Beta-endorphin attenuates the serum cortisol response to exogenous adrenocorticotropin

Controversy surrounds the issue of whether beta-endorphin affects adrenal steroidogenesis. Recent work has both supported and refuted the claim that beta-endorphin stimulates a rise in serum aldosterone. We investigated the role of beta-endorphin in adrenal steroidogenesis by examining its potential modulation of the response of serum cortisol to exogenous ACTH (Cosyntropin). Four of five normal men received: 1) synthetic beta-endorphin (1 microgram/kg X min) for 30 min, followed by a bolus dose of 0.2 micrograms ACTH; 2) beta-endorphin (100 micrograms, iv), followed by 0.2 micrograms ACTH iv; 3) 0.2 micrograms ACTH iv; and 4) beta-endorphin (100 micrograms iv) alone. The integrated cortisol response to exogenous ACTH, calculated as the area under the cortisol response curve, was significantly less when the ACTH infusion was preceded by the 30-min beta-endorphin infusion than when administered alone [163 +/- 50 (SE) microgram/dl X min vs. 282 +/- 51 micrograms/dl X min, respectively; P less than 0.01]. By contrast, there was no difference between the integrated cortisol response to exogenous ACTH alone and exogenous ACTH after the bolus dose of beta-endorphin (282 +/- 51 vs. 293 +/- 39 micrograms/dl X min, respectively). Beta-Endorphin (30-min infusion or 100-micrograms bolus dose alone) caused no change in serum aldosterone, dehydroepiandrosterone, or PRA. Serum PRL levels, however, were raised significantly (P less than 0.05) by the 30-min infusion of beta-endorphin. The infusion and bolus doses of beta-endorphin raised plasma beta-endorphin levels to over 100,000 pg/ml and 5,000 pg/ml, respectively. We conclude that very high plasma levels of beta-endorphin may influence the response of cortisol to ACTH through a direct effect on the adrenal cortex. However, even in disease states such as Addison's and Nelson's diseases, such levels of plasma beta-endorphin are not known to be achieved.     

Effect of upright posture on the aldosterone responses to dopamine, metoclopramide, angiotensin II, and adrenocorticotropin

Aldosterone secretion in man is stimulated by potassium (K), ACTH, and angiotensin II (AII) and inhibited by dopamine (DA). In normal sodium-replete supine individuals, aldosterone secretion is under maximum tonic inhibition by DA and is not inhibited further by DA administration. Sodium depletion alters plasma aldosterone responses to secretogogues. Upright posture, another physiological stimulus to aldosterone secretion, recently was demonstrated to sensitize the adrenal cortex to inhibition of aldosterone secretion by a large quantity of DA (4.0 micrograms/kg X min). The effect of upright posture on aldosterone responses to other secretogogues is unknown. In this study, we investigated the effect of upright posture on aldosterone responses to low infusion rates of DA, to the DA antagonist metoclopramide (M) and to AII and ACTH. Fourteen normal men eating a normal sodium diet were studied. In eight, PRA, plasma aldosterone (PAC), plasma cortisol (F), and serum K concentrations were determined after 4 h of upright posture and infusion of vehicle (D5W) or DA at 0.1, 0.4, and 2.0 micrograms/kg X min. Six other normal men were kept supine for 3 h and, on separate days, upright for 3 h and given iv M (10-mg bolus dose), AII (1 and 4 pmol/kg X min for 30 min), and ACTH (20 and 120 mU/h for 30 min). PAC, PRA, F, and K were measured before and after these three secretogogues were administered. In the presence of vehicle, mean PAC increased by 15.1 +/- 4.3 (+/- SEM) ng/dL after 4 h of upright posture. In the presence of DA infused at 0.1, 0.4, and 2.0 micrograms/kg X min, the PAC response to upright posture was decreased to 9.7 +/- 2.5 (P = NS), 7.5 +/- 3.9 (P less than 0.05), and 8.1 +/- 2.0 (P less than 0.05) ng/dL, respectively. This occurred without a decrease in PRA, F, or K. The stimulation of PAC 10 and 20 min after a 10-mg bolus dose of M was 9.6 +/- 3.3 and 9.3 +/- 2.6 ng/dL, respectively, in supine subjects and 8.3 +/- 2.3 and 10.8 +/- 3.4 ng/dL 10 and 20 min after the M dose in upright subjects. The responses of PAC to ACTH and AII also were unchanged after 3 h of upright posture. We conclude that upright posture sensitizes the adrenal cortex to inhibition of aldosterone secretion by DA without affecting other modifiers of aldosterone secretion.(ABSTRACT TRUNCATED AT 400 WORDS)     

