renin granules in rats. Cytobios 68:7–13[Medline]
415. Rebuffat P, Rocco S, Andreis PG, Neri G, Nowak KW, Peters J, Opocher G, Mazzocchi G, Mantero F, Nussdorfer GG 1995 Morphology and function of the adrenal zona glomerulosa of transgenic rats TGR [mRen2] 27: effects of prolonged sodium restriction. J Steroid Biochem Mol Biol 54:155–162[CrossRef][Medline]
416. Peters J, Kränzlin B, Schaeffer S, Zimmer J, Resch S, Bachmann S, Gretz N, Hackenthal E 1996 Presence of renin within intramitochondrial dense bodies of the rat adrenal cortex. Am J Physiol Endocrinol Metab 271:E439–E450
417. Kon Y, Hashimoto Y, Kitagawa H, Sugimura M, Murakami K 1990 Renin immunohistochemistry in the adrenal gland of the mouse fetus and neonate. Anat Rec 227:124–131[CrossRef][Medline]
418. Kon Y, Hashimoto Y, Sugimura M, Murakami K 1993 Adrenal renin is localized in lysosomal granules. Anat Histol Embryol 22:324–327[Medline]
419. Sander M, Ganten D, Mellon SH 1994 Role of adrenal renin in the regulation of adrenal steroidogenesis by corticotropin. Proc Natl Acad Sci USA 91:148–152[Abstract/Free Full Text]
420. Yamaguchi T, Tokita Y, Franco Saenz R, Mulrow PJ, Peters J, Ganten D 1992 Zonal distribution and regulation of adrenal renin in a transgenic model of hypertension in the rat. Endocrinology 131:1955–1962[Abstract/Free Full Text]
421. Poisner AM, Suh HH, Poisner R, Hudson P, Hong JS 1992 Stimulation of renin and prorenin release from adrenal-medullary cells by PGE₂ and forskolin. FASEB J 6:A1810 (abstract)
422. Racz K, Pinet F, Gasc JM, Guyene TT, Corvol P 1992 Coexpression of renin, angiotensinogen, and their messenger ribonucleic acids in adrenal tissues. J Clin Endocrinol Metab 75:730–737[Abstract]
423. Baba K, Yamaguchi T, Nakashima H, Doi Y, Hashiba K 1988 Evidence of activator of inactive renin to active renin in adrenal zona glomerulosa cells. Jpn Circ J 52:910
424. Dzau VJ, Ellison KE, Brody T, Ingelfinger J, Pratt RE 1987 A comparative study of the distributions of renin and angiotensinogen messenger ribonucleic acids in rat and mouse tissues. Endocrinology 120:2334–2338[Abstract/Free Full Text]
425. Klemm S, Pinet F, Rioual Caroff N, Tunny T, Corvol P, Gordon R 1993 Detection of renin mRNA in aldosterone-producing adenomas by polymerase chain reaction. Clin Exp Pharmacol Physiol 20:303–305[Medline]
426. Sarzani R, Fallo F, Dessi Fulgheri P, Pistorello M, Lanari A, Paci VM, Mantero F, Rappelli A 1992 Local renin-angiotensin system in human adrenals and aldosteronomas. Hypertension 19:702–707[Abstract/Free Full Text]
427. Shionoiri H, Hirawa N, Ueda S, Himeno H, Gotoh E, Noguchi K, Fukamizu A, Seo MS, Murakami K 1992 Renin gene expression in the adrenal and kidney of patients with primary aldosteronism. J Clin Endocrinol Metab 74:103–107[Abstract]
428. Nakamaru M, Misono KS, Naruse M, Workman RJ, Inagami T 1985 A role for the adrenal renin-angiotensin system in the regulation of potassium-stimulated aldosterone production. Endocrinology 117:1772–1778[Abstract/Free Full Text]
429. Brecher AS, Shier DN, Dene H, Wang SM, Rapp JP, Franco Saenz R, Mulrow PJ 1989 Regulation of adrenal renin messenger ribonucleic acid by dietary sodium chloride. Endocrinology 124:2907–2913[Abstract/Free Full Text]
430. Holmer S, Eckardt K, Lehir M, Schricker K, Riegger G, Kurtz A 1993 Influence of dietary NaCl intake on renin gene-expression in the kidneys and adrenal-glands of rats. Pflugers Arch 425:62–67[CrossRef][Medline]
431. Yamaguchi T, Naito Z, Stoner GD, Franco Saenz R, Mulrow PJ 1990 Role of the adrenal renin-angiotensin system on adrenocorticotropic hormone- and potassium-stimulated aldosterone production by rat adrenal glomerulosa cells in monolayer culture. Hypertension 16:635–641[Abstract/Free Full Text]
432. Gupta P, Franco-Saenz R, Mulrow PJ 1992 Regulation of the adrenal renin angiotensin system in cultured bovine zona glomerulosa cells: effect of catecholamines. Endocrinology 130:2129–2134[Abstract/Free Full Text]
433. Campbell DJ, Habener JF 1989 Hybridization in situ studies of angiotensinogen gene expression in rat adrenal and lung. Endocrinology 124:218–222[Abstract/Free Full Text]
434. Phillips MI, Speakman EA, Kimura B 1993 Levels of angiotensin and molecular biology of the tissue renin angiotensin systems. Regul Pept 43:1–20[CrossRef][Medline]
435. Kifor I, Moore TJ, Fallo F, Sperling E, Chiou CY, Menachery A, Williams GH 1991 Potassium-stimulated angiotensin release from superfused adrenal capsules and enzymatically dispersed cells of the zona glomerulosa. Endocrinology 129:823–831[Abstract/Free Full Text]
436. Chiou CY, Williams GH, Kifor I 1995 Study of the rat adrenal renin-angiotensin system at a cellular-level. J Clin Invest 96:1375–1381
437. Urata H, Khosla MC, Bumpus FM, Husain A 1994 Evidence for extracellular, but not intracellular, generation of angiotensin II in the rat adrenal zona glomerulosa. Proc Natl Acad Sci USA 85:8251–8255
438. Oda H, Lotshaw DP, Franco Saenz R, Mulrow PJ 1991 Local generation of angiotensin II as a mechanism of aldosterone secretion in rat adrenal capsules. Proc Soc Exp Biol Med 196:175–177[CrossRef][Medline]
439. Fallo F, Pistorello M, Pedini F, D’Agostino D, Mantero F, Boscaro M 1991 In vitro evidence for local generation of renin and angiotensin II/III immunoreactivity by the human adrenal gland. Acta Endocrinol (Copenh) 125:319–330[Abstract/Free Full Text]
440. Menachery A, Braley LM, Kifor I, Gleason R, Williams GH 1991 Dissociation in plasma renin and adrenal ANG II and aldosterone responses to sodium restriction in rats. Am J Physiol 261:E487–E494
441. Gupta P, Franco-Saenz R, Mulrow PJ 1995 Locally generated angiotensin-II in the adrenal-gland regulates nasal, corticotropin-, and potassium-stimulated aldosterone secretion. Hypertension 25:443–448[Abstract/Free Full Text]
442. Tamura M, Piston DW, Tani M, Naruse M, Landon EJ, Inagami T 1996 Ouabain increases aldosterone release from bovine adrenal glomerulosa cells—role of renin-angiotensin system. Am J Physiol 33:E27–E35
443. Tokita Y, Franco-Saenz R, Reimann EM, Mulrow PJ 1994 Hypertension in the transgenic rat TGR(mRen-2)27 may be due to enhanced kinetics of the reaction between mouse renin and rat angiotensinogen. Hypertension 23:422–427[Abstract/Free Full Text]
444. Bader M, Zhao Y, Sander M, Lee MA, Bachmann J, Bohm M, Djavidani B, Peters J, Mullins JJ, Ganten D 1992 Role of tissue renin in the pathophysiology of hypertension in TGR(mREN2)27 rats. Hypertension 19:681–686[Abstract/Free Full Text]
445. Dzau VJ 1993 Tissue renin-angiotensin system in myocardial hypertrophy and failure. Arch Intern Med 153:937–942[Abstract/Free Full Text]
446. McEwan PE, Lindop GB, Kenyon CJ 1996 Control of cell-proliferation in the rat adrenal-gland in-vivo by the renin-angiotensin system. Am J Physiol 34:E192–E198
447. Yamada T, Horiuchi M, Dzau VJ 1996 Angiotensin-II type-2 receptor mediates programmed cell-death. Proc Natl Acad Sci USA 93:156–160[Abstract/Free Full Text]
448. Kim S, Hosoi M, Shimamoto K, Takada T, Yamamoto K 1991 Increased production of angiotensin II in the adrenal gland of stroke-prone spontaneously hypertensive rats with malignant hypertension. Biochem Biophys Res Commun 178:151–157[CrossRef][Medline]
449. Tokita Y, Yamaguchi T, Franco-Saenz R, Mulrow PJ, Ganten D 1992 Adrenal renin is released into the circulation of the hypertensive transgenic rat TGR (mRen-2)27. Trans Assoc Am Physicians 105:123–132[Medline]
450. Tokita Y, Franco-Saenz R, Mulrow PJ, Ganten D 1994 Effects of nephrectomy and adrenalectomy on the renin-angiotensin system of transgenic rats TGR(mRen2)27. Endocrinology 134:253–257[Abstract/Free Full Text]
451. Peters J, Hilgers KF, Masergluth C, Kreutz R 1996 Role of the circulating renin-angiotensin system in the pathogenesis of hypertension in transgenic rats, tgr(mren2)27. Clin Exp Hypertens 18:933–948
452. Tokita Y, Oda H, Franco-Saenz R, Mulrow PJ 1995 Role of the tissue renin-angiotensin system in the action of angiotensin-converting enzyme-inhibitors. Proc Soc Exp Biol Med 208:391–396[CrossRef][Medline]
453. Peters J, Munter K, Bader M, Hackenthal E, Mullins JJ, Ganten D 1993 Increased adrenal renin in transgenic hypertensive rats, tgr(mren2)27, and its regulation by cAMP, angiotensin-II, and calcium. J Clin Invest 91:742–747
454. Hinson JP, Vinson GP, Whitehouse BJ, Price GM 1986 Effects of stimulation on steroid output and perfusion medium flow-rate in the isolated perfused rat adrenal-gland in situ. J Endocrinol 109:279–285[Abstract/Free Full Text]
455. Melby JC 1992 Angiotensin-converting enzyme in cardiovascular and adrenal tissues and implications for successful blood-pressure management. Am J Cardiol 69:C2–C7
456. Mukhopadhyay AK 1994 Tissue pro-renin-angiotensin systems: local regulatory roles in reproductive and endocrine organs. Regul Pept 53:133–135[CrossRef]
457. Liddle GW, Estep HL, Kendall Jr JW, Williams Jr WC, Townes AW 1959 Clinical application of a new test of pituitary reserve. J Clin Endocrinol 19:875–894
458. Naito Y, Fukata J, Tamai S, Seo N, Nakai Y, Mori K, Imura H 1991 Biphasic changes in hypothalamo-pituitary-adrenal function during the early recovery period after major abdominal surgery. J Clin Endocrinol Metab 73:111–117[Abstract/Free Full Text]
459. Kehlet H, Binder CHR 1972 Alterations in distribution volume and biological half-life of cortisol during major surgery. J Clin Endocrinol Metab 36:330–333[Abstract/Free Full Text]
