Role of angiotensin II in potassium-mediated stimulation of aldosterone secretion in the dog.

Potassium is known to enhance the aldosterone-stimulating action of angiotensin II. Such a synergistic interaction of potassium with angiotensin II could represent an action by angiotensin II to potentiate potassium as a stimulus. To examine for this effect of angiotensin II on potassium, plasma aldosterone levels were measured before and after an infusion of potassium chloride (15 meq i.v.) into dogs without and with prevention of angiotensin II formation by captopril, an angiotensin converting-enzyme inhibitor. In addition, responses to potassium were measured in a group of dogs receiving angiotensin II plus captopril. After potassium infusion, control dogs showed an increase of 7.7 +/- 1.9 (SEM) ng/dl (P less than 0.001) in the level of plasma aldosterone. In contrast, captopril-treated dogs showed no change in plasma aldosterone concentration in response to potassium. When angiotensin II was administered to captopril-treated dogs responsiveness to potassium administration was restored (plasma aldosterone concentration increased by 7.4 +/- 2.1 ng/dl, P less than 0.002). ACTH stimulated aldosterone secretion despite captopril treatment (P less than 0.001), however, ACTH produced a greater increase in the plasma aldosterone concentration in controls than in captopril-treated animals. It is evident from these results that stimulation of aldosterone secretion by potassium is considerably enhanced by angiotensin II. There appears to exist an important interdependence of these stimuli in the regulation of aldosterone secretion.     

Dopaminergic mediation of the natriuretic response to volume expansion

Previous studies have shown a direct relationship between urinary sodium excretion and both urinary dopamine excretion and plasma dopamine levels. The significance of this relationship is unclear. We therefore studied the effect of dopaminergic blockade on the renal response to volume expansion produced by the infusion of 2 L 0.9% saline solution intravenously over 4 hours in a group of six healthy adult volunteers previously shown to have appropriate sodium balance. The dopamine receptor antagonist metoclopramide was administered intravenously at a dose of 10 mg/hr throughout the study period; a separate group of control subjects received saline infusion without metoclopramide. During saline infusion urinary sodium excretion increased steadily in controls, from a basal level of 127 +/- 25 mu Eq/min to a peak value of 451 +/- 83 mu Eq/min (p less than 0.005) during the fourth hour of infusion. The study group receiving saline solution along with metoclopramide failed to show any significant increase in urinary sodium excretion over the basal levels. Cumulative sodium excretion during saline loading was significantly less in those receiving saline solution with metoclopramide (55 +/- 14 mEq) than in controls (101 +/- 15 mEq)(p less than 0.05). The plasma aldosterone levels in the control group receiving saline solution alone fell steadily from a preinfusion level of 11.0 +/- 0.9 ng/dl to the nadir of 6.5 +/- 0.9 ng/dl (p less than 0.02), reached during the third hour of infusion. In contrast, in the study group receiving saline solution with metoclopramide, the plasma aldosterone levels remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies of the control of plasma aldosterone concentration in normal man: I. Response to posture, acute and chronic volume depletion, and sodium loading

The peripheral plasma levels of aldosterone, renin activity (PRA), potassium, corticosterone, cortisol, and in some cases angiotensin II, were measured in normal subjects undergoing postural changes, acute diuretic-induced volume depletion, and alterations in dietary sodium. On a 10 mEq sodium/100 mEq potassium intake, subjects supine for 3 consecutive days had identical diurnal patterns of PRA, angiotensin II, aldosterone, cortisol, and corticosterone, with peaks at 8 a.m. and nadirs at 11 p.m. With an increase in sodium intake to 200 mEq, plasma levels of aldosterone and PRA fell to one-third their previous levels but the diurnal pattern in supine subjects was unchanged and again parallel to that of cortisol and corticosterone. There was no diurnal variation of plasma potassium on either sodium intake in the supine subjects. On a 10 mEq sodium/100 mEq potassium intake, supine 8 a.m. plasma aldosterone (55+/-7 ng/100 ml) and PRA (886+/-121 ng/100 ml per 3 hr) increased by 150-200% after subjects were upright for 3 hr. However, even though the patients maintained an upright activity pattern, there was a significant fall in plasma aldosterone to 33+/-5 ng/100 ml at 11 p.m. Potassium levels varied in a fashion parallel to aldosterone and PRA. Plasma cortisol and corticosterone had a diurnal pattern similar to that found in supine subjects. In response to acute diuretic-induced volume depletion, the nocturnal fall in aldosterone levels did not occur. The 11 p.m. value (102+/-20 ng/100 ml) and the 8 a.m. value postdiuresis (86+/-15 ng/100 ml) were both significantly greater than the prediuresis levels. PRA showed a similar altered pattern while potassium levels fell throughout the day. In some but not all studies, changes in plasma aldosterone coincided with changes in plasma cortisol, corticosterone, and/or potassium. However, in all studies, changes in plasma aldosterone were invariably associated with parallel changes in plasma renin activity and/or angiotensin II levels. These findings support the concept that PRA is the dominant factor in the control of aldosterone when volume and/or dietary sodium is altered in normal man.     

