Effects of angiotensin III (DES-1-asp-angiotensin II) and angiotensin III analogue (DES-1-asp-8-ile-angiotensin II) upon adrenal steroidogenesis and blood pressure.

Effects of angiotensin III and angiotensin III analogue upon adrenal steroidogenesis and blood pressure were studied in rats, rabbits and a man. Pressor effect of angiotensin III was about one fifth of that of angiotensin II in all the species. Degradation rate of pressor effect of angiotensin III in plasma was more rapid than that of angiotensin II. Different from the effects of angiotensin III upon blood pressure, its effect upon aldosterone was similar to that of angiotensin II. The effect of angiotensin III upon other adrenal steroids, such as DOC and cortisol, however, seemed to be slightly less than that of angiotensin II. Angiotensin III producted an additive effect to that of ACTH, but it didn't produce an additive effect to that of angiotensin II. Angiotensin III analogue, itself, stimulated adrenal steroidogenesis, but it inhibited the effects of angiotensin III and angiotensin II upon aldosterone. Effects of ACTH upon plasma DOC and cortisol were not inhibited by angiotenesin III analogue, but the effect of ACTH upon aldosterone was blunted slightly.     

Studies on the mechanisms of ACTH-induced inhibition of aldosterone biosynthesis in the rat adrenal cortex

In rats, chronic treatment with high doses of ACTH (10-40 micrograms/100 g body weight per day) leads to a marked reduction in aldosterone synthesis by adrenal capsules. The possibility that this inhibition is secondary to a decrease in plasma potassium levels or in renin angiotensin system (RAS) activity has been explored. The effects of chronic ACTH treatment were compared in (I) animals in which the endogenous RAS activity was stimulated by restricting dietary sodium intake, (II) animals in which plasma angiotensin II was increased by infusion from implanted osmotic minipumps and (III) animals which received supplementary potassium and in which hypokalaemia was prevented. In all cases, rates of aldosterone biosynthesis in vitro by adrenal capsules were decreased in ACTH-treated animals to an extent similar to those in untreated controls. In addition, ACTH treatment of hypophysectomized rats resulted in a similar inhibition of aldosterone biosynthesis to that found in sham-operated controls. It may be concluded that the ACTH-induced reduction of aldosterone biosynthesis is independent of the secretion of other pituitary hormones, and cannot be simply ascribed to either a reduction in RAS activity or in plasma potassium levels. The results are consistent with the view that the effects of chronic ACTH treatment are mediated by a direct action on the zona glomerulosa cell, which leads to its transformation into a zona fasciculata-like form.     

Regulation of angiotensin II in rat adrenal gland

Levels of angiotensin II immunoreactivity in the rat adrenal gland are over one hundredfold higher than those in plasma. It is unclear, however, whether the major source of adrenal angiotensin II immunoreactivity is intracellular synthesis by a local renin-angiotensin system, uptake by angiotensin II receptors, or both. Our studies show that angiotensin II immunoreactivity in the adrenal gland is predominantly attributable to angiotensin II (greater than 75%). Angiotensin III (16%) and other angiotensin II fragments are also present. The majority of angiotensin II immunoreactivity (73%), renin activity (73%), and angiotensin II receptor binding activity (66%) in the adrenal gland is located in the capsular glomerulosa cell layers. Dehydration produced by 2% NaCl imbibition decreased these activities in the capsular-glomerulosa. In the fasciculata-medullary regions of the adrenal gland, dehydration decreased renin activity but not angiotensin II immunoreactivity or angiotensin II receptor binding activity. Combined data from control and dehydrated rats showed a close correlation of the capsular-glomerulosa angiotensin II immunoreactivity with angiotensin II receptor binding activity (r = 0.94, p less than 0.001) and a weaker, nonsignificant correlation with renin activity (r = 0.66, p less than 0.1). In the fasciculata-medullary cell layers, no significant correlations were found between angiotensin II immunoreactivity and either renin or angiotensin II receptor binding activity. These data demonstrate that functionally distinct layers of the rat adrenal gland differentially regulate angiotensin II receptors and the renin-angiotensin system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aldosterone production by isolated glomerulosa cells: modulation of sensitivity to angiotensin II and ACTH by extracellular potassium concentration.