Aldosterone regulates salivary sodium secretion in cattle

Intravenous infusion of aldosterone (10 microgram/kg body wt per h for 5 h) in four 2-month-old calves decreased salivary and urinary sodium (Na+) concentration and increased salivary potassium (K+) concentration without modifying salivary flow or urinary K+ concentration. Intravenous angiotensin II infusion (0.3 microgram/kg body wt per min for 1 h) in four Na+-replete 16-month-old bulls decreased salivary Na+ concentration and increased that of K+. It also increased plasma cortisol and plasma aldosterone concentrations, and decreased plasma renin activity (PRA). In four 16-month-old bulls Na+ deficiency (induced by chronic cannulation of the right parotid duct and loss of saliva for 5 days) had similar effects to those observed following aldosterone infusion in calves: a decrease in salivary Na+/K+ ratio. This decrease was associated with an increase in PRA and an increase in plasma aldosterone concentration. In these animals a close positive relationship was observed between PRA and plasma aldosterone concentration (r = 0.91; n = 20; P less than 0.01). Thus in cattle, during Na+ deficiency, the effect of aldosterone on parotid glands participates in the regulation of Na+ metabolism.     

Central dopaminergic regulation of aldosterone secretion in sheep

Central dopaminergic mechanisms involved in the regulation of plasma aldosterone concentration were investigated in 16 conscious sheep following Na depletion with intramuscularly administered furosemide. Intracerebroventricular infusion of dopamine (20 micrograms/min) decreased plasma aldosterone significantly to 52 +/- 8% of basal level and increased plasma renin activity (PRA) significantly to 172 +/- 25% of basal level in this animal model. In addition, intracerebroventricular infusion of the dopamine antagonist metoclopramide (20 micrograms/min) in artificial cerebrospinal fluid vehicle significantly increased aldosterone levels to 144 +/- 14% of basal level and decreased PRA to 62 +/- 5% of basal value. Neither intracerebroventricular infusion of the vehicle nor intravenous infusions of metoclopramide or dopamine at the same doses changed aldosterone or PRA levels. Intracerebroventricular bolus injections of metoclopramide (20 micrograms/kg in 0.4 ml of vehicle) were also effective, increasing aldosterone levels to 266 +/- 22% of basal level and decreasing PRA to 70 +/- 12% of basal level. Intravenous bolus injections of the same dose of metoclopramide were ineffective. Dopamine was infused intracerebroventricularly into two uniadrenalectomized sheep with the remaining adrenal transplanted to the neck. Aldosterone levels were decreased to 49 +/- 10% of basal level, and PRA was increased to 157 +/- 10% of basal value. None of the infusions or injections changed arterial or intracranial pressure, or plasma K, Na, and cortisol levels. These data indicate that endogenous or exogenous dopamine may act on central dopamine receptors to decrease plasma aldosterone concentration by an unknown humoral mechanism. The known aldosterone regulators, plasma Na, K, angiotensin II, and adrenocorticotropic hormone, are not involved in the regulation.     

Renin and aldosterone secretion under converting enzyme inhibition

The converting enzyme inhibitor (CEI) is known to inhibit the conversion of angiotensin I to angiotensin II. In order to analyse the regulatory mechanisms involved in aldosterone secretion independent of renin-angiotensin system, one of the CEIs, SQ 14,225 was infused to the dogs in association with several pharmacological agents. To the mongrel dogs under pentobarbital anesthesia, SQ 14,225 was administered intravenously as a bolus injection (0.5 mg/kg), followed by two hour infusion (0.5 mg/kg/hr). The effects of several pharmacological agents on plasma renin activity (PRA) and aldosterone concentration (PA) were examined in the condition in which endogenous angiotensin II production was blocked by CEI. PRA was increased significantly from the basal level (6.4 +/- 1.2; mean +/- SEM) to 14.1 +/- 2.6 ng/ml/hr 60 min after the administration of SQ 14,225. PA, on the other hand, was decreased from 12.2 +/- 3.6 to 7.6 +/- 2.2 ng/dl. The CEI-induced increase in PRA was completely blocked by infusion of angiotensin II (40 ng/kg/min), physiological saline (0.25 approximately 0.44 ml/kg/min), pretreatment of propranolol (0.5 mg/kg) or norepinephrine (200 ng/kg/min). Both pindolol and indomethacin had no significant effect on the CEI-induced increase in PRA. Increase in PRA was also observed by the infusion of furosemide, prostaglandin 1 or E1. PA was increased by KCl infusion (1.0 mEq/kg/hr), but was not affected significantly by the administration of furosemide, pindolol, prostaglandin A1 or E1, during the SQ 14,225 infusion. An elevation of PRA observed under the converting enzyme inhibition, was considered to be due to decreased feedback inhibition as a result of reduction of angiotensin II formation. It was suggested from the present results, that the CEI-induced increase in PRA might be mediated by beta-receptor and baroreceptor in addition to the direct negative feedback by angiotensin II. The present data also suggested that both furosemide and prostaglandins stimulated aldosterone secretion via the renin-angiotensin system, rather than by acting directly on the adrenal cortex.     