Effects of angiotensin-converting enzyme inhibition on altered renal hemodynamics induced by low protein diet in the rat.

We assessed the role of angiotensin II in mediating the alterations in renal hemodynamics known to result from low protein feeding to normal rats by examining the effect of the angiotensin-converting enzyme (ACE) inhibitor captopril. 2 wk of low protein (6% casein) diet resulted in decreased glomerular filtration rate (normal protein [NP], 1.82 +/- 0.17 vs. low protein [LP], 0.76 +/- 0.01 ml/min; P less than 0.05) and renal plasma flow (NP, 6.7 +/- 0.2 vs. LP, 3.3 +/- 0.3 ml/min; P less than 0.05); renal vascular resistance rose (NP, 8.7 +/- 0.4 vs. LP, 19.8 +/- 1.4 dyn . s per cm5; P less than 0.05). These changes were accompanied by a significant decrease in plasma renin activity (NP, 7.0 +/- 0.7 vs. LP, 4.4 +/- 0.8 ng A I/ml per h; P less than 0.05), plasma aldosterone concentration (NP, 7.0 +/- 0.6 vs. LP, 4.1 +/- 0.7 ng/dl; P less than 0.05), and urinary PGE2 excretion (NP, 3,120 +/- 511 vs. LP, 648 +/- 95 pg/mgCr; P less than 0.05); by contrast renal renin content was significantly increased (NP, 2,587 +/- 273 vs. LP, 7,032 +/- 654 ng A I/mg protein; P less than 0.05). Treatment with captopril (30 mg/kg per d) raised glomerular filtration rate (GFR; LP + capt, 1.6 +/- 0.2 ml/min) and renal plasma flow (RPF; LP + capt, 6.7 +/- 0.7 ml/min), and reduced renal vascular resistance (LP + capt, 9.2 +/- 0.5 dyn/s per cm5) in low protein-fed animals. These values were not different from those measured in untreated and captopril-treated rats fed a normal (23%) protein diet. There were no changes in systemic mean arterial pressure in any group of rats. These data provide evidence that intrarenal angiotensin II mediates the changes in intrarenal hemodynamics induced by protein deprivation. The effects of low protein feeding may be partly potentiated by the reduction in PGE2 synthesis. However, the normalization of GFR and RPF in view of only modest increases in PGE2 excretion after captopril (LP, 648 +/- 95 vs. LP + capt, 1,131 +/- 82 pg/mgCr; P less than 0.05) suggests that if PGE2 is involved in these changes, it plays a permissive but not essential role in the increased renovascular resistance.     