The influence of extracellular potassium concentration on adrenal sensitivity to angiotensin II and ACTH was studied in isolated canine adrenal glomerulosa cells. When potassium was absent from the incubation medium, the aldosterone response to angiotensin II or ACTH was completely abolished. At physiologic angiotensin II concentrations (2.5 x 10(-11) M), aldosterone formation increased 4-fold when potassium concentration was increased from 2.5 to 5.0 mM, and rose 6-fold as potassium was increased from 2.5 to 7.5 mM. In the absence of angiotensin II, the same changes in potassium concentration increased aldosterone production only to 2-fold and 3.5-fold, respectively. The effect of potassium concentration upon the aldosterone response to ACTH was similar but less marked. The concentration and binding affinity of angiotensin II receptor sites in glomerulosa cells were not changed by increasing potassium concentrations from 0 to 7.5 mM. These observations demonstrate that the aldosterone response to the glomerulosa cell to angiotensin II is potassium-dependent within the physiological range for each of these stimuli. Such an interaction suggests that the in vivo effect of potassium upon aldosterone secretion includes a significant modulating action upon adrenal sensitivity to angiotensin II, as well as a direct action of potassium upon the adrenal glomerulosa cell.     

Selective inhibition by des-1-Asp-8-lle-angiotensin ii of the steroidogenic response to restricted sodium intake in the rat.

Angiotensin III (des-1-Asp-angiotensin II) is a potent steriodogenic agent in many species. The effects of the heptapeptide in the adrenal zona glomerulosa are resistant to blockade by C-terminally substituted analogues of angiotensin II (1-Sar-8-Ile- or 1-Sar-8-Ala-octapeptides). For this reason, the effects of 7-Ile-angiotensin III, a C-terminally substituted analogue of the heptapeptide, and 1-Sar-8-Ile-angiotensin II on aldosterone biosynthesis in rabbit adrenal cortical cell suspensions and on urinary aldosterone excretion in sodium-deprived rats were studied. In the vitro studies, 7-Ile-angiotensin III was a better antagonist of angiotensin II- or angiotensin III-induced steroidogenesis than was 1-Sar-8-Ile-angiotensin II. In the rats, subcutaneously administered 1-Sar-8-Ile-angiotensin II (0.9 mumoles/kg) produced prolonged blockade of the pressor responses to exogenous angiotensin II. 70Ile-angiotensin III (0.9 mumoles/kg) had no effect on resting blood pressure or on blood pressure responses to angiotensin II infusions. At the doses studied, however, 7-Ile-angiotensin III caused a marked decrease (50%) in aldosterone excretion in sodium-deprived rats, but 1-Sar-8-Ile-angiotensin II had no effect on aldosterone excretion. In the sodium-deprived rats, the administration of 7-Ile-angiotensin Ile was not associated with an acute increase in plasma renin activity, but treatment with 1-Sar-8-Ile-angiotensin II resulted in a sixfold increase in plasma renin activity, but otensin III was not associated with an acute increase in plasma renin activity, but treatment with 1-Sar-8-Ile-angiotensin II resulted in a sixfold increase in plasma renin activity. These results are consistent with a role for angiotensin III in the control of aldosterone biosynthesis.     

Effects of prolonged infusions of potassium chloride, adrenocorticotrophin or angiotensin II upon serum aldosterone concentration and the conversion of corticosterone to aldosterone in rats.

The temporal relation between alterations in serum aldosterone and in the conversion of labelled corticosterone to aldosterone by incubated adrenal tissue was studied in conscious rats receiving long-term infusions of KCl, ACTH or angiotensin II. When potassium-deficient rats were given KCl, a marked increase in serum aldosterone was observed only after 12 h, i.e. at a time when the conversion of corticosterone to aldosterone had become normal. After 24 h of ACTH infusion into sodium- and potassium-replete rats the serum aldosterone was markedly elevated, whereas the conversion of corticosterone to aldosterone was significantly decreased. After 48 h of continued ACTH infusion the serum aldosterone returned to normal and there was a further decrease in the conversion rate. A 24-h angiotensin II infusion into sodium- and potassium-replete rats induced significant increases in both the serum aldosterone and the conversion. After 48 h of continued angiotensin infusion the serum aldosterone returned to normal while the conversion and the blood pressure remained elevated. These results indicate that the activity of the enzymes involved in the final steps of aldosterone biosynthesis may become rate-limiting for the secretion of aldosterone during potassium deficiency and during prolonged ACTH treatment. On the other hand, the observed transiency of aldosterone stimulation by exogenous angiotensin II was not due to a suppression of the final steps of aldosterone biosynthesis and remains unexplained.     

