Corticotropin releasing factor activity of CRF 41 in normal man is potentiated by angiotensin II and vasopressin but not by desmopressin.

Multiple hypothalamic factors seem to influence ACTH release. In vitro and/or in vivo animal models have shown that angiotensin II, vasopressin and some of its analogs are ACTH secretagogues capable of potentiating the corticotropin releasing activity of CRF41. Since these effects are controversial in man, we investigated in 3 groups of volunteers the corticotropin releasing activity of a 2h-infusion of angiotensin II (7 ng/kg/min), vasopressin (1 ng/kg/min) and desmopressin (1 ng/kg/min) given alone or in combination with a bolus injection of 100 micrograms CRF41 by measuring plasma concentrations of ACTH, cortisol, dehydroepiandrosterone and delta 4-androstenedione. Given alone angiotensin II and desmopressin had no significant effect in contrast to vasopressin which increased significantly the ACTH and steroid levels. Angiotensin II and vasopressin were both able to potentiate the corticotropin releasing activity of CRF41, whereas desmopressin was unable to produce such a potentiation. These results suggest that in man vasopressin and angiotensin II may well regulate the responsiveness of the pituitary-adrenal axis in various physiological or pathophysiological situations.

Long-term effects of ACTH combined with angiotensin II on steroidogenesis and adrenal zona glomerulosa morphology in the rat.

To test the hypothesis that the trophic action of angiotensin II on the adrenal zona glomerulosa may allow a sustained stimulation of aldosterone by ACTH by preventing the morphological changes of the zona glomerulosa cells into zona fasciculata-like elements we investigated the effects in rats of a 6-day treatment with ACTH (100 micrograms/kg/day) alone or combined with angiotensin II (300 ng/kg/day) on corticosterone and aldosterone production and adrenal morphology. The responsiveness of both steroids to an acute ACTH dose was also studied on the last day of long-term treatment. Morphologic data showed that prolonged ACTH treatment stimulated the growth of zona glomerulosa cells, though it transformed the tubulo-lamellar cristae of mitochondria into a homogeneous population of vesicles. Angiotensin II furthered the trophic effects of ACTH but prevented the mitochondrial transformation. Despite its ability to conserve the well differentiated aspect of the zona glomerulosa cells, the administration of angiotensin II was unable to prevent the fall in the secretion of aldosterone caused by chronic ACTH treatment and its subsequent unresponsiveness to ACTH stimulation.

Aldosterone in panhypopituitarism: dynamic studies and therapeutic effects in Sheehan's syndrome.

To appreciate the aldosterone secretion status in panhypopituitarism, the steroid response to stimulation was studied in a homogeneous group of 20 female patients presenting with global hypopituitarism. Specific effects of glucocorticoid and thyroid hormone deficiencies were also assessed by studying the same patients before and after cortisol (F) and cortisol plus thyroid hormone (F + T) substitution. The patients were submitted to two stimulation tests before and after each treatment: the orthostasis test (O-T) and the furosemide test (Furo-T). The results obtained in the 3 situations were compared, each patient serving as her own control. Comparison was also established with the results obtained in healthy women serving as control group. Basal plasma aldosterone levels in the untreated patients were not significantly different from those of the control group (5.43 +/- 0.51 vs 7.16 +/- 0.80 ng/100 ml, mean +/- SEM). They were significantly lower after F (3.91 +/- 0.42) and F + T substitution (3.31 +/- 0.23) than those of untreated patients and controls. Response to both stimulations was blunted in the untreated patients (O-T: 14.10 +/- 2.81; Furo-T: 9.78 +/- 1.35) as compared to the control group (O-T: 26.46 +/- 4.67; Furo-T: 23.96 +/- 3.30). F treatment did not improve the response to either tests, (O-T: 11.42 +/- 2.55; Furo-T: 10.32 +/- 1.23). F + T treatment normalized the orthostasis response (20.83 +/- 3.59) and increased the response to furosemide which remained, however, lower (15.28 +/- 1.83) than in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

RU 486 inhibits peripheral effects of glucocorticoids in humans.

RU 486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)17 alpha-(prop-1-ynyl)estra-4,9-dien-3-one] is a synthetic steroid receptor antagonist. To evaluate the peripheral antiglucocorticoid action of this compound, we investigated its ability to antagonize cutaneous steroid-induced vasoconstriction. This phenomenon, produced by three different topical steroids in six normal men, was consistently and significantly attenuated or abolished by oral administration of 6 mg/kg RU 486. This demonstration of a peripheral action of RU 486 is important in relation to the potential therapeutic use of this well tolerated drug in states of hypercortisolism. It also indicates that the cutaneous vasoconstrictor effects of topical steroids are mediated by occupancy of glucocorticoid receptors.