Mild potassium depletion provokes renal sodium retention

Although severe potassium depletion has been shown to cause sodium retention, the effect of small potassium losses on sodium excretion is unknown. Seven healthy male volunteers were given a diet containing 35 mEq sodium and either low (10 mEq) or normal (90 mEq) potassium intake for 9 days. With the low potassium diet plasma potassium concentration decreased by 0.60 +/- 0.15 mEq/L. The cumulative potassium balance with this diet was negative (-124 +/- 22 mEq). Cumulative sodium balance was -82 +/- 43 mEq with the normal potassium diet but was positive (20 +/- 22 mEq) when the same subjects ingested a low potassium diet (P less than 0.05). A significant difference in sodium excretion could be detected as early as day 1 of potassium restriction. To study the effect of potassium depletion on the renal ability to handle a short-term sodium load, on day 10 each subject received a 2 L isotonic saline infusion over a period of 4 hours. Subjects while ingesting a normal potassium diet excreted 20% +/- 4% of the administered load. The same subjects while ingesting a low potassium diet excreted only 9% +/- 3% of the administered load (P less than 0.001). The difference in sodium excretion was not dependent on changes in glomerular filtration rate, renal plasma flow, plasma renin activity, plasma aldosterone, or plasma and urinary catecholamines. We conclude that variations in dietary potassium strikingly modify sodium excretion. Even mild potassium depletion impairs the renal ability to handle a short-term sodium load.     

Peripheral dopaminergic blockade for the treatment of diabetic orthostatic hypotension

This study was designed to evaluate the effects of domperidone, a peripheral dopaminergic antagonist, in diabetic patients with symptomatic orthostatic hypotension. Nine patients were admitted to the hospital, placed on a diet containing 150 mEq sodium, and studied for periods of 4 hours, on different days, in the following conditions: (1) supine position, (2) upright posture (UP), (3) UP after 10 mg domperidone, intravenously in bolus, and (4) UP after 3 days of domperidone, 30 mg orally. Before domperidone the mean blood pressure observed in supine position of 132 +/- 37/75 +/- 6 mm Hg fell to 75 +/- 22/57 +/- 13 mm Hg after 2 hours in UP. Acute domperidone did not change the blood pressure response to UP. After 3 days of oral domperidone and in UP for 2 hours, the mean blood pressure value of 89 +/- 21/61 +/- 8 mm Hg was higher than that before domperidone (p less than 0.05), with relief of symptoms in all patients. This blood pressure response to UP has been maintained in six patients who completed 6 months of therapy. No differences were observed in plasma renin activity, aldosterone, sodium, and potassium and in 4-hour urinary excretion of aldosterone, epinephrine, norepinephrine, and dopamine, determined during the UP tests. Administration of domperidone for 3 days reduced the falls in creatinine clearance and the urinary excretion of sodium and potassium induced by UP but did not alter the blood pressure and aldosterone dose-response curves to angiotensin II. Although the mechanism of action is not defined, it is concluded that domperidone is effective for the treatment of orthostatic hypotension in patients with diabetes.     

Mechanism of adrenal angiotensin II receptor changes after nephrectomy in rats.

At 48 h after bilateral nephrectomy in rats there is a two- to threefold increase in the number of adrenal angiotensin II receptors and a decrease in Kd of smooth muscle angiotensin II receptors. These changes have been attributed to the absence of circulating angiotensin II. Serum K+, which increases after nephrectomy may be an important and overlooked modulator. Therefore, the present experiments were designed to assess the role of K+ as a regulator of angiotensin II receptors after nephrectomy. Serum K+ was controlled with Na polystyrene sulfonate (Kayexalate), a resin designed to exchange Na+ for K+ in the gastrointestinal tract. Acutely nephrectomized rats were divided into two groups: experimental animals received Kayexalate resin every 12 h for four doses, and controls received Kayexalate exchanged with KCl in vitro before gavage. There was a significant positive correlation serum K+ and aldosterone (r = 0.78, P less than 0.001). Kayexalate maintained a normal serum K+ of 5.9 +/- 0.2 meq/liter (n = 27), aldosterone 25 +/- 3 ng/dl (n = 27) and adrenal receptor concentration of 934 +/- 156 fmol/mg protein (n = 4). Control animals had significantly higher serum K+ of 10.5 +/- 0.4 meq/liter (n = 23), aldosterone 435 +/- 32 (n = 23), and adrenal receptors of 2726 +/- 235 fmol/mg protein (n = 4). There was a linear relationship between serum K+ and number of adrenal receptors (r = 0.87). No such relationship was present in uterine smooth muscle. Therefore, these studies demonstrate that K+ modulates the number of adrenal but not smooth muscle angiotensin II receptors after nephrectomy. This is the first evidence that potassium modulates angiotensin II receptors independently of changes in angiotensin II blood levels.     