Adrenocorticotropin stimulation of aldosterone: prolonged continuous versus pulsatile infusion

Continuous iv administration of ACTH leads to a sustained stimulation of cortisol but a transient stimulation of aldosterone followed by a decline to prestimulation levels by 72 h. Since CRH and ACTH are released in a pulsatile pattern in man, this study sought to investigate whether pulsatile administration of alpha-cosyntropin-(1-24) would lead to the maintenance of aldosterone stimulation over time. Eight normal male subjects on a 10-meq sodium, 100-meq potassium diet received both a continuous and a pulsatile (0.33 U ACTH/pulse over 15 min, pulsed every 2 h) infusion of cosyntropin (4 U/24 h) for 48 h (n = 4) or 72 h (n = 4). Aldosterone and cortisol were sampled every 6 h, and PRA and angiotensin-II every 24 h. Continuous infusion led to a stimulation of aldosterone followed by a progressive decline to preinfusion levels by 72 h [preinfusion 29 +/- 5 ng/dL (810 +/- 139 pmol/L); 72 h, 38 +/- 10 ng/dL (1054 +/- 277 pmol/L); P = 0.40]. Pulsatile infusion led to a stimulation of aldosterone which was maintained up to 72 h [preinfusion 33 +/- 7 ng/dL (915 +/- 194 pmol/L); 72 h, 85 +/- 13 ng/dL (2358 +/- 361 pmol/L); P less than 0.05]. Regression analysis of aldosterone (y) over time (x) from the peak level at 18 h for the continuous infusion showed a significant negative relation (r = 0.63; P = 0.001), indicating a progressive decline in aldosterone. However, for the pulsatile infusion, there was no relation (r = 0.02; P = 0.85), indicating maintenance of aldosterone levels. There were no significant differences in sodium, potassium, PRA, angiotensin-II, or cortisol between infusions to explain these differences in aldosterone levels. Therefore, pulsatile infusion of cosyntropin maintains aldosterone secretion over time.     

Dopamine inhibits the aldosterone response to upright posture

Aldosterone secretion in man is stimulated by potassium, ACTH, and angiotensin II and is inhibited by dopamine (DA). In normal sodium-replete supine individuals, aldosterone secretion is under maximum tonic inhibition by DA. Dopaminergic control of aldosterone secretion is modified by dietary sodium depletion. To determine the physiological significance of dopaminergic inhibition of aldosterone secretion, we studied the effect of DA on the aldosterone response to upright posture. Twelve normal men were studied while eating an ad libitum sodium diet, and the effect of DA was determined in the supine and upright positions. Plasma aldosterone (PAC), plasma cortisol (F), plasma aldosterone-stimulating factor (ASF), PRA, and blood pressure were measured while the men were supine and after 4 h of upright posture during an infusion of 5% dextrose vehicle and during a DA infusion of 4.0 micrograms/kg X min. The men also were studied as a time control in the supine position while receiving vehicle or DA. PAC increased from a mean basal value of 20.4 +/- 3.2 ng/dl (+/- SE) by 25.9 +/- 5.1 ng/dl to a peak of 44.4 +/- 2.4 ng/dl in response to upright posture during vehicle infusion. The PAC response to upright posture was reduced to 7.4 +/- 1.8 ng/dl (P less than 0.05) when DA was infused. The increase in PRA with upright posture was 3.7 +/- 1.3 ng/ml X h during the vehicle infusion and 4.1 +/- 1.1 ng/ml X h (P = NS) during the DA infusion. ASF, F, and blood pressure were not altered by upright posture and DA. PAC did not change in the six men infused with DA while supine. Therefore, DA inhibits upright aldosterone responses without affecting PRA, ASF, or F.     