460. Naito Y, Tamai S, Shingu K, Shindo K, Matsui T, Segawa H, Nakai Y, Mori K 1992 Responses of plasma adrenocorticotropic hormone, cortisol, and cytokines during and after upper abdominal surgery. Anesthesiology 77:426–431[Medline]
461. Vermes I, Beishuizen A, Hampsink RM, Haanen C 1995 Dissociation of plasma adrenocorticotropin and cortisol levels in critically ill patients: possible role of endothelin and atrial natriuretic hormone. J Clin Endocrinol Metab 80:1238–1242[Abstract]
462. Siegel LM, Grinspoon SK, Garvey GJ, Bilezikan JP 1994 Sepsis and adrenal function. Trends Endocrinol Metab 5:324–328[CrossRef][Medline]
463. Lortholary O, Christeff N, Casassus P, Thobein N, Veyssier P, Trogoff B, Tocci O, Brauner M, Nunez CA, Guillouin L 1996 Hypothalamo-pituitary-adrenal function in human immunodeficiency virus infected men. J Clin Endocrinol Metab 81:791–796[Abstract]
464. Torpy DJ, Chrousos GP 1997 General adaptation syndrome: an overview. In: Ober KP (ed) Endocrinology of Critical Disease. Humana Press Inc. Totowa, NJ, pp 1–24
465. Soni A, Pepper GM, Wyrwinski PM, Ramirez NE, Simon R, Pina T, Gruenspan H, Vaca CE 1995 Adrenal insufficiency occurring during septic shock: incidence, outcome, and relationship to peripheral cytokine levels. Am J Med 98:266–271[CrossRef][Medline]
466. Udelsman R, Norton JA, Jelenich SE, Goldstein DS, Linehan WM, Loriaux DL, Chrousos GP 1987 Responses of the hypothalamic-pituitary-adrenal and renin-angiotensin axes and the sympathetic system during controlled surgical and anesthetic stress. J Clin Endocrinol Metab 64:986–994[Abstract/Free Full Text]
467. Lentle BC, Thomas JP 1964 Adrenal function and the complications of diabetes mellitus. Lancet 2:544–549[CrossRef][Medline]
468. Amsterdam JD, Marinelli DL, Arger P, Winokur A 1987 Assessment of adrenal gland volume by computed tomography in depressed patients and healthy volunteers: a pilot study. Psychiatry Res 21:189–197[CrossRef][Medline]
469. Gold PW, Chrousos GP, Kellner CH, Post RM, Augerinos P, Schulte HM, Oldfield E, Loriaux DL 1984 Psychiatric implications of basic and clinical studies with corticotropin-releasing factor. Am J Psychiatry 141:619–627[Abstract/Free Full Text]
470. Gold PW, Goodwin FK, Chrousos GP 1988 Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (2). N Engl J Med 319:413–420[Abstract]
471. Ehrhart-Bornstein M, Bornstein SR 1998 Regulation of adrenocortical function by the sympathoadrenal system: physiology and pathology. In: Margioris AN, Chrousos GP (eds) Adrenal Disorders. Humana Press, Totowa, NJ, in press
472. Carmichael SW, Stoddard SL, Kelly PJ 1994 Technical aspects of transplantation of the adrenal medulla to the caudate nucleus as a treatment for Parkinson’s disease. Methods Neurosci 21:272–277
473. Burak N, Loesch J, Costa J 1959 Adrenocortical adenoma, clinically simulating pheochromocytoma. NY J Med 59:1849–1851
474. Walters G, Wyatt GB, Kelleher J 1962 Carcinoma of the adrenal cortex presenting as a pheochromocytoma: report of a case. J Clin Endocrinol 22:575–580
475. Alsabeh R, Mazoujian G, Goates J, Medeiros LJ, Weiss LM 1995 Adrenal cortical tumors clinically mimicking pheochromocytoma. Am J Clin Pathol 104:382–390[Medline]
476. Sparagana M, Feldman JM, Molnar Z 1987 An unusual pheochromocytoma associated with an androgen secreting adrenocortical adenoma. Evaluation of its polypeptide hormone, catecholamine, and enzyme characteristics. Cancer 60:223–231[CrossRef][Medline]
477. Robinson PL, Baker-Bates ET 1954 Adrenal cortical carcinoma simulating a pheochromocytoma. Br J Surg 41:399–403
478. Schroeder JO, Asa SL, Kovacs K, Killinger D, Hadley GL, Volpe R 1984 Report of a case of pheochromocytoma producing immunoreactive ACTH and beta-endorphin. J Endocrinol Metab Invest 7:117–121
479. Schteingart DE, Conn JW, Orth DN, Harrison TS, Fox JE, Bookstein JJ 1972 Secretion of ACTH and ß-MSH by an adrenal medullary paraganglioma. J Clin Endocrinol Metab 34:676–683[Abstract/Free Full Text]
480. Forman BH, Marban E, Kayne RD, Passarelli NM, Bobrow SN, Livolsi VA, Merino M, Minor M, Farber LR 1979 Ectopic ACTH syndrome due to pheochromocytoma: case report and review of the literature. Yale J Biol Med 52:181–189[Medline]
481. Spark RF, Connolly PB, Gluckin DS, White R, Sacks B, Landsberg L 1979 ACTH secretion from a functioning pheochromocytoma. N Engl J Med 301:416–418[Medline]
482. Hartmann CA, Gross U, Stein H 1992 Cushing syndrome-associated pheochromocytoma and adrenal carcinoma. An immunohistological investigation. Pathol Res Pract 188:287–295[Medline]
483. Aiba M, Hirayama A, Ito Y, Fujimoto Y, Nakagami Y, Demura H, Shizume K 1988 A compound adrenal medullary tumor (pheochromocytoma and ganglioneuroma) and a cortical adenoma in the ipsilateral adrenal gland. A case report with enzyme histochemical and immunohistochemical studies. Am J Surg Pathol 12:559–566[Medline]
484. Beaser RS, Guay AT, Lee AK, Silverman ML, Flint LD 1986 An adrenocorticotropic hormone-producing pheochromocytoma: diagnostic and immunohistochemical studies. J Urol 135:10–13[Medline]
485. Hassoun J, Monges G, Giraud P, Henry JF, Charpin C, Payan H, Toga M 1984 Immunohistochemical study of pheochromocytomas. An investigation of methionine-enkephalin, vasoactive intestinal peptide, somatostatin, corticotropin, beta-endorphin, and calcitonin in 16 tumors. Am J Pathol 114:56–63[Abstract]
486. Lacroix A, Tremblay J, Rousseau G, Bouvier M, Hamet P 1997 Propranolol therapy for ectopic ß-adrenergic receptors in adrenal Cushing’s syndrome. N Engl J Med 337:1429–1434[Free Full Text]
487. Perraudin V, Delarue C, De Keyzer Y, Bertagna X, Kuhn J-M, Contesse V, Clauser E, Vaudry H 1995 Vasopressin-responsive adrenocortical tumor in a mild Cushings syndrome: in vivo and in vitro studies. J Clin Endocrinol Metab 80:2661–2667[Abstract]
488. Lacroix A, Tremblay J, Touyz RM, Deng LY, Lariviere R, Cusson JR, Schiffrin EL, Hamet P 1997 Abnormal adrenal and vascular responses to vasopressin mediated by a V1-vasopressin receptor in a patient with adrenocorticotropin-independent macronodular adrenal hyperplasia, Cushing’s syndrome, and orthostatic hypotension. J Clin Endocrinol Metab 82:2414–2422[Abstract/Free Full Text]
489. Lacroix A, Bolté E, Tremblay J, Dupré J, Poitras P, Fournier H, Garon J, Garrel D, Bayard F, Taillefer R, Flanagan RJ, Hamet P 1992 Gastric inhibitory polypeptide-dependent cortisol hypersecretion—a new cause of Cushings syndrome. N Engl J Med 327:974–980[Abstract]
490. Reznik Y, Allali-Zerah V, Chayvialle JA, Leroyer R, Leymarie P, Travert G, Lebrethon MC, Budi I, Balliere AM, Mahoudeau J 1992 Food-dependent Cushing’s syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide. N Engl J Med 327:981–986[Abstract]
491. Jagger PI 1997 Adrenocortical response to critical illness: the renin-aldosterone axis. In: Ober KP (ed) Contemporary Endocrinology: Endocrinology of Critical Disease. Humana Press, Inc, Totowa, NJ, pp 137–154
492. Carey RM 1985 Physiologic and possible pathologic relevance of dopaminergic mechanisms in the control of aldoserone secretion. In: Mantera F, Biglien EG, Funder JW, Scoggins BA (eds) The Adrenal Gland and Hypertension. Raven, New York, pp 55–65
493. Brown RD, Wisgerhof M, Carpenter PC, Brown G, Jiang NS, Kao P, Hegstad R 1979 Adrenal sensitivity to angiotensin II and undiscovered aldosterone stimulating factors in hypertension. J Steroid Biochem 11:1043–1050[CrossRef][Medline]
494. Carey RM, Ayers CR, Vaughan EDJ, Peach MJ, Herf S 1979 Activity of [des-aspartyl¹]-angiotensin II in primary aldosteronism. J Clin Invest 63:718–726
495. Sowers J, Catania R, Paris J, Tuck M 1982 Effects of bromocriptine on renin, aldosterone, and prolactin responses to posture and metoclopramide in idiopathic edema: possible therapeutic approach. J Clin Endocrinol Metab 54:510–516[Abstract/Free Full Text]
496. Guillon G, Trueba M, Joubert D, Grazzini E, Chouinard L, Côte M, Payet MD, Manzoni O, Barberis C, Robert M, Gallo-Payet N 1995 Vasopressin stimulates steroid secretion in human adrenal glands: comparison with angiotensin II effect. Endocrinology 136:1285–1295[Abstract]
497. Duntas L, Bornstein SR, Scherbaum WA, Holst JJ 1993 Atrial natriuretic peptide-like immunoreactive material (ANP-LI) is released from the adrenal gland by splanchnic nerve stimulation. Exp Clin Endocrinol 101:371–373[Medline]
498. Bornstein SR, Brown JW, Carballeira A, Goodman J, Scherbaum WA, Fishman LM 1996 Ultrastructural dynamics of mitochondrial morphology in varying functional forms of human adrenal cortical adenoma. Horm Metab Res 28:177–182[Medline]
499. Lefebvre H, Contesse V, Delarue C, Legrand A, Kuhn JM, Vaudry H, Wolf LM 1995 The serotonin-4 receptor agonist cisapride and angiotensin-II exert additive effects on aldosterone secretion in normal man. J Clin Endocrinol Metab 80:504–507[Abstract]
500. Dumuis A, Sebben M, Bockaert J 1989 The gastrointestinal prokinetic benzamide derivatives are agonists at the non-classical 5-HT receptor (5-HT₄) positively coupled to adenylate cyclase in neurons. Naunyn Schmiedebergs Arch Pharmacol 340:403–410[CrossRef][Medline]
501. Sommers DK, Snyman JR, van Wyk M 1996 Effects of metoclopramide and tropisetron on aldosterone secretion possibly due to agonism and antagonism at the 5-HT₄ receptor. Eur J Clin Pharmacol 50:371–373[CrossRef][Medline]
