Acute hypertension in a nonhuman primate: humoral and hemodynamic mechanisms

The present study assessed the contribution of the renin-angiotensin system (RAS), dietary sodium, and cardiac output (CO) to the genesis of primate hypertensin in a one-kidney model which was developed to test species-specific renin inhibitors. Reduction of renal perfusion pressure increased mean arterial pressure (MAP) from 105 +/- 4 to 127 +/- 3 mm Hg (p less than 0.0005), associated with increased plasma renin activity (PRA) from 4.9 +/- 0.7 to 13.8 +/- 1.1 ng. ml-1.hr-1 (p less than 0.0005). Correlation of MAP with PRA yielded an r value of 0.662 (p less than 0.0005). Significant blood pressure elevation was obtained with both regular (R) and low sodium (LS) diet (p less than 0.0005), although the MAP change was greater with LS. With both R and LS diet, hypertension was associated with increased PRA (p less than 0.0005), and normotensive pressures were achieved with converting enzyme inhibitor (teprotide). The hemodynamic change with hypertension was an increase of systemic vascular resistance (SVR) from 0.89 +/- 0.12 to 1.17 +/- 0.09 units (p less than 0.05); cardiac output (CO) and central blood volume did not change significantly. Thus, acute hypertension, mediated by the RAS, was developed in a one-kidney primate model. The hemodynamic correlate of hypertension was increased SVR; CO and volume redistribution were not initiating factors.     

Acute effects of captopril on cardiopulmonary hemodynamics and renin-angiotensin-aldosterone and bradykinin profile in hypertension

Hemodynamic variables were measured and plasma renin activity (PRA), angiotensin II (AII), aldosterone, and bradykinin assays performed in 21 hypertensive men on regular diet and thiazide diuretics before and 60 to 90 minutes after 25 mg oral captopril. Heart rate, right and left ventricular filling pressures, mean cardiac index (CI), and pulmonary vascular resistance (PVR) remained unchanged. The mean intra-arterial pressure (MAP) fell from 140 +/- 5 to 116 +/- 6 mm Hg (p less than 0.001) correlating with reduction of systemic vascular resistance (SVR) (r = 0.87, p less than 0.001), control PRA (r = 0.59, p less than 0.01), and All levels (r = 0.72, p less than 0.005) but not with control bradykinin or its postcaptopril rise (p less than 0.01). The fall in SVR correlated with reduction in plasma All (r = 0.80, p less than 0.001) and aldosterone concentrations (r = 0.53, p less than 0.05). Of four patients (19%) with precipitous fall in MAP after captopril, three needed volume expansion for circulatory support. We conclude: (1) All reduction by captpril and not bradykinin potentiation explains most of the agent's hemodynamic response in hypertensive circulation, (2) endogenous All may have a supportive role for SVR and possibly for CI but not for PVR, and (3) extra precaution is warranted while captopril is being started in patients taking diuretics.     

Mechanism of suppression of renin secretion by clonidine in the dog

The mechanism by which clonidine suppresses renin secretion was investigated in pentobarbital-anesthetized dogs in which renal perfusion pressure was controlled by means of an aortic clamp. Clonidine (30 microgram/kg, iv) lowered mean arterial pressure (MAP) from 124 +/- 8 to 104 +/- 4 mm Hg (P less than 0.01) and reduced plasma renin activity (PRA) to 32 +/- 4 percent of the control value (P less than 0.01) after 60 minutes. Ganglion blockade with pentolinium (3 mg/kg, im) decreased MAP from 148+/- 7 to 117 +/- 3 mm Hg (P less than 0.01) and reduced PRA to 55 +/- 13 percent of the control value (P less than 0.05) after 45 minutes. Pentolinium converted the hypotension produced by clonidine to hypertension (108 +/- 9 to 146 +/- 10 mm Hg at 60 minutes, P less than 0.05) and abolished the suppression of PRA (105 +/- 14 percent of control at 60 minutes, P less than 0.05). In a further series of experiments, the effects of oxymetazoline, an alpha-adrenergic receptor agonist which is closely related to clonidine but which does not cross the blood brain barrier, were studied. Oxymetazoline (10 microgram/kg, iv) increased MAP from 127 +/- 3 to 154 +/- 2 mm Hg (P less than 0.01) and elevated PRA TO 176 +/- 22 percent of the control value (P less than 0.02) after 30 minutes. A higher dose of oxymetazoline (30 microgram/kg) increased MAP from 129 +/- 10 to 161 +/- 9 mm Hg (P less than 0.05) and increased PRA to 256+/- 37 percent of control (P less than 0.05) after 30 minutes. Taken together, these data support the hypothesis that the inhibition of renin secretion by clonidine results from a centrally mediated decrease in sympathetic neural activity.     