Inhibition of captopril-induced increase in plasma renin activity by propranolol

The inhibition of renin release by angiotensin II (AII) is well documented. However, the interaction of this short loop feedback mechanism of AII with the sympathetic nervous system is still unclear. This study was designed to investigate the possible functional relationship between AII and the beta-adrenergic receptors with respect to renin release in vivo. First, the effect of propranolol on captopril-induced renin release was examined in conscious rats. Secondly, the effect of AII on isoproterenol-induced renin release was determined. Captopril (1 mg/Kg) increased plasma renin activity (PRA) from 1.6 +/- 0.3 ng/ml/hr to 4.5 +/- 0.6 ng/ml/hr (p less than 0.01). In contrast, there was no significant change in PRA in rats which received both captopril and propranolol (before 0.9 +/- 0.2 ng/ml/hr, after 1.3 +/- 0.3 ng/ml/hr). Thus, propranolol attenuated the increase in PRA caused by captopril. Isoproterenol infusion (0.1 micrograms/Kg/min) provoked a significant increase in PRA (before 1.3 +/- 0.4 ng/ml/hr, after 6.6 +/- 1.7 ng/ml/hr, p less than 0.01). AII infusion in combination with isoproterenol also increased PRA from 1.6 +/- 0.4 ng/ml/hr to 5.2 +/- 0.3 ng/ml/hr (p less than 0.01). AII in this dose did not suppress isoproterenol-induced renin release. These results suggest that the beta-adrenergic receptor mediating renin release is functionally located distal to the AII receptor in the short loop mechanism controlling renin release.     

Responses of plasma renin activity, aldosterone, adrenocorticotropin, and cortisol to dermorphin, a new synthetic potent opiate-like peptide, in man

This study was designed to investigate the effect of dermorphin (D), a new synthetic potent opiate-like peptide (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), on PRA, plasma aldosterone (PA), plasma cortisol (PC), and plasma ACTH levels in normal men. D infusion (5.5 micrograms/kg X min for 30 min) significantly increased PRA (P less than 0.01) and decreased PC levels (P less than 0.02). D produced a small decrease in ACTH and a small increase in PA. Pretreatment with the opioid receptor antagonist naloxone (N) blunted the D-induced PRA increase and completely prevented the D-induced PC decrease, but enhanced PC and ACTH levels. These data indicate that the action of D is mediated through opioid receptors, and are consistent with the conclusion that 1) D, a new opioid peptide, increases PRA levels, perhaps via activation of the sympathetic nervous system, providing evidence that opioid peptides may exert an influence on renin secretion; and 2) D suppresses PC levels, perhaps by affecting ACTH secretion, corroborating previous observations that opioid peptides might affect the function of the pituitary-adrenocortical axis.     

Measurement of plasma renin concentration using exogenous human renin substrate in normal subjects: correlation with plasma renin concentration and plasma aldosterone concentration.

Measurement of plasma renin concentration (PRC) was done in normal subjects at rest and under acute stimulation of renin release under unrestricted sodium intake. Concurrent measurements of plasma renin activity (PRA) and plasma aldosterone concentration (PA) were carried out. The mean values of PRC at rest and after stimulation of renin release were 12.8 +/- 1.3 (SEM) and 21.7 +/- 4.4 (SEM) ng AT I/ml/h, respectively. These corresponded to renin contents of 3.4 +/- 0.34 (SEM) X 10(-5) Goldblatt units and 5.8 +/- 0.36 (SEM) respectively. The mean percent increase of PRC (82.1 +/- 19.3 (SEM)) %) was almost indentical to that of PA (81.5 +/- 16.4 (SEM) %), but differed from that of PRA (269 +/- 83.1 (SEM) %). A very high correlation between concurrent PRC and PA (r = 0.92, P less than 0.001) was found in normal subjects at rest and under acute stimulation of renin release. A good correlation between PRC and PRA (r = 0.85, P less than 0.001) was also observed. However, a higher correlation between percent increases of PRC and PA (r = 0.92, P less than 0.001) than that of PRA and PA (r = 0.80, 0.01 less than P less than 0.005) was found. Results show that PRA is a good index of the renin content in plasma in normal subjects at rest and PRC reflects actual renin concentration in plasma at rest as well as under stimulation of renin release.     