Effects of angiotensin II, adrenocorticotropin, and potassium on aldosterone production in adrenal zona glomerulosa cells from streptozotocin-induced diabetic rats

Hyporeninemic hypoaldosteronism has been shown to occur in streptozotocin-induced chronic diabetic rats with normokalemia. To test the nature of the aldosterone deficiency, we investigated the responses of aldosterone production to angiotensin II (AII), ACTH, and potassium in adrenal zona glomerulosa cells from diabetic rats at 6 weeks after an injection of streptozotocin compared with those in the cells from control rats. In diabetic rats, plasma glucose was high and plasma immunoreactive insulin was low. Diabetic rats also had low levels of PRA and plasma AII, low levels of plasma aldosterone, and normal levels of plasma corticosterone and plasma potassium. The zona glomerulosa width was narrower in diabetic rats than in control rats. Basal aldosterone production, when corrected to an uniform number of cells per group, was similar in the cells from control and diabetic rats. Cells from diabetic rats showed a less sensitive and lower response of aldosterone production to AII, increases in the threshold and the ED50, and a decrease in the maximal AII-stimulated aldosterone level. ACTH, however, caused a similar effect on aldosterone production in the cells from control and diabetic rats. Cells from diabetic rats exhibited a less sensitive response of aldosterone production to potassium and a tendency to be low in the maximal potassium-stimulated aldosterone level, presumably attributable to the impairment of adrenal zona glomerulosa cells to AII. We conclude that the hypoaldosteronism observed in our diabetic rats may be secondary to the deficiency of AII.     

Estradiol attenuates angiotensin-induced aldosterone secretion in ovariectomized rats

Estrogen replacement therapy significantly reduces the risk of cardiovascular disease in postmenopausal women. Previous studies indicate that estradiol (E2) decreases angiotensin II (AT) receptor density in the adrenal and pituitary in NaCl-loaded rats. We used an in vivo model that eliminates the potentially confounding influence of ACTH to determine whether the E2-induced decrease in adrenal AT receptor expression affects aldosterone responses to angiotensin II (Ang II). Female rats were ovariectomized, treated with oil (OVX) or E2 (OVX+E2; 10 microg, s.c.) for 14 days, and fed a NaCl-deficient diet for the last 7 days to maximize adrenal AT receptor expression and responsiveness. On days 12-14 rats were treated with dexamethasone (DEX; 25 microg, i.p., every 12 h) to suppress plasma ACTH. On day 14 aldosterone secretion was measured after a 30-min infusion of Ang II (330 ng/min). Ang II infusion increased the peak plasma aldosterone levels to a lesser degree in the OVX+E2 than in the OVX rats (OVX, 1870 +/- 290 pg/ml; OVX+E2, 1010 +/- 86 pg/ml; P < 0.05). Ang II-induced ACTH and aldosterone secretion was also studied in rats that were not treated with DEX. In the absence of DEX, the peak plasma aldosterone response was also significantly decreased (OVX, 5360 +/- 1200 pg/ml; OVX+E2, 2960 +/- 570 pg/ml; P < 0.05). However, E2 also reduced the plasma ACTH response to Ang II (P < 0.05; OVX, 220 +/- 29 pg/ml; OVX+E2, 160 +/- 20 pg/ml), suggesting that reduced pituitary ACTH responsiveness to Ang II contributes to the effect of E2 on Ang II-induced aldosterone secretion. Adrenal AT1 binding studies confirmed that E2 significantly reduces adrenal AT1 receptor expression in both the presence and absence of DEX in NaCl-deprived rats. These results indicate that E2-induced decreases in pituitary and adrenal AT1 receptor expression are associated with attenuated pituitary ACTH and adrenal aldosterone responses to Ang II and suggest that estrogen replacement therapy may modulate Ang II-stimulated aldosterone secretion as part of its well known cardioprotective actions.     