Converting enzyme inhibition in hypertensive emergencies.

The diagnostic and therapeutic value of the angiotensin converting enzyme inhibitor teprotide (SQ 20881) was assessed in 18 patients with hypertensive emergencies. Mean blood pressure fell 31 +/- 18 mm Hg in the 10 subjects who responded to 1 mg/kg body weight administered intravenously, whereas it fell 5 +/- 3 mm Hg in the eight nonresponders. In patients who had received no previous drug treatment, log baseline plasma renin activity and change in mean blood pressure after SQ 20881 correlated significantly (r = 0.651, P less than 0.05). After acute therapy with SQ 20881, the patients who had a satisfactory response to the drug were treated with propranolol and a relatively normal sodium intake (88 meq/day). Nonresponders were treated with diuretics and sodium restriction (10 meq/day), and intermediate responders were given combination therapy. Mean blood pressure responded favorably within 24 h to the chosen regimen for each group from 152 +/- 47 to 102 +/- 31 mm Hg. SQ 20881 allows prompt evaluation of the role of renin in hypertensive emergencies and permits early choice of appropriate therapy based on the prevailing mechanism.     

Endogenous prostaglandin E2 metabolite levels, renin-angiotensin system and catecholamines versus acute hemodynamic response to captopril in chronic congestive heart failure

Hemodynamic and hormonal responses to captopril were measured in 10 patients with severe chronic heart failure poorly controlled by digitalis and diuretics. After administration of a 25-mg dose, stroke volume (SV) increased from 53 +/- 7 to 63 +/- 9 ml (p less than 0.05), while pulmonary wedge pressure (PWP) decreased from 20 +/- 2 to 14 +/- 2 mm Hg (p less than 0.01). The hemodynamic changes were associated with increases in plasma renin activity (PRA; p less than 0.05) and in plasma levels of a novel bicyclo-prostaglandin E2 metabolite (bicyclo-PGE-m; p less than 0.01), whereas norepinephrine (NE) showed a falling tendency. In general, basal hemodynamic and basal hormonal levels did not correlate. Captopril-induced changes in mean artery pressure (MAP) and mean pulmonary artery pressure (mPAP) were positively correlated to pre-captopril PRA (r = 0.74, p less than 0.01; r = 0.64, p less than 0.05) and to changes in PRA (r = 0.85, p less than 0.01; r = 0.80, p less than 0.01) with a similar trend for angiotensin II (AII); decreases of systemic vascular resistance were more pronounced in patients with higher control NE levels (r = 0.62, p less than 0.05), the reduction of NE levels being highest in patients with higher basal concentrations (p less than 0.001); the captopril-induced decreases of mPAP and PWP were inversely related to basal bicyclo-PGE-m levels (r = 0.60, p less than 0.05; r = 0.61, p less than 0.05), and changes in mPAP were closely related to basal ratios of AII/bicyclo-PGE-m (r = 0.67, p less than 0.01). Thus, captopril exerts its acute beneficial hemodynamic effect by inhibiting the generation of AII, associated with toning down of sympathetic stimulation and increased production of vasodilating prostaglandins, such as PGE2. The relation between AII and PGE2-counteracting substances-might determine the hemodynamic response to captopril in the patients.     

