Aldosterone response to angiotensin II during hypoxemia

Exercise in humans causes increases in plasma renin activity (PRA) and plasma aldosterone concentrations (PAC) except when performed at high altitude or while the subjects breathe hypoxic gas. Under those conditions, PRA increases with exercise but PAC does not. We speculated that the PAC suppression during hypoxemic exercise was due to hypoxemia-induced release of a circulating inhibitor of angiotensin II-mediated aldosterone secretion. To test this hypothesis, we measured the PAC response to graded infusions of angiotensin II during hypoxemia and normoxemia. Eight normal volunteers were given increasing doses of angiotensin II (first 2 ng X kg-1 X min-1 and then 4, 8, and finally 12 ng X kg-1 X min-1, each for 20-min periods) on 2 separate days, once while breathing room air and the other day while breathing hypoxic gas adjusted to maintain the subjects' hemoglobin saturation at 90%. The PAC response to different doses of angiotensin II did not significantly differ during hypoxemia from normoxemia. We conclude that our model of hypoxemia does not cause release of an inhibitor of angiotensin II-mediated aldosterone release.     

Enhanced response of plasma prolactin to metoclopramide during chronic converting enzyme inhibition

The effect of chronic converting enzyme inhibition with enalapril on the PRA, PRL and plasma aldosterone responses to metoclopramide was studied in 10 patients with mild to moderate essential hypertension. Enalapril reduced supine blood pressure and increased heart rate significantly. PRA and urinary sodium excretion rose significantly. PRA levels did not change after metoclopramide neither during placebo nor during enalapril. The aldosterone response to metoclopramide was not altered by enalapril, indicating that this response is independent of the renin-angiotensin system. The PRL response to metoclopramide was considerably enhanced after 4 weeks of treatment with enalapril. It is proposed that enalapril, by decreasing the formation of angiotensin II, increases the prolactin reserve.     

Effect of hypoxemia on the renin-angiotensin-aldosterone system in humans

Hypoxemia was induced in five subjects older than 40 (group 1) and five younger than 35 yr (group 2) on normal and low-salt diets by having the subjects breathe hypoxic gas. The fractional inspired O2 of the hypoxic gas was regulated so that group 1 hemoglobin saturations fell to 90% for 1 h. Group 2 subjects had desaturation to 90% for 1 h followed by desaturation to 80% for a 2nd h. Plasma renin activity (PRA), angiotensin-converting enzyme activity (ACE), and plasma cortisol levels did not change during hypoxemia. Plasma aldosterone levels fell in both groups during the 1st h of hypoxemia. Decreases were greatest during salt restriction and were significant (P less than 0.01) for the combined groups. Plasma aldosterone levels plateaued during the 2nd h of more severe hypoxemia in group 2. Hepatic blood flow, measured by indocyanine green clearance, and the adrenal response to exogenous adrenocorticotropic hormone, measured by changes in plasma cortisol and aldosterone, were not changed by hypoxemia in group 2 subjects. These results indicate that plasma aldosterone falls during hypoxemia despite unchanged PRA, ACE, hepatic blood flow, and adrenal function.     

Human alpha atrial natriuretic peptide inhibits angiotensin stimulated aldosterone biosynthesis in bovine adrenal glands

The behaviour of aldosterone output was evaluated in isolated and superfused bovine adrenal glands during superfusion with human alpha atrial natriuretic peptide on its own or with angiotensin II or a antagonist dopaminergic drug: metoclopramide. H alpha-ANP even in high concentrations did not reduce the basal amount of aldosterone released from bovine adrenal glands, nor did it modify aldosterone response to metoclopramide, but it partially inhibited aldosterone stimulation by angiotensin II. These data suggest that atrial natriuretic factor may affect sodium secretion through the modulation of aldosterone secretion.     