Effects of 1-Sar-8-Ile-angiotensin II on urinary prostaglandin excretion in patients with essential hypertension

To investigate the interaction between the renin angiotensin aldosterone system and the renal prostaglandin (PG), urinary excretion of PGE, urinary excretion of main urinary metabolite (MUM) of PGF2a, urinary excretion of aldosterone, and plasma renin activity were measured before and after infusion of 1-Sar-8-Ile-Angiotensin II, a specific competitive inhibitor of angiotensin II, in 18 patients with essential hypertension under normal and low sodium diets. The values of urinary sodium excretion in these patients before the infusion of the peptide were 160.8 +/- 13.3 and 27.0 +/- 2.7 mEq per day on normal and low sodium diet, respectively. On normal sodium diet, urinary excretion of PGE was found to correlate with the level of plasma renin activity before the infusion (r = 0.6977, p less than 0.01), and it was decreased slightly from 0.37 +/- 0.05 ng/min to 0.26 +/- 0.04 ng/min after the infusion of the antagonist. On low sodium diet, urinary excretion of PGE was not significantly changed by the infusion of the peptide and showed no correlation with the level of plasma renin activity before the infusion, while urinary excretion of PGE showed a significant correlation with the excretion of urinary aldosterone (r = 0.6719, p less than 0.02). Excretion of PGF2aMUM decreased after the infusion of this peptide on both sodium diets, but the changes were not statistically significant. The present data suggest that angiotensin II influences the synthesis or release of renal PG in patients with essential hypertension on normal sodium diet, but not when they are on low sodium diet.     

Effects of pretreatment with propranolol on potassium, calcium, and magnesium shifts after ventricular fibrillation in dogs

Hypokalemia and other electrolyte changes have been observed after resuscitation from ventricular fibrillation. We studied the effect of propranolol on postresuscitation electrolytes in a canine model of ventricular fibrillation and cardiac resuscitation by randomizing 40 anesthetized dogs to four groups: ventricular fibrillation--no drug (VF), ventricular fibrillation--propranolol pretreatment (VF-prop), control-no drug (NoVF), control--propranolol (NoVF-prop). We measured serum electrolytes at baseline and periodically for 3 hours. In VF dogs, serum potassium decreased from 3.9 +/- 0.4 to 3.2 +/- 0.2 mEq/L 60 minutes after resuscitation (p less than 0.001). The decrease in potassium was prevented (p less than 0.001) by propranolol. Serum calcium decreased from 10.6 +/- 0.8 to 10.2 +/- 0.8 mg/dl in VF dogs 15 minutes after resuscitation (p less than 0.05); this decrease was not blocked by propranolol (p = NS). Serum magnesium increased from 1.5 +/- 0.2 to 1.8 +/- 0.1 mEq/L in VF dogs 7 minutes after resuscitation (p less than 0.001); this rise was partially blocked by propranolol (p less than 0.01). Serum glucose increased from 105 +/- 6 to 183 +/- 27 mg/dl in VF dogs 7 minutes after resuscitation (p less than 0.001); this increase was diminished by propranolol (p less than 0.001). Thus propranolol prevents the decrease in serum potassium after ventricular fibrillation in this canine model, providing evidence that postresuscitation hypokalemia is caused by the beta-adrenergic effects of catecholamines secreted in response to cardiac arrest. Propranolol blocks the rise in magnesium and glucose but does not block the decrease in calcium after resuscitation.     