The systemic beta-adrenergic pathway to renin secretion: relationships with the renal prostaglandin system

The relationship between renin release evoked by circulating beta-agonists and the renal prostaglandin (PG) system is incompletely defined. Thus, we evaluated systemic and renal hemodynamic responses to iv (0.5 micrograms/kg X min) and intrarenal arterial (0.6 micrograms/kg X min) infusions of the beta1-agonist prenalterol (PNL) in four separate groups of anesthetized dogs. Consecutive iv PNL infusions (n = 6) resulted in a reversible decrease in mean arterial pressure (130 to 117 mm Hg; P less than 0.05) and increases in cardiac output (3.93 to 4.90 liters/min; P less than 0.001), PRA (1.96 to 5.12 ng/ml X h; P less than 0.01), and 6-keto-PGF 1 alpha levels (190 to 482 pg/ml; P less than 0.01). The glomerular filtration rate and renal blood flow were modestly, but not significantly, decreased by the PNL infusions. In a second group of dogs, the infusion of the PG synthesis inhibitor indomethacin (IN; 10 mg/kg, iv; n = 7) before the second PNL infusion blunted PG increases but did not significantly modify the systemic or renal hemodynamic responses to PNL. The magnitude of the PRA and renin secretory rate (RSR) increases post-IN administration was similar to control values, but the absolute levels achieved were not as great as before IN infusion. To assess the role of the renal baroreceptor pathway to renin release after PNL, a suprarenal clamp was used to maintain a constant renal perfusion pressure during PNL infusion in a third group of dogs. In this group (n = 5), both PRA and RSR (from innervated and denervated kidneys) increased after PNL infusion, although IN again diminished the maximum PRA and RSR responses observed. Finally, the unilateral intrarenal arterial infusion of PNL in the last group of dogs did not alter PRA, RSR, or renal hemodynamics. These results demonstrate that renin release elicited by a circulating beta-agonist functions independently of PG synthesis, and that the pathway operates via an extrarenal mechanism.     

Effect of baroreceptor denervation on the inhibition of renin release by vasopressin

Previous studies have suggested that the inhibition of renin secretion by acute administration of vasopressin in conscious dogs results from a reflex reduction in renal nerve activity. In the present investigation, this hypothesis was tested by studying the effect of total baroreceptor denervation or selective low pressure baroreceptor denervation on the suppression of PRA by vasopressin in conscious, chronically prepared dogs. In eight sham-operated dogs, a 45-min infusion of vasopressin (2.0 ng/kg.min, iv) decreased PRA from 10.5 +/- 1.9 to 5.9 +/- 1.0 ng/ml.3 h (P less than 0.01). Mean arterial pressure did not change (110 +/- 10 to 107 +/- 7 mm Hg), but heart rate decreased from 84 +/- 9 to 69 +/- 8 beats/min (P less than 0.05). In contrast, vasopressin infusion failed to significantly decrease PRA in seven sinoaortic/cardiac denervated dogs (9.5 +/- 1.7 to 7.4 +/- 2.0 ng/ml.3 h), although decreases did occur in three of the dogs. Mean arterial pressure increased from 104 +/- 5 to 125 +/- 6 mm Hg (P less than 0.01), but heart rate did not change (112 +/- 4 to 107 +/- 5 beats/min). When renal perfusion pressure was maintained at the preinfusion level in three sinoaortic/cardiac denervated dogs, vasopressin infusion failed to decrease PRA (2.3 +/- 0.6 to 2.4 +/- 0.6 ng/ml.3 h). In six cardiac denervated dogs, vasopressin infusion decreased PRA from 5.3 to 0.9 to 3.1 +/- 0.7 ng/ml.3 h (P less than 0.01). Results obtained with two lower doses of vasopressin (0.5 and 1.0 ng/kg.min) were generally similar to the responses observed during infusion at 2.0 ng/kg.min. Angiotensin II (5.0 ng/kg.min) suppressed PRA in all groups of dogs. These experiments demonstrate that the inhibition of renin secretion by acute administration of vasopressin in conscious dogs is prevented by total baroreceptor denervation, but not by denervation of the low pressure baroreceptors alone. These results suggest that the suppression of renin release by vasopressin is a reflex response resulting from activation of the high pressure baroreceptors.     

Effects of incremental infusions of atrial natriuretic factor on aldosterone, renin, and blood pressure in humans

To evaluate the physiological effects of human atrial natriuretic factor-(99-126) (ANF), we infused ANF, 0.1, 0.3, and 1.0 micrograms/min, or placebo for 125 minutes on different days into six sodium-deprived normal men. During the last 45 minutes of infusion, angiotensin II, 6 ng/kg/min, was infused. Blood pressure, heart rate, plasma concentrations of ANF, aldosterone, and cortisol, and plasma renin activity (PRA) were measured before and during infusion. Steady state mean plasma ANF levels during infusion were 26.2 (placebo), 68.8 (0.1 micrograms ANF/min), 221 (0.3 micrograms ANF/min), and 648 pg/ml (1.0 microgram ANF/min). Systolic blood pressure fell significantly (with 1.0 microgram ANF/min), and diastolic pressure tended to rise in a dose-dependent manner, while heart rate was unchanged. PRA and plasma aldosterone fell during ANF infusion in a dose-dependent manner (significant with 0.3 and 1.0 microgram ANF/min infused). The blood pressure-raising and aldosterone-stimulating effects of angiotensin II were blunted by ANF (significant only with 1.0 microgram ANF/min). It is concluded that effects of ANF on blood pressure and the renin-aldosterone system occur with plasma ANF levels close to the physiological range, as well as with slightly elevated ANF levels, as observed in congestive heart failure and renal insufficiency.     