Plasma vasopressin and atrial natriuretic factor in response to blood volume changes in the anaesthetized rabbit

The influence of aortic baroreceptors and vagal afferent nerves on the release of immunoreactive vasopressin (iVP) and immunoreactive atrial natriuretic factor (iANF) was examined in anaesthetized rabbits. Changes in plasma concentrations of iVP and iANF, heart rate, mean arterial pressure, and right atrial pressure were measured in response to blood volume changes (+20, +10, -10, -20%). Carotid sinus pressure was maintained at 100 mmHg (1 mmHg = 133.3 Pa), and blood volume changes were performed before and after bilateral vagotomy (VNX) in all experiments. Two experimental groups were studied: rabbits with aortic depressor nerves intact (ADNI) and those with aortic depressor nerves sectioned (ADNX). Mean arterial and right atrial pressures decreased during haemorrhage and increased in response to volume expansion. Plasma iVP concentrations increased with haemorrhage and decreased with volume expansion in the ADNI group. Plasma iANF, however, decreased with haemorrhage and increased during volume expansion in both ADNI and ADNX groups. Vagotomy caused an increase in baseline plasma iANF in the ADNX group. The responses of iANF to blood volume changes were augmented after VNX and ADNX. The results show that neither the aortic baroreceptor nor the vagal afferent input are needed for the iANF response to changes in blood volume, over the range of +/- 20%. In contrast, intact aortic baroreceptors are essential for changes in circulating iVP in this preparation.     

Effect of metoclopramide on adrenal secretion in sheep: influence of dexamethasone and sodium intake

Metoclopramide, a competitive dopamine antagonist, stimulates aldosterone in man and monkey without affecting cortisol secretion. In sheep, metoclopramide also stimulates aldosterone but ist action on adrenocortical secretion is more controversial. To clarify the action of metoclopramide in conscious sheep, the response of plasma aldosterone, cortisol, angiotensin II and potassium were studied after 0.16 and 0.64 mg/kg metoclopramide, with and without pretreatment with dexamethasone. The effect of sodium status on the response was also studied by repeating the experiments after 7 days of dietary sodium restriction. In the absence of dexamethasone, plasma aldosterone was significantly increased by metoclopramide in both sodium-replete and restricted sheep. In sodium-replete sheep, plasma cortisol was also increased by 0.64 mg/kg, and by both doses when salt-restricted. However all cortisol responses were completely suppressed by dexamethasone pretreatment. Dexamethasone also suppressed the aldosterone response to metoclopramide in sodium-replete but not in sodium-restricted sheep where significant responses of aldosterone to both doses of metoclopramide still occurred without changes in plasma angiotensin II or potassium. While a nonspecific stress effect of metoclopramide can contribute to the aldosterone response, these results show that the sheep's adrenal glomerulosa is capable of responding to metoclopramide without change in ACTH, angiotensin or potassium.     

Dopaminergic modulation of aldosterone secretion: effect of sodium balance and postural changes

The influence of an increased endogenous production of angiotensin II and of sodium homeostasis upon the response of plasma aldosterone to metoclopramide administration has been investigated in 5 normal volunteers. Our results show that the increase of plasma aldosterone after metoclopramide administration is independent of angiotensin II, ACTH and potassium, and that it increases even further due to the endogenous production of angiotensin II induced by postural changes. The state of sodium balance seems to influence the response of plasma aldosterone to metoclopramide administration as it occurs with other stimuli of aldosterone secretion.     

Dopaminergic control of aldosterone secretion in hypertensive patients chronically treated with an angiotensin converting enzyme inhibitor

To investigate whether dopamine plays a role in the regulation of aldosterone secretion during long-term blockade of the renin-angiotensin system, we studied the effect of metoclopramide, a competitive antagonist of dopamine, in 6 patients with essential hypertension chronically treated with the angiotensin converting enzyme inhibitor enalapril. All but one of these patients received a diuretic in addition to enalapril. Six hours after the daily morning dose of enalapril (10-40 mg p.o.) a 10 mg bolus dose of metoclopramide was injected intravenously. In one patient a hypotensive episode developed following metoclopramide administration. In the 5 other patients plasma aldosterone significantly rose within 30 min after metoclopramide from 51 +/- 8.7 to 128.2 +/- 29.2 pg/ml. This metoclopramide-induced release of aldosterone occurred in the absence of concomitant changes in circulating angiotensin 11, potassium and ACTH levels. Metoclopramide given during chronic blockade of the renin-angiotensin system caused anxiety and agitation in 2 patients. The increase in plasma aldosterone following competitive dopamine blockade in the face of chronic angiotensin converting enzyme inhibition, unchanged plasma potassium and ACTH levels strongly suggests that in hypertensive patients, dopamine exerts a direct inhibitory effect on aldosterone secretion.     