Calcitonin gene-related peptide modulates adrenal hormones in conscious dogs.

The effects of a small dose (2 pmol/kg) of human calcitonin gene-related peptide I on plasma renin activity and hormones, including, aldosterone, ACTH, cortisol, AVP and ANH, were investigated in 14 conscious dogs. In addition, we studied the effects of calcitonin gene-related peptide on aldosterone secretion when it is stimulated by angiotensin II and ACTH. An intravenous bolus injection of 2 pmol/kg of calcitonin gene-related peptide raised plasma renin activity (by 216%, p less than 0.05), ACTH (by 85%, p less than 0.05), AVP (by 89%, p less than 0.05), and ANH (by 36%, p less than 0.05). Despite the elevation of plasma renin activity, aldosterone was decreased (by 52%, p less than 0.05). Cortisol did not change significantly. Infusion of 1 pmol.kg-1.min-1 of angiotensin II produced an elevation of aldosterone (by 186%, p less than 0.01), which was completely inhibited by pretreatment with an injection of 2 pmol/kg of calcitonin gene-related peptide. On the other hand, aldosterone secretion stimulated by ACTH was not altered significantly by pretreatment with an injection of 2 pmol/kg of calcitonin gene-related peptide. These results suggest that calcitonin gene-related peptide inhibits aldosterone secretion, especially when aldosterone is stimulated by angiotensin II. In addition, calcitonin gene-related peptide may be involved as an endocrine modulator in the physiological control of other several hormones closely related to the hemodynamics.     

Pomc knockout mice have secondary hyperaldosteronism despite an absence of adrenocorticotropin

Aldosterone production is controlled by angiotensin II, potassium, and ACTH. Mice lacking Pomc and its pituitary product ACTH have been reported to have absent or low aldosterone levels, suggesting that ACTH is required for normal aldosterone production. However, this is at odds with the clinical finding that human aldosterone deficiency is not a component of secondary adrenal insufficiency. To resolve this, we measured plasma and urine electrolytes, together with plasma aldosterone and renin activity, in Pomc(-/-) mice. We found that these mice have secondary hyperaldosteronism (elevated aldosterone without suppression of renin activity), indicating that ACTH is not required for aldosterone production or release in vivo. Exogenous ACTH stimulates a further increase in aldosterone in Pomc(-/-) mice, whereas angiotensin II has no effect, and the combination of angiotensin II and ACTH is no more potent than ACTH alone. These data suggest that aldosterone production and release in vivo do not require the action of ACTH during development or postnatal life and that secondary hyperaldosteronism in Pomc(-/-) mice is a consequence of glucocorticoid deficiency.     

Mechanisms of inhibition of aldosterone secretion by adrenocorticotropin

The mechanisms by which prolonged administration of ACTH causes a decrease in aldosterone secretion were studied in the rat. After 6 days of treatment with ACTH (2 U/day), blood corticosterone was elevated and plasma aldosterone was decreased in rats maintained on either a normal or low sodium diet. PRA was also decreased, probably secondary to increased sodium and/or fluid retention. In collagenase-dispersed glomerulosa cells from adrenals of ACTH-treated rats, angiotensin II receptors were markedly decreased, as were the in vitro aldosterone responses to angiotensin II, ACTH, 8-bromo-cAMP, and potassium. However, the production of deoxycorticosterone and precursor steroids was increased, indicating the presence of a block in the late aldosterone biosynthetic pathway. Measurement of the activity of biosynthetic enzymes of the steroidogenic pathway in isolated mitochondria revealed an 80% increase in side-chain cleavage enzyme in both glomerulosa and fasciculata mitochondria from ACTH-treated rats. Although ACTH injection also increased 11-hydroxylase activity in the fasciculata zone, this enzyme was reduced by 50% in capsular mitochondria. The 18-hydroxylase activity in adrenal capsular mitochondria was markedly decreased by ACTH treatment in both normal and sodium-restricted animals. The importance of ACTH-induced steroidogenesis in the development of altered glomerulosa cell function was indicated by the ability of aminoglutethimide to prevent the inhibitory effects of ACTH on angiotensin II receptors and PRA. It is likely that the observed inhibition of the renin-angiotensin system is responsible for the decrease in angiotensin II receptors and 18-hydroxylase, since both are highly dependent on the trophic effect of angiotensin II. The specific lesions produced in adrenal glomerulosa cells by long term ACTH treatment include decreased levels of angiotensin II receptors, 11-hydroxylase, and 18-hydroxylase. These changes are secondary to the suppression of renin-angiotensin activity and are responsible for the impaired aldosterone secretion that results from prolonged treatment with ACTH. (Endocrinology 108: 522, 1981)     