Pressor response to saralasin (1-sar-8-ala-angiotensin II) bolus injection in hypertensive patients

A 10 mg bolus of the angiotensin blocker saralasin was injected 113 times in 68 subjects with essential or renovascular hypertension. Ninety percent of injections caused a transient increase in blood pressure, which correlated with plasma renin activity (PRA) (r = -0.54); Mean increase at 2 minutes was 21/13.4 mm Hg (P less than 0.001) and was independent of pre-injection control blood pressure, with a rapid decrease to or below control values thereafter. Thirty-seven subjects were studied on successive days before and after furosemide-induced sodium depletion (152 +/- 26 mEq [SE] sodium loss). In the low renin group, sodium depletion did not change PRA or the magnitude of the pressor response to saralasin, but significantly decreased control MAP by 13 mm Hg (P less than 0.01). In normal and high renin patients, MAP was unchanged after diuresis, but PRA increased significantly and the pressor response was attenuated. The net effect of sodium depletion was to reduce the pressor response to saralasin in all renin subgroups by 9 to 12 mm Hg. Saralasin bolus injection, unlike infusion, saturates available vascular receptors only briefly, eliminating prolonged pressor responses.     

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.     

A clinical study on the role of the renin-angiotensin-aldosterone system and catecholamines in chronic congestive heart failure

In order to evaluate the roles of the renin-angiotensin-aldosterone system and of catecholamines in 117 normotensive patients with chronic congestive heart failure (CHF), a study was made of the relationships between plasma concentrations, hepatic extraction of these humoral factors and hemodynamic parameters. In 6 patients with moderate to severe CHF, the acute effect of oral; administration of angiotensin I converting enzyme inhibitor, SQ 14225 (captopril), on mean arterial pressure (MAP), peripheral venous pressure (VP) and these humoral factors was investigated. In patients with CHF of Class III-IV (according to NYHA classification), the urinary norepinephrine (U-NE) excretion increased. Plasma norepinephrine (P-NE) levels increased in proportion to the severity of CHF (p less than 0.001) and had a positive correlation with systemic vascular resistance (SVR) (p less than 0.01), VP (p less than 0.05), pulmonary artery wedge pressure (PWP) (p less than 0.01) and plasma renin activity (PRA) (p less than 0.01). P-NE correlated negatively with the cardiac index (p less than 0.02). Hepatic extraction of norepinephrine (EX-NE) was reduced in patients with elevated right atrial pressure (RAP) (p less than 0.05) and negatively correlated with VP (p less than 0.05). In patients with elevated P-NE, U-NE increased significantly (p less than 0.01), despite their decreased renal clearance of norepinephrine (CNE) (p less than 0.02). There was no significant difference in EX-NE between these patients and patients with normal P-NE. PRA was higher in Class III-IV patients than in Class I-II patients in the prediuretic period (p less than 0.01). PA showed a significant positive correlation with PRA (p less than 0.001). Hepatic extraction of aldosterone (EX-A) was reduced in patients with elevated RAP (p less than 0.05) and was negatively correlated with VP (p less than 0.05). Following captopril administration, PRA increased consistently and PA decreased. MAP fell, especially in 2 patients with mitral stenosis. The heart rate tended to decrease. VP also fell with symptomatic improvement. The decline in VP was correlated with the decrease in P-NE (p less than 0.01). These findings suggest that the sympathetic nervous system contributes to the elevation of SVR and PWP even before frank heart failure develops. The rise of P-NE seems to be due to increased norepinephrine release from sympathetic nerve beds, whereas a decrease in hepatic extraction and renal clearance probably has only a minor effect. The renin-angiotensin system also seems to contribute to elevation of SVR, to maintain effective arterial pressure by enhanced sympathetic activity, and the renin-angiotensin system seems to be a main determinant of PA in CHF.     