Responses of plasma bradykinin and the renin angiotensin axis to angiotensin II in hyperthyroid patients

The present investigation was undertaken to elucidate the possible interplay between the circulating kinin(s) and the renin angiotensin axis in hyperthyroidism. The responsiveness of plasma aldosterone (p-Ald), kinin (p-BK), plasma renin activity (PRA) and serum angiotensin converting enzyme activity (ACEA) to infusion of angiotensin II at a dose of 4, 8 and 16 ng/kg.min. was asessed in 15 hyperthyroid patients and 10 euthyroid controls. There was impaired angiotensin II induced response of blood pressure in hyperthyroid patients, and basal concentrations of p-Ald were 7.7 +/- 3.8 ng/dl in euthyroid controls and 12.6 +/- 3.1 ng/dl in hyperthyroid patients (p less than 0.05). As compared to the euthyroid controls, the hyperthyroid patients showed a reduced response of plasma aldosterone to angiotensin II infusion. Angiotensin II infusion increased p-BK from basal levels of 19.1 +/- 8.2 pg/ml to 31.0 +/- 7.8 pg/ml (p less than 0.05) only in hyperthyroid patients and did not increase ACEA in either group. Next, the effects of a single administration of captopril (50 mg p.o.) on blood pressure and p-BK in hyperthyroid patients and euthyroid controls were studied. In the two groups blood pressure was not changed by captopril, but p-BK increased significantly. The present results do not support the view that there may be a direct linkage between the kallikrein kinin system and the renin angiotensin axis mediated by kininase II or angiotensin converting enzyme in human peripheral blood. Also it is unlikely that kinin may play a role in the mechanism of reduced responsiveness of aldosterone and blood pressure to angiotensin II in hyperthyroidism.     

Evidence that the beta-adrenergic system and prostaglandins stimulate renin release through different mechanisms

In normal man, converting enzyme inhibition (CEI) acutely increases plasma active renin and decreases plasma inactive renin. This reciprocal relationship suggests that conversion of inactive to active renin may be important in the acute response to stimulation of renin secretion. To determine whether the beta-adrenergic system or prostaglandins (PGs) participate in the acute effect of CEI on renin, we administered captopril (50 mg) alone and with either propranolol (P; 80 mg) or a PG cyclooxygenase inhibitor [PI; indomethacin (50 mg) or ibuprofen (800 mg)] to normal subjects ingesting a 25 meq/day Na diet. Supine blood pressure fell by 12 +/- 2 (+/- SE) mm Hg with CEI alone, 10 +/- 1 mm Hg with CEI plus P, and 7 +/- 1 mm Hg with CEI plus PI. Active renin rose 8-fold (P less than 0.01), with a peak at 1-2 h, after CEI and 3-fold (P less than 0.02) in response to CEI plus P or CEI plus PI. P did not block the fall in acid-activated inactive renin compared to CEI alone. The nadir of the inactive renin response to both CEI or CEI plus P occurred at 1-2 h. PI, however, prevented the fall in inactive renin. To extend this observation, we compared the effects of infusion of a vasodilator PG (PGA1; 0.6 micrograms/kg X min) and a pure beta-agonist (isoproterenol; 0.3 micrograms/kg X min). PGA1 increased active renin 2.5-fold and decreased inactive renin by 80% (both P less than 0.02), while isoproterenol increased active renin 4.1-fold, but did not significantly change inactive renin. These data suggest that the beta-adrenergic system and PGs at least acutely stimulate renin production at different steps of its biosynthesis or secretion.     