Effect of spironolactone on electrolytes, renin, ACTH and corticosteroids in the rat.

Spironolactone (S), known to act as a mineralocorticoid antagonist, has been shown in some circumstances to inhibit steroid biosynthesis. To investigate these two actions in vivo in the rat, animals fed a normal or low Na+ diet were treated with S for 7 days. In animals fed a normal Na+ diet, urinary and faecal electrolytes, aldosterone and corticosterone excretion were measured daily, plasma renin, aldosterone, corticosterone, ACTH, progesterone, DOC and 18-OH-DOC were determined after 4 and 7 days of treatment. In animals fed a low Na+ diet, urinary electrolytes were measured daily and plasma and urinary aldosterone and corticosterone were determined at intervals during the introduction of the diet and in the course of treatment. On a normal Na+ diet, S induced a slight non significant rise in the urinary Na+/K+ ratio on the first day of treatment, no change in faecal electrolyte excretion, and a sustained increase in aldosterone but not in corticosterone excretion. It produced a 6-fold elevation in plasma aldosterone levels, a less marked rise in renin and progesterone, a delayed increase in DOC and no change in ACTH, 18-OH-DOC or corticosterone concentration. On a low Na+ diet, treatment induced a rise in the urinary Na+/K+ ratio, and in urine and plasma aldosterone levels and no change in corticosterone values. Our results confirm, in the intact rat, the antimineralocorticoid action of S characterized by an increase in Na+ excretion but no change in K+ elimination. No inhibitory effect of spironolactone on aldosterone, corticosterone or 18-OH-DOC biosynthesis could be demonstrated in our experimental model.

Mineralocorticoid escape in man: role of renal prostaglandins.

The role of renal prostaglandins (PGE2 and PGF2 alpha) and kallikrein in the renal escape from excess mineralocorticoid has been evaluated in 10 normal volunteers on a high sodium diet. Escape from 9-alpha-fluorohydrocortisone (9-alpha-FF) administered for 12 days (0.6 mg daily) occurred within 4-5 days when 345 +/- 50 mmol sodium had accumulated. Indomethacin, a cyclooxygenase inhibitor, was then administered for 3 days while maintaining 9-alpha-FF. This was followed by a further cumulative gain of 105 +/- 28 mmol sodium after which escape resumed. Potassium balance remained negative throughout the study. Both PGE2 and PGF2 alpha excretion increased significantly under 9-alpha-FF from respective control values of 220 +/- 50 and 818 +/- 86 ng/24 h. to 610 +/- 317 and 1213 +/- 132 ng/24 h at the time of escape. Concomitantly urinary kallikrein increased from 1.1 +/- 0.2 to 2.5 +/- 0.3 units/24 h. Creatinine clearance increased from a mean baseline value of 111 +/- 4 to 123 +/- 4 ml/min during the same period. Indomethacin produced an inhibition of prostaglandin excretion without significant alteration of kallikrein excretion. Overall these results and particularly the transient sodium retention induced by indomethacin at the time of mineralocorticoid escape, suggest that prostaglandins may contribute to the escape phenomenon, whereas the role of kallikrein does not appear to be determinant.

Response of the renin-aldosterone system and antidiuretic hormone to oral water loading and hypertonic saline infusion during and after pregnancy.

Amongst the man physiological changes in human pregnancy are the sustained stimulation of the renin-angiotensin system and a decreases in plasma osmolality (Posm). In this study the effect osmolar and water loading on the renin-angiotensin system and arginine vasopressin (AVP) secretion has been tested in seven women during the third trimester and again 8-10 weeks after delivery. Pregnant women had markedly increased plasma renin substrate (PRS), plasma renin activity (PRA) and plasma renin concentration (PRC) values as well as aldosterone levels when compared to their post-partum values. Osmolar loading with intravenous infusion of hypertonic saline resulted in a decrease in PRA and aldosterone levels both during and after pregnancy but even at the end of the infusion the pregnant women still had values greater than the pre-infusion levels obtained post-partum. Surprisingly, oral water loading also significantly decreased PRA and aldosterone levels in pregnancy, possibly related to the redistribution of extracellular fluid centrally when the pregnant women were in left lateral recumbency. Despite the decreased basal Posm of pregnancy, urinary AVP increased and decreased appropriately during osmolar and water loading. Exact characterisation of the resetting of the threshold for AVP secretion in pregnancy awaits the development of a reliable radioimmunoassay for the determination of AVP in human pregnancy plasma.