502. Marx C, Bornstein SR, Wolkersdörfer GW, Peter M, Sippell WG, Scherbaum WA 1997 Relevance of major histocompatibility complex class II expression as a hallmark for the cellular differentiation in the human adrenal cortex. J Clin Endocrinol Metab 82:3136–3140[Abstract/Free Full Text]
503. Wolkersdörfer GW, Ehrhart-Bornstein M, Brauer S, Marx C, Scherbaum WA, Bornstein SR 1996 Differential regulation of apoptosis in the normal human adrenal gland. J Clin Endocrinol Metab 81:4129–4136[Abstract/Free Full Text]
504. Marx C, Wolkersdörfer GW, Brown J, Scherbaum WA, Bornstein SR 1996 MHC class II expression—a new tool to assess dignity in adrenocortical tumours. J Clin Endocrinol Metab 81:4488–4491[Abstract]
505. Mokuda O, Sakamoto Y, Kawagoe R, Ubukata E, Shimizu N 1992 Epinephrine augments cortisol secretion from isolated perfused adrenal glands of guinea pigs. Am J Physiol 262:E806–E809
506. Kawamura M, Nakamichi N, Imagawa N, Tanaka Y, Tomita C, Matsuba M 1984 Effect of adrenaline on steroidogenesis in primary cultured bovine adrenocortical cells. Jpn J Pharmacol 36:35–41[Medline]
507. Walker SW, Lightly ERT, Clyne C, Williams BC, Bird IM 1991 Adrenergic and cholinergic regulation of cortisol secretion from the zona fasciculata/reticularis of bovine adrenal cortex. Endocr Res 17:237–265[Medline]
508. Walker SW, Lightly ERT, Milner SW, Williams BC 1988 Catecholamine stimulation of cortisol secretion by 3-day primary cultures of purified zona fasciculata/reticularis cells isolated from bovine adrenal cortex. Mol Cell Endocrinol 57:139–147[CrossRef][Medline]
509. De Léan A, Rácz K, McNicoll N, Desrosiers ML 1984 Direct ß-adrenergic stimulation of aldosterone secretion in cultured bovine adrenal subcapsular cells. Endocrinology 115:485–492[Abstract/Free Full Text]
510. Pratt JH, Turner DA, McAteer JA, Henry DP 1985 ß-adrenergic stimulation of aldosterone production by rat adrenal capsular explants. Endocrinology 117:1189–1194[Abstract/Free Full Text]
511. Pratt JH, McAteer JA 1989 Beta-adrenergic enhancement of angiotensin II-stimulated aldosterone secretion. Life Sci 44:2089–2095[CrossRef][Medline]
512. Horiuchi T, Tanaka K, Shimizu N 1987 Effect of catecholamine on aldosterone release in isolated rat glomerulosa cell suspensions. Life Sci 40:2421–2428[CrossRef][Medline]
513. Mazzocchi G, Gottardo G, Nussdorfer GG 1997 Catecholamines stimulate steroid secretion of dispersed fowl adrenocortical cells, acting through the beta-receptor subtype. Horm Metab Res 29:190–192[Medline]
514. Hanke W, Kloas W 1995 Comparative aspects of regulation and function of the adrenal complex in different groups of vertebrates. Horm Metab Res 27:389–397[Medline]
515. Porter ID, Whitehouse BJ, Price GM, Hinson JP, Vinson GP 1992 Effects of dopamine, high potassium concentration and field stimulation on the secretion of aldosterone by the perfused rat adrenal gland. J Endocrinol 133:275–282[Abstract/Free Full Text]
516. Aguilera G, Catt KJ 1984 Dopaminergic modulation of aldosterone secretion in the rat. Endocrinology 114:176–181[Abstract/Free Full Text]
517. Braley LM, Menachery AI, Williams GH 1983 Specificity of metoclopramide in assessing the role of dopamine in regulating aldosterone secretion. Endocrinology 112:1352–1357[Abstract/Free Full Text]
518. Gallo-Payet N, Chouinard L, Balestre MN, Guillon G 1990 Dual effects of dopamine in rat adrenal glomerulosa cells. Biochem Biophys Res Commun 172:1100–1108[CrossRef][Medline]
519. Rácz K, Buu NT, Kuchel O, De Léan A 1984 Dopamine-3-sulfate inhibits aldosterone sescretion in cultured bovine adrenal cells. Am J Physiol 247:E431–E435
520. Sequiera SJ, McKenna TJ 1985 Examination of the effects of epinephrine, norepinephrine and dopamine on aldosterone production in bovine glomerulosa cells in vitro. Endocrinology 117:1947–1952[Abstract/Free Full Text]
521. McKenna TJ, Island DP, Nicholson WE, Liddle GW 1979 Dopamine inhibits angiotensin-stimulated aldosterone biosynthesis in bovine adrenal cells. J Clin Invest 84:287–291
522. Morra M, Leboulenger F, Vaudry H 1992 Characterization of dopamine receptors associated with steroid secretion in frog adrenocortical cells. J Mol Endocrinol 8:43–52[Abstract/Free Full Text]
523. Morra M, Leboulenger F, Homo-Delarche F, Netchitailo P, Vaudry H 1989 Dopamine inhibits corticosteroid secretion in frog adrenocortical cells: evidence for the involvement of prostaglandins in the mechanism of action of dopamine. Life Sci 45:175–181[CrossRef][Medline]
524. Morra M, Leboulenger F, Desrues L, Tonon MC, Vaudry H 1991 Dopamine inhibits inositol phosphate production, arachidonic acid formation, and corticosteroid release by frog adrenal gland through a pertussis toxin-sensitive G-protein. Endocrinology 128:2625–2632[Abstract/Free Full Text]
525. Jones CT, Edwards AV, Bloom SR 1991 Endocrine responses to intraaortic infusions of acetylcholine. J Physiol (Lond) 439:481–499[Abstract/Free Full Text]
526. Jones CT, Edwards AV 1991 Muscarinic adrenal responses to acetylcholine in conscious calves. J Physiol (Lond) 444:605–614[Abstract/Free Full Text]
527. Edwards AV, Jones CT 1993 Adrenal-cortical and medullary responses to acetylcholine and vasoactive-intestinal-peptide in conscious calves. J Physiol (Lond) 468:515–527[Abstract/Free Full Text]
528. Porter ID, Whitehouse BJ, Taylor AH, Nussey SS 1988 Effect of arginine vasopressin and oxytocin on acetylcholine-stimulation of corticosteroid and catecholamine secretion from the rat adrenal gland perfused in situ. Neuropeptides 12:265–271[CrossRef][Medline]
529. Hadjian AJ, Guidicelli C, Chambaz EM 1982 Cholinergic muscarinic stimulation of steroidogenesis in bovine adrenal cortex fasciculata cell suspensions. Biochem Biophys Acta 714:157–163[Medline]
530. Kojima I, Kojima K, Shibata H, Ogata E 1986 Mechanism of cholinergic stimulation of aldosterone secretion in bovine adrenal glomerulosa cells. Endocrinology 119:284–291[Abstract/Free Full Text]
531. Walker SW, Strachan MW, Lightly ER, Williams BC, Bird IM 1990 Acetylcholine stimulates cortisol secretion through the M3 muscarinic receptor linked to a poly-phosphoinositide-specific phospholipase C in bovine adrenal fasciculata/reticularis cells. Mol Cell Endocrinol 72:227–238[CrossRef][Medline]
532. Feuilloley M, Netchitailo P, Delarue C, Leboulenger F, Benyamina M, Pelletier G, Vaudry H 1988 Involvement of the cytoskeleton in the steroidogenic response of frog adrenal glands to angiotensin II, acetylcholine and serotonin. J Endocrinol 118:365–374[Abstract/Free Full Text]
533. Benyamina M, Leboulenger F, Lirhmann I, Delarue C, Feuilloley M, Vaudry H 1987 Acetylcholine stimulates steroidogenesis in isolated frog adrenal gland through muscarinic receptors: evidence for a desensitization mechanism. J Endocrinol 113:339–348[Abstract/Free Full Text]
534. Delarue C, Leboulenger F, Homo-Delarche F, Benyamina M, Lihrmann I, Perroteau I, Vaudry H 1986 Involvement of prostaglandins in the response of frog adrenocortical cells to muscarinic receptor activation. Prostaglandins 32:87–91[CrossRef][Medline]
535. Rosenkrantz H 1959 A direct influence of 5-hydroxytryptamine on the adrenal cortex. Endocrinology 64:355–362
536. Rosenkrantz H, Laferte RC 1960 Further observations on the relationship between serotonin and the adrenal. Endocrinology 66:832–841[Abstract/Free Full Text]
537. Connors M, Rosenkrantz H 1962 Serotonin uptake and action on the adrenal cortex. Endocrinology 71:407–413
538. Lefebvre H, Contesse V, Delarue C, Soubrane C, Legrand A, Kuhn J, Wolf L, Vaudry H 1993 Effect of the serotonin-4 receptor agonist zacopride on aldosterone secretion from human adrenal cortex: in vivo and in vitro studies. J Clin Endocrinol Metab 77:1662–1666[Abstract]
539. Verdesca AS, Westermann CD, Crampton RS, Black WC, Nedelijkovic RI, Hilton JG 1961 Direct adrenocortical stimulatory effect of serotonin. Am J Physiol 201:1065–1067[Abstract/Free Full Text]
540. Haning Tait SAS, Tait JF 1970 In vitro effects of ACTH, angiotensin II, serotonin and potassium on steroid output and conversion of corticosterone to aldosterone by isolated adrenal cells. Endocrinology 87:1147–1167[Abstract/Free Full Text]
541. Al Dujaili EAS, Boscaro M, Edwards CRW 1982 An in vitro stimulatory effect of indolamines on aldosterone biosynthesis in the rat. J Steroid Biochem 17:351–355[CrossRef][Medline]
542. Matsuoka H, Ishii M, Goto A, Sugimoto T 1985 Role of serotonin type 2 receptors in regulation of aldosterone production. Am J Physiol 249:E234–E238
543. Rocco S, Cimolato M, Opocher G, Mantero F 1992 Effects of serotonin, ANF and endothelin on adrenal steroidogenesis. In: Saez JM, Brownie AC, Capponi EM, Chambaz EM, Mantero F (eds) Cellular and Molecular Biology of the Adrenal Cortex. John Libbey Eurotext, London, pp 293–305
544. Contesse V, Hamel C, Delarue C, Lefebvre H, Vaudry H 1994 Effect of a series of 5-HT4 receptor agonists and antagonists on steroid secretion by the adrenal gland in vitro. Eur J Pharmacol 265:127–133
545. Idres S, Delarue C, Lefebvre H, Larcher A, Feuilloley M, Vaudry H 1989 Mechanism of action of serotonin on frog adrenal cortex. J Steroid Biochem 34:547–550[CrossRef][Medline]
546. Leboulenger F, Benyamina M, Delarue C, Netchitailo P, Saint-Pierre S, Vaudry H 1988 Neuronal and paracrine regulation of adrenal steroidogenesis: interactions between acetylcholine, serotonin and vasoactive intestinal peptide (VIP) on corticosteroid production by frog interrenal tissue. Brain Res 453:103–109[CrossRef][Medline]