Fluid-electrolyte shift and renin-aldosterone responses to exercise under hypoxia

In order to describe fluid-electrolyte shift and endocrine response to exercise under moderate acute hypoxia, 8 healthy male subjects (24 +/- 3 years old) were evaluated at 40, 60, 80 and 100% VO2 max in normoxic (N) and hypoxic (H) conditions (14.5% O2). VO2 max decreased from 55.5 +/- 1.3 to 45.8 +/- 1.4 ml/kg X min in H condition. Plasma volume reductions with increasing relative workloads were similar in N (9.4%) and H (9.9%) conditions. The rise in plasma osmolality was in part related to blood lactate accumulation which occurred in both conditions. However, variations in plasma solute content and osmolality suggested that exercise under hypoxia results in a greater electrolyte loss from vascular space and in a greater K+ loss from working skeletal muscles. Increase in catecholamine concentrations were similar in normoxic and hypoxic conditions except for lower maximal norepinephrine concentration under hypoxia. Finally, although plasma renin activity increased with workload in both conditions, plasma aldosterone did not significantly change. This dissociation between renin and aldosterone suggest that aldosterone release during exercise might depend upon other factors. However, changes in plasma potassium concentration do not appear as an important stimulus for aldosterone secretion during exercise.     

Effects of angiotensin II on arterial pressure, renin and aldosterone during exercise

To evaluate the effect of isotonic exercise on the response to angiotensin II, angiotensin II in saline solution was infused intravenously (7.5 ng X kg-1 X min-1) in seven normal sodium replete male volunteers before, during and after a graded uninterrupted exercise test on the bicycle ergometer until exhaustion. The subjects performed a similar exercise test on another day under randomized conditions when saline solution only was infused. At rest in recumbency angiotensin II infusion increased plasma angiotensin II from 17 to 162 pg X ml-1 (P less than 0.001). When the tests with and without angiotensin II are compared, the difference in plasma angiotensin II throughout the experiment ranged from 86 to 145 pg X ml-1. The difference in mean intra-arterial pressure averaged 17 mmHg at recumbent rest, 12 mmHg in the sitting position, 9 mmHg at 10% of peak work rate and declined progressively throughout the exercise test to become non-significant at the higher levels of activity. Plasma renin activity rose with increasing levels of activity but angiotensin II significantly reduced the increase. Plasma aldosterone, only measured at rest and at peak exercise, was higher during angiotensin II infusion; the difference in plasma aldosterone was significant at rest, but not at peak exercise. In conclusion, the exercise-induced elevation of angiotensin II does not appear to be an important factor in the increase of blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dissociated response of aldosterone from plasma renin activity during prolonged exercise under hypoxia

6 healthy male subjects on a fixed salt-diet performed 1 hour ergocycle exercise at 65% of VO2 max in normoxic (N) and hypoxic (H) conditions. Blood samples were taken at intervals for estimations of plasma aldosterone (PAC), angiotensin converting enzyme (ACE), adrenocorticotrophic hormone (ACTH) and catecholamine concentrations. Plasma volume reductions with exercise were similar in N (4.3 +/- 1%) and H (4.0 +/- 1%). PRA response to exercise was increased by hypoxia while PAC and plasma catecholamine rose to a similar extent in both conditions. Increases in ACTH concentration occurred at the end of exercise but no difference was found between high and low altitudes. Plasma ACE remained unchanged throughout exercise in either condition. These results indicate that hypoxemia interferes with PRA-mediated aldosterone secretion. The variations in plasma ACTH levels during exercise in hypoxia do not appear responsible for this interference.     