Atrial natriuretic factor inhibits the stimulation of aldosterone secretion by angiotensin II, ACTH and potassium in vitro and angiotensin II-induced steroidogenesis in vivo

Since atrial natriuretic factor (ANF) blocks the contractile effect of angiotensin II on vascular strips, we investigated the action of the synthetic 48-73 ANF (previously called 8-33 ANF) on another target tissue of angiotensin II, the adrenal glomerulosa. ANF did not affect basal aldosterone output by isolated rat adrenal glomerulosa cells. ANF inhibited aldosterone secretion stimulated by 10(-8)M angiotensin II with an IC50 of 1.3 X 10(-9)M. Aldosterone secretion stimulated by 2.9 X 10(-10)M ACTH and by 15 mM potassium was similarly inhibited by ANF. In vivo, ANF blocked the effect of angiotensin II infused iv on aldosterone secretion in conscious unrestrained rats. We conclude that ANF is a non-selective inhibitor of stimulated aldosterone output.     

Plasma aldosterone and corticosterone responses to adrenocorticotropin, angiotensin, potassium, and stress in spontaneously hypertensive rats

The responses of plasma aldosterone and corticosterone to ACTH, angiotensin II (AII), and potassium chloride (KCl) infusion and the aldosterone, corticosterone and PRA responses to immobilization stress were studied in 2-month-old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) normotensive controls. Basal levels of plasma aldosterone and corticosterone were greater and PRA was less in the SHR than in the WKY. Aldosterone and corticosterone responses to graded AII were similar in both groups. Aldosterone and corticosterone responses to graded doses of KCl and ACTH, however, were significantly greater in SHR than in WKY normotensive rats. Plasma corticosterone, PRA, and aldosterone responses to immobilization stress were reduced in SHR compared to WKY. At 2 months of age, blood pressure was definitely elevated in SHR and was associated with low PRA and relatively high basal levels of aldosterone and corticosterone. Discordance between the renin-angiotensin system and mineralocorticoid secretion in the SHR may be due to enhanced adrenal sensitivity to factors such as ACTH and potassium. Suppressed PRA in SHR may be due, in part, to increased mineralocorticoid secretion, resulting in sodium retention and intravascular volume expansion.     

Role of angiotensin II in the hormonal, renal, and electrolyte response to sodium restriction

Adrenal responses to angiotensin II (ANG II) are enhanced with restriction of sodium intake. To determine whether increased circulating ANG II levels are responsible for the enhanced responsiveness, the adrenal and blood pressure responses to ANG II in human subjects were assessed four times: in balance on a high and a low salt diet and before and after the administration of a converting enzyme inhibitor (enalapril). Before enalapril administration, sodium restriction significantly increased (p less than 0.02) plasma renin activity, ANG II, and aldosterone levels; the aldosterone response to ANG II was enhanced twofold (p less than 0.01); and the blood pressure response to ANG II infusion was reduced significantly (p less than 0.05). Despite a fixed and low plasma ANG II concentration when enalapril was employed, the adrenal response to ANG II on the low salt diet was enhanced to the same degree as that observed before administration of the converting enzyme inhibitor. Conversely, enalapril substantially altered the blood pressure response to ANG II with sodium restriction, completely preventing the reduction in responsiveness. If the subjects were first given enalapril and then sodium intake was restricted, ANG II levels did not change significantly but renal excretion of both sodium and potassium was substantially modified. The rate at which renal excretion of sodium fell to match intake was retarded strikingly (p less than 0.001); conversely, renal retention of potassium increased significantly (p less than 0.03) as low salt balance was attained. Possibly because of the potassium retention, aldosterone levels rose, but significantly less than when enalapril was absent.     