547. Contesse V, Hamel C, Lefebvre H, Dumuis A, Vaudry H, Delarue C 1996 Activation of 5-hydroxytryptamine₄ receptors causes calcium influx in adrenocortical cells: involvement of calcium in 5-hydroxytryptamine-induced steroid secretion. Mol Pharmacol 49:481–493[Abstract]
548. Lefebvre H, Contesse V, Delarue C, Kuhn JM, Vaudry H 1994 Serotonergic control of corticosteroid secretion. J Serotonin Res 3:189–198
549. Bornstein SR, Ehrhart-Bornstein M, Stromeyer H, Adler G, Scherbaum WA, Holst JJ 1993 Vasoactive intestinal peptide (VIP) stimulates androstenedione release in isolated perfused pig adrenals. Life Sci 52:135–140[CrossRef][Medline]
550. Bornstein SR, Haidan A, Ehrhart-Bornstein M 1996 Cellular communication in the neuro-adrenocortical axis: role of vasoactive intestinal polypeptide (VIP). Endocr Res 22:819–829[Medline]
551. Bloom SR, Edwards AV, Jones CT 1987 Adrenal cortical responses to vasoactive intestinal peptide in conscious hypophysectomized calves. J Physiol 391:441–450[Abstract/Free Full Text]
552. Li ZG, Queen G, LaBella FS 1990 Adrenocorticotropin, vasoactive intestinal polypeptide, growth hormone-releasing factor, and dynorphin compete for common receptors in brain and adrenal. Endocrinology 126:1327–1333[Abstract/Free Full Text]
553. Hinson JP, Purbrick A, Cameron LA, Kapas S 1994 The role of neuropeptides in the regulation of adrenal zona fasciculata/reticularis function. Effects of vasoactive intestinal polypeptide, substance P, neuropeptide Y, met- and leu-enkephalin and neurotensin on corticosterone secretion in the intact perfused rat adrenal gland in situ. Neuropeptides 26:391–397[CrossRef][Medline]
554. Hinson JP, Cameron LA, Purbrick A, Kapas S 1994 The role of neuropeptides in the regulation of adrenal zona glomerulosa function: effects of substance P, neuropeptide Y, neurotensin, met-enkephalin, leu-enkephalin and corticotrophin-releasing hormone on aldosterone secretion in the intact perfused rat adrenal. J Endocrinol 140:91–96[Abstract/Free Full Text]
555. Cunningham LA, Holzwarth MA 1988 Vasoactive intestinal peptide stimulates adrenal aldosterone and corticosterone secretion. Endocrinology 122:2090–2097[Abstract/Free Full Text]
556. Nussdorfer GG, Mazzocchi G 1987 Vasoactive intestinal peptide (VIP) stimulates aldosterone secretion by rat adrenal gland in vivo. J Steroid Biochem 26:203–205[CrossRef][Medline]
557. Mazzocchi G, Malendowicz LK, Meneghelli V, Gottardo G, Nussdorfer GG 1993 Vasoactive intestinal polypeptide (VIP) stimulates hormonal secretion of the rat adrenal cortex in vitro: evidence that adrenal chromaffin cells are involved in the mediation of mineralocorticoid, but not glucocorticoid secretagogue action of VIP. Biomed Res 14:435–440
558. Mazzocchi G, Malendowicz LK, Nussdorfer GG 1994 Stimulatory effect of vasoactive intestinal peptide (VIP) on the secretory activity of dispersed rat adrenocortical cells. Evidence for the interaction of VIP with ACTH receptors. J Steroid Biochem Mol Biol 48:507–510[CrossRef][Medline]
559. Leboulenger F, Leroux P, Delarue C, Tonon MC, Charnay Y, Dubois PM, Coy DH, Vaudry H 1983 Co-localization of vasoactive intestinal peptide (VIP) and enkephalins in chromaffin cells of the adrenal gland of amphibia. Stimulation of corticosteroid production by VIP. Life Sci 32:375–383[CrossRef][Medline]
560. Holst JJ, Ehrhart-Bornstein M, Messell T, Poulsen SS, Harling H 1991 Release of galanin from isolated perfused porcine adrenal glands. Role of splanchnic nerves. Am J Physiol 261:E31–E40
561. Mazzocchi G, Malendowicz LK, Rebuffat P, Nussdorfer GG 1992 Effects of galanin of the secretory activity on the rat adrenal cortex: in vivo and in vitro studies. Res Exp Med 192:373–381[Medline]
562. Mazzocchi G, Malendowicz LK, Nussdorfer GG 1992 Galanin stimulates corticosterone secretion by isolated rat adrenocortical cells. Biomed Res 13:181–184
563. Gasman S, Vaudry H, Cartier F, Tramu G, Fournier A, Conlon JM, Delarue C 1996 Localization, identification, and action of galanin in the frog adrenal gland. Endocrinology 137:5311–5318[Abstract]
564. Lesniewska B, Nussdorfer GG, Nowak M, Malendowicz LK 1992 Comparison of the effects of neurotensin and vasopressin on the adrenal cortex of dexamethasone-suppressed rats. Neuropeptides 23:9–13[CrossRef][Medline]
565. Lesniewska B, Nowak M, Miskowiak B, Nussdorfer GG, Malendowicz LK 1991 Effects of arginine vasopressin on the pituitary-adrenocortical axis on intact and dexamethasone-suppressed rats. Exp Pathol 43:181–188[Medline]
566. Hinson JP, Vinson GP, Porter ID, Whitehouse BJ 1987 Oxitocin and arginine vasopressin stimulate steroid secretion by the isolated perfused rat adrenal gland. Neuropeptides 10:1–7[CrossRef][Medline]
567. Payet N, Lehoux JG 1980 A comparative study of the role of vasopressin and ACTH in the regulation of growth and function of rat adrenal glands. J Steroid Biochem 12:461–467[CrossRef][Medline]
568. Payet N, Deziel Y, Lehoux JG 1984 Vasopressin: a potent growth factor in adrenal glomerulosa cells in culture. J Steroid Biochem 20:449–454[CrossRef][Medline]
569. Woodcock EA, McLeod JK, Johnston CI 1986 Vasopressin stimulates phosphatidylinositol turnover and aldosterone synthesis in rat adrenal glomerulosa cells: comparison with angiotensin II. Endocrinology 118:2432–2436[Abstract/Free Full Text]
570. Gallo-Payet N, Guillon G, Balestre MN, Jard S 1986 Vasopressin induces breakdown of membrane phosphoinositides in adrenal glomerulosa and fasciculata cells. Endocrinology 119:1042–1047[Abstract/Free Full Text]
571. Guillon G, Balestre MN, Chouinard L, Gallo-Payet N 1990 Involvement of distinct G-proteins in the action of vasopressin on rat glomerulosa cells. Endocrinology 126:1699–1708[Abstract/Free Full Text]
572. Perraudin V, Delarue C, Lefebvre H, Contesse V, Kuhn J, Vaudry H 1993 Vasopressin stimulates cortisol secretion from human adrenocortical tissue through activation of V1 receptors. J Clin Endocrinol Metab 76:1522–1528[Abstract]
573. Mazzocchi G, Nussdorfer GG 1987 Neuropeptide-Y acutely stimulates rat zona glomerulosa in vivo. Neuropeptides 9:257–262[CrossRef][Medline]
574. Rebuffat P, Malendowicz LK, Belloni AS, Mazzocchi G, Nussdorfer GG 1988 Long-term stimulatory effect of neuropeptide Y on the growth and steroidogenic capacity of rat adrenal zona glomerulosa. Neuropeptides 11:133–136[CrossRef][Medline]
575. Neri G, Andreis PG, Nussdorfer GG 1990 Effects of neuropeptide-Y and substance-P on the secretory activity of dispersed zona-glomerulosa cells of rat adrenal gland. Neuropeptides 17:121–125[CrossRef][Medline]
576. Bernet F, Maubert E, Bernard J, Montel V, Dupouy JP 1994 In vitro steroidogenic effects of neuropeptide Y (NPY1–36), Y1 and Y2 receptor agonists (Leu31-Pro34 NPY, NPY18–36) and peptide YY (PYY) on rat adrenal capsule/zona glomerulosa. Regul Pept 52:187–193[CrossRef][Medline]
577. Mazzocchi G, Malendowicz LK, Macchi K, Gottardo G, Nussdorfer GG 1996 Further investigations on the effects of neuropeptide-Y (NPY) on the secretion and growth of rat adrenal zona glomerulosa. Neuropeptides 30:19–27[CrossRef][Medline]
578. Malendowicz LK, Lésniewska B, Miskowiak B 1990 Neuropeptide Y inhibits corticosterone secretion by isolated rat adrenocortical cells. Experentia 46:721–722[CrossRef][Medline]
579. Neri G, Andreis PG, Malendowicz LK, Nussdorfer GG 1991 Acute action of poypeptide-YY (PYY) on rat adrenocortical cells—in vivo vs. in vitro effects. Neuropeptides 19:73–76[CrossRef][Medline]
580. Mazzocchi G, Malendowicz LK, Andreis PG, Meneghelli V, Markowska A, Belloni AS, Nussdorfer GG 1994 Neuropeptide K enhances glucocorticoid release by acting directly on the rat adrenal gland: the possible involvement of zona medullaris. Brain Res 661:91–96[CrossRef][Medline]
581. Nussdorfer GG, Malendowicz LK, Belloni AS, Mazzocchi G, Rebuffat P 1988 Effects of substance P on the rat adrenal zona glomerulosa in vivo. Peptides 9:1145–1149[CrossRef][Medline]
582. Yoshida T, Mio M, Tasaka K 1992 Cortisol secretion induced by substance P from bovine adrenocortical cells and its inhibition by calmodulin inhibitors. Biochem Pharmacol 43:513–517[CrossRef][Medline]
583. Leboulenger F, Vaglini L, Conlon JM, Homo-Delarche F, Wang Y, Kerdelhue B, Pelletier G, Vaudry H 1993 Immunohistochemical distribution, biochemical characterization, and biological action of tachykinins in the frog adrenal gland. Endocrinology 133:1999–2008[Abstract/Free Full Text]
584. Kodjo MK, Leboulenger F, Porcedda P, Lamacz M, Conlon JM, Pelletier G, Vaudry H 1995 Evidence for the involvement of chromaffin cells in the stimulatory effect of tachykinins on corticosteroid secretion by the frog adrenal gland. Endocrinology 136:3253–3259[Abstract]
585. Kodjo MK, Leboulenger F, Morra M, Conlon JM, Vaudry H 1996 Pharmacological profile of the tachykinin receptor involved in the stimulation of corticosteroid secretion in the frog Rana ridibunda. J Steroid Biochem Mol Biol 57:329–335[CrossRef][Medline]
586. Bodart V, Babinski K, Ong H, De Léan A 1997 Comparative effect of pituitary adenylate cyclase-activating polypeptide on aldosterone secretion in normal bovine and human tumorous adrenal cells. Endocrinology 138:566–573[Abstract/Free Full Text]
587. Mazzocchi G, Gottardo G, Nussdorfer GG 1997 Pituitary adenylate cyclase-activating peptide enhances steroid production by interrenal glands in fowls: evidence for an indirect mechanism of action. Horm Metab Res 29:86–87[Medline]