19-hydroxyandrostenedione and 6 beta-hydroxyandrostenedione: new steroids regulated by the renin-angiotensin system in man

The changes of plasma 19-hydroxyandrostenedione (19-OH-A-dione) and 6 beta-hydroxyandrostenedione (6 beta-OH-A-dione) during the infusion of angiotensin II were evaluated and were compared with those of plasma aldosterone in man. Angiotensin II was infused into 5 normal subjects with an infusion pump at rates of 0.5, 1.0, 2.0 and 4.0 ng/kg per min. Each dose was infused for 20 min. Plasma 19-OH-A-dione rose significantly following the infusion of angiotensin II at a rate of 0.5 ng/kg per min and plasma 6 beta-OH-A-dione rose significantly following the infusion of angiotensin II at a rate of 1.0 ng/kg per min. In contrast, plasma aldosterone did not change significantly until the infusion rate reached 4.0 ng/kg per min. These results indicate that the secretion of 19-OH-A-dione and 6 beta-OH-A-dione is under the control of angiotensin II and the release of 19-OH-A-dione and 6 beta-OH-A-dione is induced earlier by the smaller doses of angiotensin II prior to the secretion of aldosterone. As 19-OH-A-dione and 6 beta-OH-A-dione amplify the action of aldosterone in bioassays using adrenalectomized rats and work as sodium-retaining and hypertensinogenic agents in intact rats, they are newly recognized biologically active steroids which are regulated by the renin-angiotensin system in man.     

Effects of truncated angiotensins in humans after double blockade of the renin system

Angiotensins different from ANG II exhibit biological activities, possibly mediated via receptors other than ANG II receptors. We studied the effects of 3-h infusions of ANG III, ANG-(1-7), and ANG IV in doses equimolar to physiological amounts of ANG II (3 pmol. kg-1. min-1), in six men on low-sodium diet (30 mmol/day). The subjects were acutely pretreated with canrenoate and captopril to inhibit aldosterone actions and ANG II synthesis, respectively. ANG II infusion increased plasma angiotensin immunoreactivity to 53 +/- 6 pg/ml (+490%), plasma aldosterone to 342 +/- 38 pg/ml (+109%), and blood pressure by 27%. Glomerular filtration rate decreased by 16%. Concomitantly, clearance of endogenous lithium fell by 66%, and fractional proximal reabsorption of sodium increased from 77 to 92%; absolute proximal reabsorption rate of sodium remained constant. ANG II decreased sodium excretion by 70%, potassium excretion by 50%, and urine flow by 80%, whereas urine osmolality increased. ANG III also increased plasma aldosterone markedly (+45%), however, without measurable changes in angiotensin immunoreactivity, glomerular filtration rate, or renal excretion rates. During vehicle infusion, plasma renin activity decreased markedly ( approximately 700 to approximately 200 mIU/l); only ANG II enhanced this decrease. ANG-(1-7) and ANG IV did not change any of the measured variables persistently. It is concluded that 1) ANG III and ANG IV are cleared much faster from plasma than ANG II, 2) ANG II causes hypofiltration, urinary concentration, and sodium and potassium retention at constant plasma concentrations of vasopressin and atrial natriuretic peptide, and 3) a very small increase in the concentration of ANG III, undetectable by usual techniques, may increase aldosterone secretion substantially.     