Phenobarbital in the genetically obese Zucker rat. I. Pharmacokinetics after acute and chronic administration

We measured both pulmonary and plasma angiotensin converting enzyme (ACE) activity in conscious rabbits before and for 6 days after administration of captopril (2 mg/kg i.v.). Pulmonary ACE activity was measured by means of modified indicator-dilution techniques after bolus injection of [3H]benzoyl-phenyl-alanyl-alanyl-proline ( BPAP , synthetic substrate for ACE). Plasma ACE activity was also determined radiometrically with [3H] BPAP as substrate. In addition, we measured the systemic pressor response to i.v. bolus dose of angiotensin I both before and after captopril. Twenty-four hours after captopril, pulmonary metabolism of BPAP had decreased from control of 73 +/- 5 to 8 +/- 2%; even 6 days after drug treatment there was still evidence of inhibition. In contrast, plasma ACE activity was significantly (P less than .05) reduced within 15 min of treatment (to 20% of control levels) but recovered within 24 hr. The time course of changes in the pressor response to angiotensin I, after captopril, resembled that of plasma ACE activity. Mean systemic arterial blood pressure was 81 +/- 4 torr at control and reached its nadir at 24 hr (64 +/- 2 torr; P less than .05); thereafter a gradual recovery ensued, similar in time course to that of pulmonary ACE. These data suggest that inhibition of plasma ACE and also the pressor response to angiotensin I are unrelated temporally to the hypotensive effects of captopril.     

Effects of dietary sodium on circadian rhythm and physiological responses of 18-hydroxycorticosterone

1. The effects of dietary sodium intake on plasma 18-hydroxycorticosterone (18-OHB) responses to physiological stimuli and recumbent 24-h-plasma 18-OHB levels have been examined in nine normal male subjects. 2. Basal supine levels of 18-OHB during a 40 mmol of sodium intake period (62.5 +/- 6.0 ng/dl) were considerably greater (P less than 0.0001) than the levels during a 200 mmol of sodium intake period (9.8 +/- 1.2 ng/dl). Further incremental and percentage changes of 18-OHB in response to graded dose infusions of angiotensin II and adrenocorticotropic hormone (ACTH) were greater during the 40 mmol of sodium intake period. 3. Although the mean 24 h levels of plasma 18-OHB during the 40 mmol of sodium intake period (43.9 +/- 4.0 ng/dl) were greater (P less than 0.001) than those during the 200 mmol of sodium intake period (9.4 +/- 1.2 ng/dl), the circadian rhythm of 18-OHB secretion was similar under the two extremes of sodium intake. 4. Factors which increase angiotensin II levels, such as sodium restriction, isometric exercise and angiotensin infusion, selectively increase 18-OHB and aldosterone, suggesting that angiotensin II increases 18-OHB and aldosterone secretion, in part, by modulation of the 18-hydroxylation reaction involved in conversion of corticosterone into 18-OHB.     

Converting enzyme inhibition with captopril in patients with primary hyperaldosteronism

The humoral and hemodynamic effects of converting enzyme inhibition captopril are presented in two patients with primary hyperaldosteronism (PHA). In all, 20 patients with resistant hypertension were treated with the angiotensin converting enzyme inhibitor captopril. In 18 patients with essential or renovascular hypertension mean (+/- SEM) plasma renin activity (PRA) rose from 5.0 +/- 1.4 to 35.3 +/- 5.3 ng/ml/hr (P less than 0.01) and mean (+/- SEM) plasma aldosterone (PA) declined from 25.8 +/- 2.9 to 15.1 +/- 1.9 ng/ml (P less than 0.01) after captopril. In two patients with PHA the PRA was not stimulated by converting enzyme inhibition, although there was modest decline in PA and a temporary reduction in blood pressure. After surgical removal of aldosterone-producing adenomas, PRA responsed appropriately to captopril. These cases illustrate that a disease process can modify the response to a drug and demonstrate that, in patients with PHA, captopril does not stimulate PRA, induces only minor decrements in PA, and is relatively ineffective as an antihypertensive.     