588. Yon L, Feuilloley M, Chartrel N, Arimura A, Fournier A, Vaudry H 1993 Localization, characterization and activity of pituitary adenylate cyclase-activating polypeptide in the frog adrenal gland. J Endocrinol 139:183–194[Abstract/Free Full Text]
589. Mazzocchi G, Robba C, Rebuffat P, Gottardo G, Nussdorfer GG 1985 Effect of somatostatin on the zona glomerulosa of rats treated with angiotensin-II or captoril—stereology and plasma-hormone concentrations. J Steroid Biochem 23:353–356[CrossRef][Medline]
590. Rebuffat P, Belloni AS, Musajo FG, Rocco S, Markowska A, Mazzocchi G, Nussdorfer GG 1994 Evidence that endogenous somatostatin (SRIF) exerts an inhibitory control on the function and growth of rat adrenal zona glomerulosa. The possible involvement of zona medullaris as a source of endogenous SRIF. J Steroid Biochem Mol Biol 48:353–360[CrossRef][Medline]
591. Aguilera G, Parker DS, Catt KJ 1982 Characterization of somatostatin receptors in the rat adrenal glomerulosa zone. Endocrinology 111:1376–1384[Abstract/Free Full Text]
592. Aguilera G, Harwood JP, Catt KJ 1981 Somatostatin modulates effects of angiotensin II in adrenal glomerulosa zone. Nature 292:262–263[CrossRef][Medline]
593. Nawata H, Ohashi M, Haji M, Takayanagi R, Higuchi K, Fujio N, Hashiguchi T, Ogo A, Nakao R, Ohnaka K, Nishi Y 1991 Atrial and brain natriuretic peptide in adrenal steroidogenesis. J Steroid Biochem Mol Biol 40:367–379[CrossRef][Medline]
594. Rácz K, Kuchel O, Cantin M, De Léan A 1985 Atrial natriuretic factor inhibits the early pathway of steroid biosynthesis in bovine adrenal cortex. FEBS Lett 192:19–22[CrossRef][Medline]
595. De Léan A, Rácz K, Gutkowska J, Nguyen TT, Cantin M, Genest J 1984 Specific receptor-mediated inhibiton by synthetic atrial natriuretic factor of hormone-stimulated stereoidogenesis in cultured bovine adrenal cells. Endocrinology 115:1636[Abstract/Free Full Text]
596. Higuchi K, Nawata H, Kato K, Ibayashi H, Matsuo H 1986 -Human atrial natriuretic polypeptide inhibits steroidogenesis in cultured human adrenal cells. J Clin Endocrinol Metab 62:941[Abstract/Free Full Text]
597. Heisler S, Tallerico-Melnyk T, Yip C, Schimmer BP 1989 Y-1 adrenocortical tumor cells contain atrial natriuretic peptide receptors which regulate cyclic nucleotide metabolism and steroidogenesis. Endocrinology 125:2235–2243[Abstract/Free Full Text]
598. Kocsis JF, McIlroy PJ, Carsia RV 1995 Atrial natriuretic peptide stimulates aldosterone production by turkey (Meleagris gallopavo) adrenal steroidogenic cells. Gen Comp Endocrinol 99:364–372[CrossRef][Medline]
599. Lihrmann I, Netchitailo P, Feuilloley M, Cantin M, Delarue C, Leboulenger F, De Lean A, Vaudry H 1988 Effect of atrial natriuretic factor on corticosteroid production by perifused frog interrenal slices. Gen Comp Endocrinol 71:55–62[CrossRef][Medline]
600. Bloom SR, Edwards AV, Jones CT 1989 Adrenal responses to calcitonin gene-related peptide in conscious hypophysectomized calves. J Physiol (Lond) 409:29–41[Abstract/Free Full Text]
601. Esneu M, Delarue C, Remy-Jouet I, Manzardo E, Fasolo A, Fournier A, Saint-Pierre S, Conlon JM, Vaudry H 1994 Localization, identification, and action of calcitonin gene-related peptide in the frog adrenal gland. Endocrinology 135:423–430[Abstract]
602. Neri G, Andreis PG, Malendowicz LK, Nussdorfer GG 1990 Inhibitory effect of dynorphin on the secretory activity of isolated rat adrenocortical cells. Biomed Res 11:277–281
603. Rácz K, Gláz E, Kiss R, Lada G, Varga I, Vida S, Di Gleria K, Medzihradszky K, Lichtwald K, Vescei P 1980 Adrenal cortex—a newly recognized peripheral site of action of enkephalins. Biochem Biophys Res Commun 97:1346–1353[CrossRef][Medline]
604. Hervonen A, Pelto-Huikko M, Linnoila I 1980 Ultrastructural localization of enkephalin-like immunoreactivity in the rat adrenal medulla. Am J Anat 157:445–448[CrossRef][Medline]
605. Hervonen A, Linnoila I, Vaalasti A, Alho H, Pelto-Huikko M 1989 Electron microscopic localization of enkephalin-like immunoreactivity in the human adrenal medulla. J Electron Microsc Techn 12:380–388[CrossRef][Medline]
606. Pelto-Huikko M, Salminen T, Hervonen A 1987 Localization of enkephalin- and neurotensin-like immunoreactivities in cat adrenal medulla. Histochemistry 88:31–36[CrossRef][Medline]
607. Varndell IM, Tapia FJ, De Mey J, Rush RA, Bloom SR, Polak JM 1982 Electron immunocytochemical localization of enkephalin-like material in catecholamine-containing cells of the carotid body, the adrenal medulla, and in pheochromocytomas of man and other mammals. J Histochem Cytochem 30:682–690[Abstract]
608. Leboulenger F, Charnay Y, Dubois PM, Rossier J, Vaudry H 1984 Presence of proenkephalin in chromaffin cells of the frog adrenal gland. Neurochem Int 6:773–777[CrossRef]
609. Pelto-Huikko M, Salminen T, Hervonen A 1985 Localization of enkephalins in adrenaline cells and the nerves innervating adrenaline cells in rat adrenal medulla. Histochemistry 82:377–383[CrossRef][Medline]
610. Leboulenger F, Cupo A, Castanas E, Benyamina M, Pelletier G, Vaudry H 1986 Immunohistochemical and biochemical evidence for the presence of the pentapeptide Met-enkephalin and the heptapeptide Met-enkephalin-Arg⁶-Phe⁷ but not the octapeptide Met-enkephalin-Arg⁶-Gly⁷-Leu⁸ in amphibian chromaffin cells. Neurochem Int 8:303–309[CrossRef]
611. Kondo H, Yui R 1984 Co-existence of enkephalin and adrenalin in the frog adrenal gland. Histochemistry 80:243–246[CrossRef][Medline]
612. Kobayashi S, Ohashi T, Uchida T, Yanaihara N 1983 Met-enkephalin-Arg⁶-Gly⁷-Leu⁸-like immunoreactivity in presynaptic nerve terminals on both adrenaline-storing (A) and noradrenaline-storing (NA) cells of rat adrenal medulla. Biomed Res 4:151–157
613. Kondo H, Kuramoto H, Iwanaga T 1984 Immunohistochemical study on Met-enkephalin-Arg-Gly-Leu-like immunoreactive nerve fibers in the rat adrenal medulla. Brain Res 310:371–375[CrossRef][Medline]
614. Kobayashi S, Miyabayashi T, Uchida T, Yanaihara N 1985 Met-enkephalin-Arg⁶-Gly⁷-Leu⁸ in large-cored vesicles of splanchnic nerve terminals innervating guinea pig adrenal chromaffin cells. Neurosci Lett 53:247–252[CrossRef][Medline]
615. Osamura RY, Tsutsumi Y, Yanaihara N, Imura H, Watanabe K 1987 Immunohistochemical studies for multiple peptide-immunoreactivities and co-localization of met-enkephalin-Arg⁶-Gly⁷-Leu⁸, neuropeptide Y and somatostatin in human adrenal medulla and pheochromocytoma. Peptides 8:77–87[CrossRef][Medline]
616. Varndell IM, Polak JM, Allen JM, Terenghi G, Bloom SR 1984 Neuropeptide tyrosine (NPY) immunoreactivity in norepinephrine-containing cells and nerves of the mammalian adrenal gland. Endocrinology 114:1460–1462[Abstract/Free Full Text]
617. Fischer-Colbrie R, Diez-Guerra J, Emson PC, Winkler H 1986 Bovine chromaffin granules: immunological studies with antisera against neuropeptide Y, [Met]-enkephalin and bombesin. Neuroscience 18:167–174[CrossRef][Medline]
618. Lesouhaitier O, Feuilloley M, Lihrmann I, Ugo I, Fasolo A, Tonon MC, Vaudry H 1996 Localization of diazepam-binding inhibitor-related peptides and peripheral type benzodiazepine receptors in the frog adrenal gland. Cell Tissue Res 283:403–412[CrossRef][Medline]
619. Gamse R, Saria A, Bucsics A, Lembeck F 1981 Substance P in tumors: pheochromocytoma and carcinoid. Peptides 2 [Suppl 2]:275–280
620. Heym C, Braun B, Klimaschewski L, Kummer W 1995 Chemical codes of sensory neurons innervating the guinea-pig adrenal gland. Cell Tissue Res 279:169–181[CrossRef][Medline]
621. Basile S, Cheung NS, Livett BG 1992 Chromatographic evidence for the presence of multiple tachykinins in the bovine adrenal medulla. J Neurochem 58:1584–1586[CrossRef][Medline]
622. Bucsics A, Saria A, Lembeck F 1981 Substance P in the adrenal gland: origin and species distribution. Neuropeptides 1:329–341[CrossRef]
623. Wang JM, De Ridder EF, De Potter WP, Weyns AL 1994 Localization of neurokinin A and chromogranin A immunoreactivity in the developing porcine adrenal medulla. Histochem J 26:431–436[CrossRef][Medline]
624. Kondo H, Kuramoto H, Fujita T 1986 An immuno-electron-microscopic study of the localization of VIP-like immunoreactivity in the adrenal gland of the rat. Cell Tissue Res 245:531–538[CrossRef][Medline]
625. Heym C, Colombo-Benckmann M, Mayer B 1994 Immunohistochemical demonstration of the synthesis enzyme for nitric oxide and of comediaters in neurons and chromaffin cells of the human adrenal medulla. Anat Anz 176:11–16[Medline]
626. Eiden LE, Eskay RL, Scott J, Pollard H, Hotchkiss AJ 1983 Primary cultures of bovine chromaffin cells synthesize and secrete vasoactive intestinal polypeptide (VIP). Life Sci 33:687–693[CrossRef][Medline]
627. Leboulenger F, Leroux P, Tonon MC, Coy DH, Vaudry H, Pelletier G 1983 Coexistence of vasoactive intestinal peptide and enkephalins in the adrenal chromaffin granules of the frog. Neurosci Lett 37:221–225[CrossRef][Medline]
628. Pelto-Huikko M, Salminen T, Partanen M, Toivanen M, Hervonen A 1985 Immunohistochemical localization of neurotensin in hamster adrenal medulla. Anat Rec 211:458–464[CrossRef][Medline]
629. Bauer FE, Hacker GW, Terenghi G, Adrian TE, Polak JM, Bloom SR 1986 Localization and molecular forms of galanin in human adrenals: elevated levels in pheochromocytomas. J Clin Endocrinol Metab 63:1372–1378[Abstract/Free Full Text]