Effect of aldosterone on vascular angiotensin II receptors in the rat

The effect of aldosterone on the density and affinity of binding sites for 125I-labelled angiotensin II was investigated in a particulate fraction prepared from the rat mesenteric arteriolar arcades. The infusion of aldosterone 6.6 micrograms/h intraperitoneally via Alzet osmotic minipumps for 6 d produced an increase in the density of binding sites for 125I-labelled angiotensin II without change in affinity. After sodium depletion, mesenteric artery angiotensin II receptors were down-regulated as expected. An increase in the number of binding sites could be found when aldosterone was infused into sodium-depleted rats with no change in the elevated plasma renin activity. The intraperitoneal infusion of angiotensin II (200 ng X kg-1 X min-1 for 6 d) simultaneously with aldosterone resulted in down-regulation of vascular angiotensin II receptors, whereas after intravenous angiotensin II infusion (at 60 ng X kg-1 X min-1) the density of angiotensin II binding sites rose with aldosterone infusion. Plasma renin activity (PRA) was reduced and plasma angiotensin II increased in a dose-dependent fashion after angiotensin II infusion. An aldosterone concentration of 3 ng/mL for 18 h produced an increase in the number of angiotensin II binding sites in rat mesenteric artery smooth muscle cells in culture. We conclude that increased plasma aldosterone may result in up-regulation of vascular angiotensin II receptors independently of changes in plasma renin activity, and may in certain physiological states effectively antagonize the down-regulating action of angiotensin II.     

Recurrent Hyperkalaemia due to Selective Aldosterone Deficiency: Correction by Angiotensin Infusion

A patient with recurrent weakness and blurring of consciousness associated with hyperkalaemia due to aldosterone deficiency is reported. The plasma concentrations of renin, angiotensin II, and aldosterone were low and did not increase during sodium deprivation. Blood angiotensin I was also low while renin-substrate concentration was normal. Infusion of angiotensin produced a distinct rise in plasma aldosterone. The patient was treated successfully with fludrocortisol.The results support the concept that the renin-angiotensin system is an important regulator of aldosterone secretion and that in the syndrome of acquired selective hypoaldosteronism the primary abnormality may be a deficiency of renin. It is suggested that a selective lack of aldosterone should be considered in all cases of otherwise unexplained hyperkalaemia.     

Comparison of Surgery and Prolonged Spironolactone Therapy in Patients with Hypertension,Aldosterone Excess,and Low Plasma Renin

The effect of prolonged preoperative treatment with spironolactone has been studied in a series of 67 patients with hypertension, aldosterone excess, and low plasma renin. In the series as a whole a highly significant reduction in both systolic and diastolic pressures was achieved, with no evidence of escape from control during therapy lasting several years in some cases. The drug was equally effective in controlling blood pressure in patients with and without adrenocortical adenomata. Occasional unresponsive patients were encountered in both groups; pretreatment blood urea levels in these were significantly higher than in the responsive patients. The hypotensive effect of spironolactone usually predicted the subsequent response to adrenal surgery.Spironolactone in all cases corrected plasma electrolyte abnormalities; significant increases in total exchangeable (or total body) potassium and significant reductions in total exchangeable sodium, total body water, extracellular fluid, and plasma volumes were seen. Plasma urea rose during treatment and there was a slight fall in mean body weight. Significant increases in peripheral venous plasma renin and angiotensin II concentrations occurred during treatment.In two patients no increase in aldosterone secretion rate was found during treatment, although plasma aldosterone rose in three of four subjects studied.Severe side effects were rare; in only two of the 67 patients did the drug have to be stopped.In addition to its routine preoperative use, spironolactone can now be advised as long-term therapy in selected patients.     

Suppression of plasma aldosterone by chronic ACTH administration is offset by converting enzyme inhibitor

In order to elucidate the mechanism of suppression of plasma aldosterone by chronic ACTH administration, especially the role of the renin-angiotensin system and dopamine, we administered ACTH with or without MK422, a converting enzyme inhibitor, to reduce the endogenous angiotensin II in rats, and measured the plasma renin activity, plasma corticoid concentrations and urinary dopamine excretion. The plasma aldosterone concentration (PAC) was decreased after chronic ACTH administration. However, in the ACTH + MK422 administered group, aldosterone suppression was not observed. It appeared therefore that the aldosterone suppressing mechanism was independent of the weakened renin-angiotensin system following chronic ACTH administration, since PAC was not decreased in the ACTH + MK422 administered group when angiotensin II might be completely eliminated. The urinary excretion of dopamine was significantly increased in the chronic ACTH + MK422 administered group as well as in the chronic ACTH administered group. This suggested that the inhibitory effect of dopamine on aldosterone did not contribute significantly to the suppression of plasma aldosterone. The present results suggest therefore that the mechanism of suppression of plasma aldosterone following chronic ACTH administration was not dependent on the renin-angiotensin system and dopamine.     