Plasma aldosterone response to acute stimulation in panhypopituitarism.

The influence of acute stimulation by ACTH, upright posture and angiotensin II on plasma aldosterone levels was assessed in human panhypopituitarism. While stimulation by ACTH in hypopituitary patients induced a plasma aldosterone increase similar to that observed in healthy controls, stimulation by upright posture or by infusion of angiotensin II resulted in a lower plasma aldosterone response than in controls in most of the patients. These results suggest that the presence of an anterior pituitary hormone, most likely ACTH, directly or indirectly exerts a permissive action on aldosterone secretion in man.

Primary aldosteronism with bilateral adrenal adenomas.

An unusual case of primary aldosteronism with bilateral single adenomas is reported. The two tumors were revealed by computerized axial tomography and subsequently confirmed by surgical exploration. Spironolactone therapy prior to the operation induced the formation of spironolactone bodies in only one of the two adenomas. As it has been postulated that these cytoplasmic inclusions may reflect the activity of the adenomatous cells, the presence of the bodies in a single adenoma would indicate a unilateral source of the hyperaldosteronism. Thus, the existence of spironolactone bodies could corroborate the data of functional localizing tests more closely than the morphological findings of computerized tomography.

Detection of Na+ and K+ in the rat adrenal cortex with the electron microprobe.

1. In order to demonstrate whether modification of aldosterone secretion is mediated by parallel changes of K+ in the adrenal zona glomerulosa, the total (intracellular+extracellular) Na+ and K+ content of the rat adrenal cortex was determined with the electron microprobe. 2. Groups of rats were submitted to one of the following dietary regimens: standard, low Na+, high K+ or high Na+. 3. Distribution of Na+ and K+ across the zona glomerulosa and zona fasciculata was compared. Standards of known electrolyte concentration were also analysed. 4. The [Na+] was found to be greater in the zona glomerulosa than in the zona fasciculata but K+ was distributed evenly in both zones. This was independent of dietary regimen. 5. Aldosterone production, assessed by plasma aldosterone concentrations, could not be correlated with zona glomerulosa K+ content.

Effect on plasma aldosterone, renin activity and cortisol of acute volume depletion induced by ethacrynic acid under constant infusion of angiotensin II and dexamethasone in man.

The influence on plasma aldosterone of acute volume depletion induced by ethacrynic acid was studied in man. The experiments were performed during the morning in supine healthy males receiving a control infusion of 5% glucose or an infusion of angiotensin II (AII) to suppress endogenous renin production or an infusion of dexamethasone to suppress endogenous ACTH. Ethacrynic acid induced in all circumstances a similar diuresis and volume depletion. The rise of plasma renin activity (PRA) was effectively suppressed by AII and the rise of plasma cortisol by dexamethasone. Plasma aldosterone (PA) rose markedly even when the elevation of PRA or cortisol were suppressed. Yet when both endogenous renin and ACTH secretion were blocked, PA rose much less after ethacrynic acid. This residual increase could be attributed mainly to a decrease of the metabolic clearance rate (MCR) of aldosterone which had been measured before and after ethacrynic acid administration. The data presented indicate that multiple factors influencing PA after acute volume depletion could be dissected out and that renin, ACTH and a decrease of the MCR each contribute to the elevation of PA.

Influence of acute administration of human growth hormone and alpha-MSH on plasma concentrations of aldosterone, cortisol, corticosterone and growth hormone in man.

The effect of acute administration of human growth hormone (HGH) and of alpha-melanocyte stimulating hormone (alpha-MSH) on plasma aldosterone, cortisol, corticosterone and growth hormone has been studied in normal man and in patients with panhypopituitarism. There is no acute effect of exogenous HGH on plasma levels of aldosterone, cortisol and corticosterone in normal man and in patients with panhypopituitarism. The plasma level of immunoreactive HGH measured during acute HGH infusion in man does not seem to be proportional to the dose administred in our study. Alpha-MSH raises the concentartion of plasma HGH, BYT THIS STIMULATION IS NOT DOSE-DEPENDENT. Aldosterone, cortisol and corticosterone concentrations are not influenced by the elevation of HGH mediated by alpha-MSH in normal man. Although in some patients with panhypopituitarism an elevation of plasma aldosterone concenntration following alpha-MSH infusion is observed, it is unlikely that MSH is directly involved in the acute regulation of aldosterone secretion in healthy subjects.