630. Nguyen TT, Babinski K, Ong H, De Léan A 1990 Differential regulation of natriuretic peptide biosynthesis in bovine adrenal chromaffin cells. Peptides 11:973–978[CrossRef][Medline]
631. Nguyen TT, Ong H, De Lean A 1988 Secretion and biosynthesis of atrial natriuretic factor by cultured adrenal chromaffin cells. FEBS Lett 231:393–396[CrossRef][Medline]
632. Morel G, Chabot JG, Garcia-Caballero T, Gossard F, Dihl F, Belles-Isles M, Heisler S 1988 Synthesis, internalization, and localization of atrial natriuretic peptide in rat adrenal medulla. Endocrinology 123:149–158[Abstract/Free Full Text]
633. Moller K, Sundler F 1996 Expression of pituitary adenylate cyclase activating peptide (PACAP) and PACAP type I receptors in the rat adrenal medulla. Regul Pept 63:129–139[CrossRef][Medline]
634. Frodin M, Hannibal J, Wulff BS, Gammeltoft S, Fahrenkrug J 1995 Neuronal localization of pituitary adenylate cyclase-activating polypeptide 38 in the adrenal medulla and growth inhibitory effect on chromaffin cells. Neuroscience 65:599–608[CrossRef][Medline]
635. Tabarin A, Chen D, Hakanson R, Sundler F 1994 Pituitary adenylate cyclase-activating peptide in the adrenal gland of mammals: distribution, characterization and responses to drugs. Neuroendocrinology 59:113–119[Medline]
636. Shiotani Y, Kimura S, Ohshige Y, Yanaihara C, Yanaihara N 1995 Immunohistochemical localization of pituitary adenylate cyclase-activating polypeptide (PACAP) in the adrenal medulla of the rat. Peptides 16:1045–1050[CrossRef][Medline]
637. Ghatei MA, Takahashi K, Suzuki Y, Gardiner J, Jones PM, Bloom SR 1993 Distribution, molecular characterization of pituitary adenylate cyclase-activating polypeptide and its precursor encoding messenger RNA in human and rat tissues. J Endocrinol 136:159–166[Abstract/Free Full Text]
638. Fernandez-Vivero J, Rodriguez-Sanchez F, Verastegui C, Cordoba Moriano F, Romero A, de Castro JM 1993 Immunocytochemical distribution of serotonin and neuropeptide Y (NPY) in mouse adrenal gland. Histol Histopathol 8:509–520[Medline]
639. Brownfield MS, Poff BC, Holzwarth MA 1985 Ultrastructural immunochemical co-localiziation of serotonin and PNMT in adrenal medullary vesicles. Histochemistry 83:41–46[CrossRef][Medline]
640. Delarue C, Becquet D, Idres S, Hery F, Vaudry H 1992 Serotonin synthesis in adrenochromaffin cells. Neuroscience 46:495–500[CrossRef][Medline]
641. Arevolov VA, Dimitriev AD, Tennov AV, Valdman AV 1986 Immunochemical demonstration of pro-opiomelanocortin peptide fragments (7-beta-endorphin and ACTH) in rat and mouse adrenals. Bull Exp Biol Med 101:474–477[CrossRef]
642. De Bold CR, Menefee JK, Nicholson WE, Orth DN 1988 Proopiomelanocortin gene is expressed in many normal human tissues and in tumors not associated with ectopic adrenocorticotropin syndrome. Mol Endocrinol 2:862–870[Abstract/Free Full Text]
643. Saito H, Saito S, Ohuchi T, Oka M, Sano T, Hosoi E 1984 Co-storage and co-secretion of somatostatin and catecholamine in bovine adrenal medulla. Neurosci Lett 52:43–47[CrossRef][Medline]
644. Vincent SR, McIntosh CHS, Reiner PB, Brown JC 1987 Somatostatin immunoreactivity in the cat adrenal medulla. Histochemistry 87:483–486[CrossRef][Medline]
645. Morel G, Leroux P, Garcia-Caballero T, Beiras A, Gossard F 1990 Ultrastructural distribution of somatostatin-14 and -28 in rat adrenal cells. Cell Tissue Res 261:517–524[CrossRef][Medline]
646. Washimine H, Asada Y, Kitamura K, Ichiki Y, Hara S, Yamamoto Y, Kangawa K, Sumiyoshi A, Eto T 1995 Immunohistochemical identification of adrenomedullin in human, rat, and porcine tissue. Histochem Cell Biol 103:251–254[CrossRef][Medline]
647. Satoh F, Takahashi K, Murakami O, Totsune K, Sone M, Ohneda M, Sasano H, Mouri T 1996 Immunocytochemical localization of adrenomedullin-like immunoreactivity in the human hypothalamus and the adrenal-gland. Neurosci Lett 203:207–210[CrossRef][Medline]
648. Satoh F, Takahashi K, Murakami O, Totsune K, Sone M, Ohneda M, Abe K, Miura Y, Hayashi Y, Sasano H, Mouri T 1995 Adrenomedullin in human brain, adrenal-glands and tumor-tissues of pheochromocytoma, ganglioneuroblastoma and neuroblastoma. J Clin Endocrinol Metab 80:1750–1752[Abstract/Free Full Text]
649. Mulder H, Ahren B, Karlsson S, Sundler F 1996 Adrenomedullin - localization in the gastrointestinal-tract and effects on insulin-secretion. Regul Pept 62:107–112[CrossRef][Medline]
650. Ichiki Y, Kitamura K, Kangawa K, Kawamoto M, Matsuo H, Eto T 1995 Distribution and characterization of immunoreactive adrenomedullin in porcine tissue, and isolation of adrenomedullin[26–52] and adrenomedullin[34–52] from porcine duodenum. J Biochem 118:765–770[Abstract/Free Full Text]
651. Washimine H, Kitamura K, Ichiki Y, Yamamoto Y, Kangawa K, Matsuo H, Eto T 1994 Immunoreactive proadrenomedullin N-terminal-20 peptide in human tissue, plasma and urine. Biochem Biophys Res Commun 202:1081–1087[CrossRef][Medline]
652. Kuwasako K, Kitamura K, Ichiki Y, Kato J, Kangawa K, Matsuo H, Eto T 1995 Human proadrenomedullin N-terminal-20 peptide in pheochromocytoma and normal adrenal-medulla. Biochem Biophys Res Commun 211:694–699[CrossRef][Medline]
653. Inatsu H, Sakata J, Shimokubo T, Kitani M, Nishizono M, Washimine H, Kitamura K, Kangawa K, Matsuo H, Eto T 1996 Distribution and characterization of rat immunoreactive proadrenomedullin N-terminal 20 peptide (PAMP) and the augmented cardiac pamp in spontaneously hypertensive rat. Biochem Mol Biol Int 38:365–372[Medline]
654. Lemaire S, Chouinard L, Mercier P, Day R 1986 Bombesin-like immunoreactivity in bovine adrenal medulla. Regul Pept 13:133–146[CrossRef][Medline]
655. Hawthorn J, Nussey SS, Henderson JR, Jenkins JS 1987 Immunohistochemical localization of oxytocin and vasopressin in the adrenal glands of rat, cow, hamster and guinea pig. Cell Tissue Res 250:1–6[CrossRef][Medline]
656. Nussey SS, Ang VT, Jenkins JS, Chowdrey HS, Bisset GW 1984 Brattleboro rat adrenal contains vasopressin. Nature 310:64–66[CrossRef][Medline]
657. Ravid R, Oosterbaan HP, Hansen BL, Swaab DF 1986 Localisation of oxytocin, vasopressin and parts of precursors in the human neonatal adrenal. Histochemistry 84:401–407[CrossRef][Medline]
658. Larcher A, Delarue C, Idres S, Lefebvre H, Feuilloley M, Vandesande F, Pelletier G, Vaudry H 1989 Identification of vasotocin-like immunoreactivity in chromaffin cells of the frog adrenal gland: effect of vasotocin on corticosteroid secretion. Endocrinology 125:2691–2700[Abstract/Free Full Text]
659. Oomori Y, Okuno S, Fujisawa H, Iuchi H, Ishikawa K, Satoh Y, Ono K 1994 Ganglion-cells immunoreactive for catecholamine-synthesizing enzymes, neuropeptide-Y and vasoactive intestinal polypeptide in the rat adrenal-gland. Cell Tissue Res 275:201–213[CrossRef][Medline]
660. Kong JY, Thureson-Klein Å, Klein RL 1989 Differential distribution of neuropeptides and serotonin in pig adrenal glands. Neuroscience 28:765–775[CrossRef][Medline]
661. Maubert E, Tramu G, Beauvillain JC, Dupouy JP 1990 Co-localisation of vasoactive intestinal polypeptide and neuropeptide Y immunoreactivities in the nerve fibres of the rat adrenal gland. Neurosci Lett 113:121–126[CrossRef][Medline]
662. Majane EA, Alho H, Kataoka Y, Lee CH, Yang HT 1985 Neuropeptide Y in bovine adrenal glands: distribution and characterisation. Endocrinology 117:1162–1168[Abstract/Free Full Text]
663. Varndell IM, Polak JM, Allen JM, Terenghi G, Bloom SR 1984 Neuropeptide Y in bovine adrenal glands: distribution and characterisation. Endocrinology 114:1460–1462
664. Kuramoto H 1987 An immunohistochemical study of chromaffin cells and nerve fibers in the adrenal gland of the bullfrog, Rana catesbeiana. Arch Histol Jpn 50:15–38[Medline]
665. Kleitman N, Holzwarth MA 1985 Catecholaminergic innervation of the rat adrenal cortex. Cell Tissue Res 241:139–147[CrossRef][Medline]
666. Charlton BG, McGadey J, Russel D, Neal DE 1992 Noradrenergic innervation of the human adrenal cortex as revealed by dopamine ß-hydroxylase immunohistochemistry. J Anat 180:501–506
667. Oomori Y, Okuno S, Fujisawa H, Ishikawa K, Satoh Y, Matsuda M, Yamano M, Ono K 1989 Tyrosine-hydroxylase-immunoreactive nerve-fibers in the separated capsule of the rat adrenal-gland. Acta Anat (Basel) 136:49–54[Medline]
668. Zeng ZP, Naruse M, Guan BJ, Naruse K, Sun ML, Zang MF, Demura H, Shi YF 1992 Endothelin stimulates aldosterone secretion in vitro from normal adrenocortical tissue but not adenoma tissue in primary aldosteronism. J Clin Endocrinol Metab 74:874–878[Abstract]
669. Pecci A, Gomez-Sanchez CE, Debedners MEO, Lantos CP, Cozza EN 1993 In vivo stimulation of aldosterone biosynthesis by endothelin—loci of action and effects of doses and infusion rate. J Steroid Biochem Mol Biol 45:555–561[CrossRef][Medline]
670. Remy-Jouet I, Delarue C, Feuilloley M, Vaudry H 1994 Involvement of the cytoskeleton in the mechanism of action of endothelin on frog adrenocortical cells. J Steroid Biochem Mol Biol 50:55–59[CrossRef][Medline]
671. Murray SA, Pharrams SY 1997 Comparison of gap junction expression in the adrenal gland. Microsc Res Tech 36:510–519
672. Murray SA, Oyoyo UAA, Pharrams SY, Kumar NM, Gilula NB1995 Characterization of gap junction expression in the adrenal gland. Endocr Res 21:221–229
673. Decker RS, Donta ST, Larsen WJ, Murray SA 1978 Gap junctions and ACTH sensitivity in Y-1 adrenal tumor cells. J Supramol Struct 9:497–507