Captopril enhances vascular and adrenal responsiveness to angiotensin II in essential hypertension

The converting-enzyme inhibitor captopril (25-50 mg orally every 6 h for 66 h) was used to dissociate the circulating levels of angiotensin II (ANG II) from changes in sodium balance in 11 patients with normal renin essential hypertension on 10 mmol of sodium/day intake. Pressor, renal vascular and adrenal responses to graded infusions of ANG II (0.3, 1 and 3 pmol kg-1 min-1) were measured before and after captopril administration. Systemic vascular responses were assessed by measuring diastolic blood pressure (DBP), renovascular responses by measuring p-aminohippurate (PAH) clearance and adrenal responses by measuring plasma aldosterone. After receiving captopril for 66 h the hypertensive subjects showed a significantly (P less than 0.004) enhanced blood pressure response to the infused ANG II but not to noradrenaline when compared with the response before captopril. ANG II (3 pmol kg-1 min-1) also produced a significantly (P less than 0.03) greater reduction in PAH clearance after (-194 +/- 40 ml/min) compared with before (-104 +/- 15 ml/min) captopril. These results suggest that the responsiveness to ANG II in these two target tissues is determined by the circulating ANG II level. In the adrenal gland the aldosterone responses to ANG II also were significantly greater after (P less than 0.01) than before captopril (increment at 3 pmol kg-1 min-1: 660 +/- 88 vs 381 +/- 94 pmol/l). These results are in distinct contrast with the responses previously reported for normotensive subjects and support the hypothesis that the regulation of aldosterone secretion is altered in subjects with essential hypertension.     

Failure of potassium adaptation in vivo in the colon of aldosterone-deficient rats

Prolonged potassium loading results in an adaptive change in colonic epithelium that increases the capacity for potassium excretion. We evaluated the role of aldosterone in colonic potassium adaptation, because potassium loading also increases the production of aldosterone. Experiments were performed in intact animals and in adrenalectomized rats with a high potassium intake replaced over a prolonged period with low physiologic amounts of corticosterone to provide a stable plasma level of 3 to 5 micrograms/dl. Net electrolyte movement and transmural potential difference were measured by an in vivo luminal perfusion technique. Compared with the rate of potassium secretion of -3.6 +/- 0.5 mu Eq/min/gm dry weight in potassium-loaded rats with intact adrenal glands, net secretion was significantly impaired (P less than 0.025) in potassium-loaded adrenalectomized animals with only corticosterone replacement (-1.1 +/- 0.5 mu Eq/min/gm dry weight). The rate in adrenalectomized animals, however, was comparable to that in intact animals receiving a normal potassium intake (0.3 +/- 0.2 mu Eq/min/gm dry weight). In addition, in intact animals prolonged potassium loading significantly increased transmural potential difference to -68 +/- 6 mV (P less than 0.005), compared with that in adrenalectomized, corticosterone-replaced, potassium-loaded animals (-30 +/- 4 mV) and intact animals with a normal intake of potassium (-25 +/- 7 mV). Net sodium absorption was reduced in aldosterone-deficient animals compared with the value in control and potassium-loaded animals with intact adrenal glands. These data indicate, therefore, that potassium adaptation is not induced in the absence of aldosterone and suggest that hyperaldosteronism plays an important role in induction of colonic potassium adaptation.     

Renal and vascular effects of S21402, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase,in healthy subjects with hypovolemia

OBJECTIVE: To examine the mechanism of action of dual inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase, also called vasopeptidase inhibitors, we compared the effects of S21402 [(2S)-2-[(2S,3R)-2-thiomethyl-3-phenylbutanamido]propionic acid], which belongs to this pharmacologic class, with those of captopril, an ACE inhibitor, on blood pressure, endocrine parameters, and renal in healthy subjects with hypovolemia. METHODS: Ten subjects participated to this double-blind, 2-period, randomized, crossover study. Hypovolemia was induced in these subjects with a 7-day treatment of hydrochlorothiazide. They received a single oral dose of 50 mg captopril or 250 mg S21402 on the last day of diuretic treatment. Blood pressure was measured, and urine and blood samples were collected before and during a 12-hour period after drug administration. RESULTS: The plasma angiotensin II/angiotensin I ratio and aldosterone concentration decreased to the same degree with both drugs, 3 hours after dosing. Compared with captopril, S21402 increased levels of plasma atrial natriuretic peptide (P <.05) and urinary cyclic guanosine monophosphate (P <.001); these increases were the result of inhibition of neutral endopeptidase activity (P <.001). The increase in plasma renin concentration related to ACE inhibition was less marked (P <.001) after S21402 than after captopril. S21402, but not captopril, increased urinary sodium excretion (P <.05), without modifying blood pressure and creatinine clearance, whereas blood pressure transiently fell after captopril administration (P <.05). CONCLUSIONS: In healthy hypovolemic subjects, the vasopeptidase inhibitor S21402 exhibits a natriuretic effect and does not affect blood pressure or glomerular filtration rate. In these conditions, the acute endocrine, vascular, and renal effects of vasopeptidase inhibition differ from those of ACE inhibition.     