Modulation of aldosterone secretion in frusemide-induced hypokalaemia

To study the effect of hypokalaemia in the regulation of aldosterone secretion, repeated injections of frusemide (3 mg/kg) plus saline with or without simultaneous infusion of potassium chloride (1 mEq/kg/h) were performed in 24 conscious female rabbits for 7 h. Without potassium supplementation, the plasma renin activity (PRA) remained elevated throughout the study, while an initial increase (1 h to 3 h) in plasma aldosterone (PA) gradually returned to normal with reduction of the serum potassium. In rabbits on potassium supplements to prevent the development of hypokalaemia, both PRA and PA remained elevated. The incremental aldosterone response to administration of potassium chloride, angiotensin II or ACTH, was considerably smaller in potassium-depleted rabbits than in potassium-repleted rabbits. These results suggest that serum potassium modulates the effects of angiotensin II or ACTH on aldosterone secretion, and that a certain level of potassium is necessary to maintain the aldosterone secretory capacity of the adrenal gland.     

Aldosterone responses to angiotensin II, adrenocorticotropin, and potassium in chronic experimental diabetes mellitus in rats

To investigate alterations in aldosterone secretion in diabetes mellitus, the effects of angiotensin II, ACTH, and potassium on aldosterone secretion were examined in conscious unrestrained streptozotocin-induced diabetic rats (60 mg/kg, 12 weeks before study). In chronic experimental diabetic rats where PRA, plasma aldosterone concentration, and urinary excretion of prostaglandin E2 were significantly decreased, a significant attenuated response of aldosterone secretion was demonstrated after infusion of angiotensin II, ACTH, or potassium. Yet the plasma fluorogenic corticosteroids response to ACTH in diabetic rats was not significantly different from that in control rats. After acute potassium infusion (0.30 meq/kg X min), plasma potassium levels in diabetic rats were significantly higher than in control rats, although immunoreactive insulin levels remained unchanged compared to the significant elevation in control rats. These results suggest that defects in aldosterone synthesis exist in chronic experimental diabetic rats and that potassium homeostasis is impaired during acute potassium loading. This change in potassium homeostasis may be related to both insulin and aldosterone deficiencies.     

Aldosterone production by isolated adrenal glomerulosa cells: stimulation by physiological concentrations of angiotensin II.

The production of aldosterone by isolated canine zona glomerulosa cells was measured after the incubation of cell suspensions with angiotensin II and ACTH, and during changes in extracellular potassium concentration. Adrenal cell suspensions were prepared by collagenase digestion and physical dispersion of the capsular layer of the dog adrenal cortex, and aldosterone production was determined by direct radioimmunoassay of cell incubation media. The isolated dog adrenal cells were highly responsive to angiotensin II, with aldosterone production significantly stimulated by concentrations of the octapeptide as low as 10(-11)M. Thus, the steroidogenic response of zona glomerulosa cells was consistently observed at peptide concentrations within the physiological range of angiotensin II in dog plasma, i.e., 2.0-5.0 X 5.0 X 10(-11)M. The maximum aldosterone response of 3-8 times the basal level of steroid production was induced by 3 X 10(-10)M angiotensin II, and a decrease in aldosterone production occurred at peptide concentrations above 10(-9)M. The aldosterone response of isolated adrenal cells to ACTH was consistently less sensitive than their response to angiotensin II, by a factor of 10-20 fold. Aldosterone production was significantly increased by 10(-10)M ACTH, and reached a maximum at 10(-8)M ACTH. By contrast with angiotensin II, ACTH usually evoked a higher maximal level of aldosterone production, and did not produce a decline in steroidogenesis at peptide concentrations above the level which caused maximum stimulation of aldosterone formation. Changes in the potassium concentration of cell incubation media were also accompanied by marked effects upon aldosterone synthesis which was abolished in the absence of potassium and became detectable in the presence of 0.5 mM K+. After remaining constant between 2.5 and 4.0 mM K+, aldosterone production rose sharply above 4.5 mM K+ and reached a maximum at 8 mM K+. These observations provide direct evidence that aldosterone production by zona glomerulosa cells is influenced by changes in angiotensin II levels within the normal plasma range.     