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				J. Puurunen, T. Piltonen, P. Jaakkola, A. Ruokonen, L. Morin-Papunen, and J. S. Tapanainen Adrenal Androgen Production Capacity Remains High up to Menopause in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., June 1, 2009; 94(6): 1973 - 1978. [Abstract] [Full Text] [PDF]

				T. Dickmeis Glucocorticoids and the circadian clock J. Endocrinol., January 1, 2009; 200(1): 3 - 22. [Abstract] [Full Text] [PDF]

				R H Straub, L B Tanko, C Christiansen, P J Larsen, and D S Jessop Higher physical activity is associated with increased androgens, low interleukin 6 and less aortic calcification in peripheral obese elderly women J. Endocrinol., October 1, 2008; 199(1): 61 - 68. [Abstract] [Full Text] [PDF]

				E. D. Bruder, J. K. Taylor, K. J. Kamer, and H. Raff Development of the ACTH and corticosterone response to acute hypoxia in the neonatal rat Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2008; 295(4): R1195 - R1203. [Abstract] [Full Text] [PDF]

				H. Otani, F. Otsuka, K. Inagaki, J. Suzuki, T. Miyoshi, Y. Kano, J. Goto, T. Ogura, and H. Makino Aldosterone Breakthrough Caused by Chronic Blockage of Angiotensin II Type 1 Receptors in Human Adrenocortical Cells: Possible Involvement of Bone Morphogenetic Protein-6 Actions Endocrinology, June 1, 2008; 149(6): 2816 - 2825. [Abstract] [Full Text] [PDF]