The effect of insulin on the rise in blood pressure and plasma aldosterone after angiotensin II in normal man

1. The effect of an intravenous infusion of insulin [2.5 units h-1 (m2 of body surface area)-1] on the rise in blood pressure and plasma aldosterone after intravenous angiotensin II (5, 10, and 20 ng min-1 kg-1) was investigated in six healthy, sodium-loaded men. 2. Serum insulin reached 96.8 +/- 18.1 mu-units/ml (control: 7.0 +/- 1.5 mu-units/ml) and serum potassium fell from 4.2 +/- 0.2 mmol/l to 3.6 +/- 0.2 mmol/l (P less than 0.005). 3. Hyperinsulinaemia increased (P less than 0.05) the secretion of aldosterone during the largest dose of angiotensin II (20 ng min-1 kg-1), but had no effect on the rise in blood pressure after angiotensin II.     

Effect of indomethacin on salt and water homeostasis.

The effects of indomethacin-induced prostaglandin inhibition on sodium and chloride homeostasis in normal man were assessed. Seven normal subjects were on a 150-mEq sodium diet for 3 days prior to receiving indomethacin or no drug. Indomethacin decreased fractional excretions of sodium and chloride without affecting fractional excretion of potassium, creatinine clearance, or percent fractional reabsorption of free water. Cumulative sodium excretion at 8 hr fell from 49.8 +/- 7.2 to 16.1 +/- 4.8 mEq (p less than 0.005) after indomethacin. Chloride fell at 8 hr from 49.7 +/- 6.4 to 21.3 +/- 5.1 mEq (p less than 0.005). Urinary volume and osmolal clearance decreased in similar magnitudes such that free water reabsorption was not changed by indomethacin. This study showed that indomethacin decreased renal sodium and chloride excretion, implying that endogenous prostaglandins may be modulators of renal sodium excretion.     

Blood levels and renal effects of atrial natriuretic peptide in normal man.

Since mammalian atria were recently found to contain vasoactive and natriuretic peptides, we investigated the following in normal humans: plasma human atrial natriuretic peptide concentrations, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), urinary water and electrolyte excretion, blood pressure (BP), and catecholamine, antidiuretic hormone (ADH), angiotensin II, and aldosterone levels before, during, and after intravenous administration of the newly synthetized alpha-human atrial natriuretic peptide (alpha hANP). In 10 subjects alpha hANP given as an initial bolus of 50 micrograms followed by a 45-min maintenance infusion at 6.25 micrograms/min increased plasma alpha hANP from 58 +/- 12 to 625 +/- 87 (mean +/- SEM) pg/ml; caused an acute fall in diastolic BP (-12%, P less than 0.001) and a hemoconcentration (hematocrit +7%, P less than 0.01) not fully explained by a negative body fluid balance; increased GFR (+15%, P less than 0.05) despite unchanged or decreased ERPF (filtration fraction +37%, P less than 0.001); augmented (P less than 0.05- less than 0.001) urinary chloride (+317%), sodium (+224%), calcium (+158%), magnesium (+110%), phosphate excretion (+88%), and free water clearance (from -0.76 to +2.23 ml/min, P less than 0.001) with only little change in potassium excretion; and increased plasma norepinephrine (P less than 0.001) while plasma and urinary epinephrine and dopamine, and plasma ADH, angiotensin II, and aldosterone levels were unchanged. The magnitude and pattern of electrolyte and water excretion during alpha hANP infusion could not be accounted for by increased GFR alone. Therefore, in normal man, endogenous alpha hANP seems to circulate in blood. alpha hANP can cause a BP reduction and hemoconcentration which occur, at least in part, independently of diuresis and are accompanied by sympathetic activation. An increase in GFR that occurs in the presence of unchanged or even decreased total renal blood flow is an important but not sole mechanism of natriuresis and diuresis induced by alpha hANP in man.     