Effect of physiological levels of atrial natriuretic peptide on hormone secretion: inhibition of angiotensin-induced aldosterone secretion and renin release in normal man

Large doses of atrial natriuretic peptide (ANP) inhibit renin and aldosterone secretion in normal man, but the effect of physiological levels is unknown. We, therefore, studied the effect of a low infusion rate of alpha-human ANP (alpha hANP; 0.5 microgram/min for 180 min) on the plasma corticosteroid response to graded physiological doses of angiotensin II (0.5, 1.0, 2.0, and 4.0 ng/kg X min, each for 30 min) and ACTH (6.25, 12.5, 25, and 50 mIU, each for 30 min) in six normal men eating a low salt diet (10 mmol sodium and 100 mmol potassium daily). The angiotensin II and ACTH infusions were given from 0900-1100 h on separate days, during which randomized infusions of placebo or alpha hANP were given from 0800-1100 h according to a single blind protocol. Plasma immunoreactive ANP levels were less than 10 pmol/L on the placebo day compared to 30-50 pmol/L during the alpha hANP infusions, and were not altered by either ACTH or angiotensin II. Compared with the control observations, there was no significant change in arterial pressure or heart rate during either the alpha hANP or angiotensin II infusions. ACTH infusions evoked an incremental response in plasma aldosterone and cortisol, and the dose-response relationship was unaltered by alpha hANP. In contrast, while an incremental and significant increase in plasma aldosterone in response to angiotensin II occurred with the placebo infusion, no significant increase occurred in response to angiotensin during the alpha hANP infusion. The slope of the angiotensin II/aldosterone regression line was significantly less during all alpha hANP infusions compared to that during the placebo infusion (P less than 0.02). In addition, on the ACTH infusion day significant suppression of both PRA (P less than 0.05) and plasma angiotensin II (P less than 0.008) occurred during the alpha hANP infusion compared to that during the placebo infusion, whereas PRA was equally suppressed by angiotensin II in the presence or absence of alpha hANP. alpha hANP also increased urine volume [176 +/- 31 (+/- SEM) vs. 113 +/- 19 mL/mmol creatinine with placebo; P less than 0.03] and sodium excretion (2.14 +/- 0.48 vs. 0.58 +/- 0.22 mmol/mmol creatinine with placebo; P less than 0.004) on the ACTH infusion days. With angiotensin II, urine volume was also significantly increased by alpha hANP (150 +/- 27 vs. 81 +/- 15 mL/mmol creatinine with placebo; P less than 0.03), and urine sodium excretion doubled.(ABSTRACT TRUNCATED AT 400 WORDS)     

DOPAMINERGIC BLOCKADE OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM: EFFECT OF HIGH AND LOW SODIUM INTAKES

Recent investigations suggest that dopamine inhibits aldosterone secretion. To test the hypothesis that dopamine contributes to the reduced aldosterone secretion on a high sodium intake, eight normal subjects were studied in metabolic balance on both 200 and 10 mmol sodium diets. On each diet, the subjects received a constant 4 h intravenous infusion of the dopamine antagonist, metoclopramide (MCP). Although MCP significantly increased plasma aldosterone (PA) throughout the infusion on both diets, the maximum increment in PA was greater on the low (37 +/- 5 ng/dl) than on the high (14 +/- 4 ng/dl) sodium intake (P less than 0.02). The greater response on the low sodium intake could not be ascribed to changes in potassium, cortisol or ACTH. However, plasma renin activity (PRA) and angiotensin II (AII) levels were significantly (P less than 0.01) increased by MCP while on the low but not the high sodium intake. We conclude that the rise in PA while on a high sodium intake reflects dopaminergic antagonism by MCP directly at the level of the adrenal gland. On the low sodium intake, the enhanced PA response to MCP probably reflects both a direct adrenal effect and an indirect effect mediated via activation of the renin-angiotensin system.     

Aldosterone Responsiveness to Angiotensin II After Sodium Restriction in Subjects With Low Renin Essential Hypertension

Plasma aldosterone (PA) responses to sodium restriction (25 mEq sodium/day for 4 days) and to graded angiotensin II (All) infusions (2,4 and 8 ng/kg/min each for 30 min) during a low sodium intake were studied in 14 subjects with low renin essential hypertension (LREH) versus 16 normotensive subjects. The PA response to sodium restriction in relation to changes in plasma renin activity (PRA) was estimated by the ratio of PA increment to PRA increment after sodium restriction (ΔPA/ΔPRA). In 8 of 14 LREH subjects, whose ΔPA/ΔPRA ratios were normal, the PA responses to the graded All doses were similar to those in the normotensive subjects. However, in the remaining 6 LREH subjects whose ΔPA/ΔPRA ratios were high the PA responses to the graded All doses were greater. Apparently some LREH subjects, whose ΔPA/ΔPRA ratios after sodium restriction were high, have an abnormally enhanced aldosterone responsiveness to All under the condition of low sodium intake.     