				B. Root, J. Abrassart, D. A. Myers, T. Monau, and C. A. Ducsay Expression and Distribution of Glucocorticoid Receptors in the Ovine Fetal Adrenal Cortex: Effect of Long-term Hypoxia Reproductive Sciences, May 1, 2008; 15(5): 517 - 528. [Abstract] [PDF]

				D. G. Romero, M. W. Plonczynski, C. A. Carvajal, E. P. Gomez-Sanchez, and C. E. Gomez-Sanchez Microribonucleic Acid-21 Increases Aldosterone Secretion and Proliferation in H295R Human Adrenocortical Cells Endocrinology, May 1, 2008; 149(5): 2477 - 2483. [Abstract] [Full Text] [PDF]

				L. Engstrom, K. Rosen, A. Angel, A. Fyrberg, L. Mackerlova, J. P. Konsman, D. Engblom, and A. Blomqvist Systemic Immune Challenge Activates an Intrinsically Regulated Local Inflammatory Circuit in the Adrenal Gland Endocrinology, April 1, 2008; 149(4): 1436 - 1450. [Abstract] [Full Text] [PDF]

				A. L Rosas, A. A Kasperlik-Zaluska, L. Papierska, B. L. Bass, K. Pacak, and G. Eisenhofer Pheochromocytoma crisis induced by glucocorticoids: a report of four cases and review of the literature Eur. J. Endocrinol., March 1, 2008; 158(3): 423 - 429. [Abstract] [Full Text] [PDF]

				D. G. Romero, M. W. Plonczynski, B. L. Welsh, C. E. Gomez-Sanchez, M. Y. Zhou, and E. P. Gomez-Sanchez Gene expression profile in rat adrenal zona glomerulosa cells stimulated with aldosterone secretagogues Physiol Genomics, December 19, 2007; 32(1): 117 - 127. [Abstract] [Full Text] [PDF]

				C. Roberge, A. C. Carpentier, M.-F. Langlois, J.-P. Baillargeon, J.-L. Ardilouze, P. Maheux, and N. Gallo-Payet Adrenocortical dysregulation as a major player in insulin resistance and onset of obesity Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1465 - E1478. [Abstract] [Full Text] [PDF]

				S. Morita, M. Otsuki, M. Izumi, N. Asanuma, S. Izumoto, Y. Saitoh, T. Yoshimine, and S. Kasayama Reduced epinephrine reserve in response to insulin-induced hypoglycemia in patients with pituitary adenoma Eur. J. Endocrinol., September 1, 2007; 157(3): 265 - 270. [Abstract] [Full Text] [PDF]

				C. E. Gomez-Sanchez Regulation of Adrenal Arterial Tone by Adrenocorticotropin: The Plot Thickens Endocrinology, August 1, 2007; 148(8): 3566 - 3568. [Full Text] [PDF]

				L. Green-Golan, C. Yates, B. Drinkard, C. VanRyzin, G. Eisenhofer, M. Weise, and D. P. Merke Patients with Classic Congenital Adrenal Hyperplasia Have Decreased Epinephrine Reserve and Defective Glycemic Control during Prolonged Moderate-Intensity Exercise J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3019 - 3024. [Abstract] [Full Text] [PDF]

				P. Val, J.-P. Martinez-Barbera, and A. Swain Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage Development, June 15, 2007; 134(12): 2349 - 2358. [Abstract] [Full Text] [PDF]

				M. Otis, S. Campbell, M. D Payet, and N. Gallo-Payet Expression of extracellular matrix proteins and integrins in rat adrenal gland: importance for ACTH-associated functions J. Endocrinol., June 1, 2007; 193(3): 331 - 347. [Abstract] [Full Text] [PDF]