Primary Aldosteronism: Effects of Inhibition of ACTH and Potassium Administration on Plasma Aldosterone Concentration

The relative roles of ACTH, angiotensin and potassium in influencing aldosterone secretion in primary aldosteronism were assessed by direct or indirect means. In untreated patients with primary aldosteronism caused either by adrenal adenoma or hyperplasia plasma aldosterone and cortisol concentrations fluctuated in unison and dexamethasone reduced both hormones markedly. Only when renin-angiotens in system was greatly activated and plasma potassium normalized by medical treatment was dexamethasone less successful in lowering plasma aldosterone concentration. Potassium infusion of 10, 20 and 30 mEq/hr in patients with adenoma failed to elicit any increase in plasma aldosterone concentration despite significant increases in plasma potassium levels. These results suggest that patients with primary aldosteronism due to adrenal adenoma are relatively more sensitive to small changes in plasma ACTH level than those in plasma angiotensin or potassium levels. In recumbent patients with adrenal hyperplasia ACTH also modulates plasma aldosterone concentration.     

Evidence for cholinergic modulation of aldosterone secretion in man

Acetylcholine stimulates aldosterone secretion in bovine glomerulosa cells in vitro via specific cholinergic receptors. In this study we examined the effect of peripheral muscarinic blockade with atropine on metoclopramide-, angiotensin-II-, and ACTH-stimulated aldosterone secretion in man. Atropine (0.6 mg, iv) administered 10 min before MCP delayed the onset of the plasma aldosterone response and attenuated the mean peak response from 502 +/- 103 (+/- SE) to 322 +/- 72 pmol/L (P less than 0.05) without affecting zero time mean plasma aldosterone levels (144 +/- 28 vs. 136 +/- 36 pmol/L for control and atropine, respectively). This inhibitory effect was not mediated by changes in PRA or plasma potassium or ACTH (as reflected by cortisol) concentrations. Atropine also attenuated the plasma aldosterone response to a low dose angiotensin II infusion (2 ng/kg.min; control, 449 +/- 99 pmol/L; atropine, 297 +/- 78 pmol/L; P less than 0.05). In contrast, atropine had no effect on the plasma aldosterone response to a bolus dose (250 micrograms) of ACTH. Neither atropine (0.6 mg, iv) nor the cholinergic muscarinic agonist bethanechol (5 mg, sc) alone elicited a change in plasma aldosterone. Collectively, these data provide evidence for cholinergic modulation of aldosterone secretion in man. We conclude that cholinergic mechanisms may facilitate the aldosterone responses to angiotensin-II and metoclopramide, but not to ACTH.     

Abnormal regulation of adrenal angiotensin II receptors in spontaneously hypertensive rats

The aldosterone response to angiotensin II is blunted in spontaneously hypertensive rats (SHR). To determine whether this blunting is due to a defect in angiotensin II receptors, we assessed angiotensin II binding to intact adrenal glomerulosa cells in SHR and normotensive Wistar-Kyoto rats (WKY) that had been fed high or low sodium diets before sacrifice. In rats on high salt intake, we observed no difference between the two strains in either receptor affinity (Kd = 1.0-1.2 nM) or binding capacity (36,000-38,000 receptors/cell). When sodium-restricted, WKY increased receptor content more than fourfold to 167,000 sites/cell. SHR increased receptor number to only 103,000 sites/cell, which was significantly (p less than 0.01) less than the WKY increase. The cause of the abnormal receptor regulation remains unclear. Two known receptor regulators, the plasma angiotensin II level and the state of potassium balance, were similar in the two strains. Our results suggest that the blunted aldosterone response to angiotensin previously reported in SHR is due to abnormal angiotensin receptor up-regulation in the adrenal gland in response to sodium restriction.