Diminished aldosterone responses to angiotensin II and adrenocorticotropin in hypocalcemic subjects: restoration of responsiveness with normocalcemia

ACTH-, angiotensin II (AII)-, and K+-mediated aldosterone responses in vitro are dependent on extracellular and intracellular Ca concentrations. This study examined in vivo the relationship of changes in ambient serum calcium (serum Ca) to ACTH- and AII-mediated aldosterone release in hypoparathyroid subjects. Plasma aldosterone (PA) responses to graded dose infusions of ACTH and AII were examined in hypoparathyroid (HypoPTH) patients before (n = 8) and after correction of hypocalcemia (n = 6) and compared to responses in 20 normotensive normocalcemic subjects. ACTH and AII were infused for 90 min at rates increasing from 12.5 to 50 mIU/30 min and 0.5 to 2.0 ng/kg X min, respectively. Pretreatment mean serum Ca was 6.8 +/- 0.2 (+/- SEM) mg/dl, and it rose to 9.3 +/- 0.2 mg/dl after 3-8 weeks of vitamin D administration. In the untreated HypoPTH patients, basal mean PA (5.4 +/- 1.3 ng/dl) was lower (P less than 0.01) than in the normal subjects (10.6 +/- 0.6 ng/dl) or treated HypoPTH patients (9.5 +/- 1.8 ng/dl). There was a marked reduction in PA responses to ACTH at all doses in the untreated HypoPTH patients compared to the normal subjects. With normalization of serum Ca in four patients, the mean peak PA response to ACTH (25.1 +/- 6.0 ng/dl) was not significantly different from normal (28.9 +/- 1.7 ng/dl). During graded dose AII infusion in five untreated HypoPTH patients, mean PA levels increased from 6.9 +/- 1.2 to 11.6 +/- 2.2 ng/dl; when the serum Ca was normal, the corresponding values were 8.7 +/- 1.8 and 20.2 +/- 3.61 ng/dl. There was a positive correlation (r = 0.475; P less than 0.05) between basal PA and serum Ca levels. In addition, maximum changes in mean arterial pressure in response to AII infusions were significantly greater after correction of hypocalcemia. These observations indicate that in HypoPTH patients, extracellular Ca concentrations can influence humoral aldosterone response to ACTH and AII and pressor responses to AII.     

Effect of pressor agents on blood pressure, plasma renin activity and plasma aldosterone concentration in essential hypertension.

The responses of blood pressure, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) to infusion of either angiotensin II (10 ng/Kg/min) or norepinephrine (100 ng/Kg/min) were observed in 25 patients with essential hypertension. The difference in modes of response between low renin essential hypertension and normal or high renin essential hypertension was analyzed. For comparison, 5 patients with Conn's syndrome, 4 with renovascular hypertension, and 5 normotensive subjects were also studied. Following infusion of antiotensin II the changes in diastolic blood pressure (DBP) were +24+/-3.0 mmHg in low renin essential hypertension and +25+/-3.1 mmHg in normal or high renin essential hypertension in PRA -0.28+/-0.06 ng/ml/h in low renin essential hypertension and -0.69+/-0.02 mg/ml/h in order and in PAC +3.7+/-1.4 and +7.6+/-1.8 ng/100 ml respectively. There was a significant difference in magnitude of response in PRA between the 2 groups of essential hypertension (p less than 0.05). Norepinephrine induced rise in DBP with decreases both in PRA and PAC. The mean changes in DPB were +6+/-1.4 mmHg in low renin essential hypertension and +16+/-2.2 mmHg in another and the pressor response in the later was significantly greater (p less than 0.01). The changes in PRA were -0.14+/-0.07 ng/ml/h in low renin essential hypertension and -0.67+/-0.26 ng/ml/h in normal or high renin essential hypertension, and in PAC -4.9+/-1.3 and -3.3+/-1.9 ng/100 ml respectively. The greater fall in PRA in normal or high renin essential hypertension was observed but the difference between the 2 groups of essential hypertension was not significant. The changes in PAC did not parallel the changes in PRA. Angiotensin II indcued essentially similar effects on blood pressure in both groups but the greater feedback inhibition of PRA was produced by this peptide in normal or high renin essential hypertension than in low renin essential hypertension. Norepinephrine induced significantly greater pressor effect in normal or high renin essential hypertension. The adopted dose of norepinephrine suppressed both PRA and PAC and a tendency to the greater fall in PRA was observed in normal or high renin essential hypertension. There was no difference in responses of PAC to both agents between the 2 groups of essential hypertension.