The renin-angiotensin-aldosterone system in decompensated cirrhosis: its activity in relation to sodium balance

Plasma renin activity (PRA), plasma renin concentration (PRC), plasma angiotensin II concentration (AII), plasma and urinary aldosterone (PA, UA) and urinary sodium excretion (UNaV) were measured in 51 normal controls, 16 patients with decompensated cirrhosis (i.e. ascites and/or oedema present) in sodium equilibrium (Group 1) and 13 patients with decompensated cirrhosis in a phase of active sodium retention (Group 2). In Group 1 the mean supine and erect values, although lower, were not significantly different from controls. In Group 2 the mean values were significantly elevated, but several individual values were within the normal range; there were significant direct relationships between plasma renin activity and plasma renin concentration (r = 0.85, p less than 0.001 erect), plasma renin concentration and plasma angiotensin II concentration (r = 0.86, p less than 0.001 erect), and plasma angiotensin II concentration and plasma aldosterone (r = 0.70, p less than 0.01 erect). In Group 2 there was an inverse correlation between urinary sodium excretion and both urinary aldosterone (r = -0.50) and erect plasma aldosterone (r = -0.36) but, perhaps because of the narrow range of sodium excretion rates, significance was not reached. The normal values in Group 1 indicate that hyperaldosteronism is not essential for the maintenance of established ascites, but do not exclude a role for aldosterone in the control of sodium excretion if it is accepted that renal tubular sensitivity to aldosterone is increased in these patients. In Group 2, the raised mean plasma and urinary aldosterone levels and the trend towards an inverse relationship with urinary sodium excretion suggests a role for aldosterone in the active retention of sodium. It appears that stimulation of the renin-angiotensin system is the major factor in the elevation of plasma aldosterone; there was no relationship between plasma aldosterone and either plasma sodium or potassium levels. The mechanism of renin hypersecretion is unclear but this may represent part of a sympathetically mediated response in order to maintain blood pressure. The close relationship between plasma renin activity and plasma renin concentration indicates that the former is a valid measure of circulating renin levels in cirrhosis, despite low renin-substrate levels.     

Studies of the Control of Plasma Aldosterone Concentration in Normal Man: III. RESPONSE TO SODIUM CHLORIDE INFUSION

The peripheral plasma levels of aldosterone, renin activity, potassium, sodium, corticosterone, and cortisol were measured in six normal subjects four times daily-10 a.m., 2 p.m., 5 p.m., 11 p.m.-on 3 consecutive days. A constant daytime activity program was maintained throughout the study. After 5 days on a 10 mEq sodium/100 mEq potassium isocaloric intake, the mean upright 10 a.m. plasma renin activity was 1773+/-186 ng/100 ml per 3 hr and the mean plasma aldosterone, 81+/-14 ng/100 ml. These two parameters fell continuously throughout the day parallel to the fall in plasma cortisol and corticosterone. In response to 2 liters of normal saline infused from 10 a.m. to 2 p.m. on 2 consecutive days, plasma aldosterone levels fell significantly to 13+/-5 ng/100 ml at 2 p.m. after the 1st day's infusion and to 6+/-1 ng/100 ml at 2 p.m. after the 2nd. Plasma renin activity demonstrated a parallel fall to 368+/-63 ng/100 ml per 3 hr and 189+/-27 ng/100 ml per 3 hr at 2 p.m. on the 1st and 2nd days, respectively. There was no significant alteration in plasma levels of cortisol, corticosterone, potassium, or sodium on the 2 days of sodium loading in comparison with the control day. In an additional study, five normal supine subjects received 500 ml saline/hr for 6 hr. As in the 2 day study, plasma aldosterone and renin activity had parallel decrements at 1, 2, 4, and 6 hr after the start of the saline infusion. From these studies, it is concluded that plasma renin activity is the dominant factor controlling plasma aldosterone when sodium-depleted normal subjects are acutely repleted.