Absent aldosterone response to metoclopramide in patients with high spinal cord transection: evidence that metoclopramide stimulates aldosterone secretion through central pathways

This study evaluates dopaminergic regulation of aldosterone secretion in 6 patients with high spinal cord transections. Administration of the dopamine antagonist metoclopramide resulted in a marked rise in plasma aldosterone and 18-hydroxycorticosterone levels in 12 normal individuals, but no change in plasma levels of these zona glomerulosa corticosteroid products in spinal cord patients. Spinal cord transected patients also did not have the rise in plasma renin activity that was observed in normals following metoclopramide administration. Basal levels of aldosterone, 18 hydroxycorticosterone, corticosterone and renin activity as well as the aldosterone responses to graded dose infusion of adrenocorticotropin were similar in the spinal cord patients and the normals. These data suggest that dopaminergic regulation of adrenal zona glomerulosa corticosteroid and renal renin secretion is absent in patients with high spinal cord transections, suggesting that intact neural pathways from the central nervous system are necessary for metoclopramide stimulation of aldosterone and renin secretion in men. Since basal plasma aldosterone levels were normal in spinal cord transected patients, it appears that the absence of dopaminergic control does not result in elevated secretion.     

Influence of season on plasma antidiuretic hormone, angiotensin II, aldosterone and plasma renin activity in young volunteers

We investigated seasonal changes in hormonal and thermoregulatory responses. Eight volunteers were subjected to the experiment at four times of the year: around the vernal and autumnal equinoxes, and at the summer and winter solstices at latitude 35° N. Plasma antidiuretic hormone (ADH), angiotensin II (ANG II), aldosterone (ALD) and plasma renin activity (PRA) were analyzed before and after water immersion. Seasonal changes in thermoregulatory responses were assessed by measuring core temperature and sweat rate during immersion of the leg in hot water (at 42°C) for 30 min in a room maintained at 26°C. The concentration of plasma ADH and ALD before water immersion was significantly higher in summer than in other seasons. The concentrations of ANG II and PRA did not show seasonal variations. Changes in tympanic temperature during water immersion showed significant differences between seasons, and were higher in winter than in other seasons. The sweat rate was significantly higher in summer than in other seasons. In summary, ADH and ALD concentrations displayed a seasonal rhythm with marked elevation in summer; this may be a compensative mechanism to prevent dehydration from increased sweat loss during summer due to heat acclimatization.     

Effect of atrial natriuretic peptide on ACTH, dibutyryl cAMP, angiotensin II and potassium-stimulated aldosterone secretion by rat adrenal glomerulosa cells

We examined the effect of rat atrial natriuretic peptide (ANP) on ACTH, dibutyryl cAMP, angiotensin II and potassium-stimulated aldosterone secretion by dispersed rat adrenal glomerulosa cells. ANP inhibited ACTH, angiotensin II and potassium-stimulated aldosterone secretion with IC50's between 0.15-0.20 nM. Inhibition by 10 nM ANP could not be overcome with higher concentrations of these stimuli. ANP shifted the dibutyryl cAMP dose-response curve slightly to the right but did not blunt the maximal aldosterone secretory response. The sites of ANP inhibition in the aldosterone biosynthetic pathway for these stimuli were also examined. ANP inhibited activation of the cholesterol desmolase (CD) enzyme complex by ACTH, angiotensin II and potassium. Activation of the corticosterone methyl oxidase (CMO) enzyme complex by potassium was inhibited by ANP, however, activation by ACTH was not blocked. We concluded that: 1) ANP is a potent inhibitor of ACTH, angiotensin II and potassium-stimulated aldosterone secretion; 2) inhibition of ACTH stimulation is primarily due to lower cAMP levels and; 3) inhibition of angiotensin II and potassium stimulation reflects a block in the activating mechanism of the CMO and/or CD enzyme complexes, whereas CD but not CMO activation by ACTH is inhibited by ANP.