The antihypertensive effect of captopril. Evidence for an influence of kinins

The acute effect of the orally-active converting enzyme inhibitor, captopril, was compared to that of saralasin in 13 patients with various forms of hypertension on ad libitum sodium intake. A significant difference between the effects of the two drugs on mean arterial pressure (MAP) was found (-11 +/- 3 mm Hg with saralasin, -24 +/- 4.5 mm Hg after captopril). This difference was not correlated with control plasma renin activity (PRA). To determine the influence of the endogenous kallikrein-kinin system in the antihypertensive action of captopril, the effect of aprotinin (Apro), an inhibitor of kinin generation, on the MAP level achieved by captopril was assessed in five normal subjects and 15 patients with hypertension on ad libitum sodium intake. In normal subjects, captopril did not alter MAP, nor did Apro have any effect. In six patients with essential hypertension and normal PRA, MAP decreased by 5.5 +/- 2 mm Hg following captopril, and Apro did not modify this level. In nine patients with renovascular hypertension (RVH), MAP fell by 22 +/ 3 mm Hg after captopril administration, and Apro infusion induced a rise in MAP of 13 +/- 1.7 mm Hg. A positive correlation between log control PRA and the effect of aprotinin was obtained ( r = 0.63, p less than 0.005). Apro had no effect in two patients with RVH who experiences a large drop in MAP during salasin. These results suggest that endogenous kinins as well as other substances, the generation of which is inhibited by aprotinin, may participate to the antihypertensive effect of captopril in patients with angiotensin-dependent hypertension. The lack of an aprotinin effect on the MAP level achieved during saralasin infusion suggests that the influence of the kallikrein-kinin system is related to the effect of captopril rather than the fall in arterial pressure resulting from angiotensin blockade.     

Interactions between coronary occlusion and the renin-angiotensin system in the dog

Studies were carried out in 39 barbiturate-anesthetized dogs to determine whether the renin-angiotensin system is important in control of hemodynamics and coronary flow during myocardial ischemia. Plasma renin activity (PRA) was 2.2 +/- 0.4 ng x ml-l x hr-1 immediately before coronary artery occlusion (CAO) and increased to 3.8 +/- 0.5 (p less than .005) 15 minutes after CAO. In nephrectomized dogs, PRA was 0.76 +/- 0.14 ng x ml-l x hr-1 two hours after nephrectomy and remained unchanged after CAO. In contrast, hemodynamic changes following CAO were similar between nephrectomized and intact dogs: mean arterial pressure fell from 126 +/- 4 pre CAO to 116 +/- 4 mm Hg post CAO (p less than 0.005) in nephrectomized dogs and from 130 +/- 11 to 120 +/- 11 mm Hg (p less than 0.005) in intact dogs. Left atrial pressure rose from 5.4 +/- 0.9 pre CAO to 7.7 +/- 0.9 mm Hg (p less than 0.005) post CAO in nephrectomized from 5.4 +/- 0.9 pre CAO to 7.7 +/- 0.9 mm Hg (p less than 0.005) post CAO in nephrectomized dogs and 6.3 +/- 1.3 to 9.0 +/- 1.8 mm Hg (p less than 0.005) in intact dogs. Heart rate remained unchanged in both groups. In sham-operated dogs without CAO, neither the angiotensin II blocker Saralasin nor the converting enzyme inhibitor Captopril had significant effects on systemic (SVR) and coronary (CVR) vascular resistances. In contrast, in dogs with CAO, these drugs reduced CVR from 1.28 +/- 0.13 mm Hg x ml-1 x min x 100 g heart weight (resistance units = RU) to 0.85 +/- 0.08 RU (p less than 0.05) (Saralasin) 15 minutes after treatment and from 1.17 +/- 0.09 to 0.88 +/- 0.08 RU (p less than 0.025), (Captopril) respectively. However, only Captopril reduced SVR, from 10.7 +/- 1.13 to 8.2 +/- 0.8 RU (p less than 0.025). Both Captopril and Saralasin induced a significant increase in collateral blood flow. Nephrectomy, two hours prior to CAO, significant increase in collateral blood flow. Nephrectomy, two hours prior to CAO, significantly reduced the effect of Captopril on CVR and collateral blood flow while the effect on SVR persisted. Thus the reduction in CVR appears to be an effect of inhibition of the renin-angiotensin system; this system participates in control of CVR during CAO and may limit coronary collateral blood flow.     

Acute vascular effects of the angiotensin II receptor antagonist olmesartan in normal subjects: relation to the renin-aldosterone system

The extent to which the clinical effects of angiotensin receptor blockers (ARB) are related to ambient renin system activity remains poorly defined. Therefore, we measured blood pressure (BP), large (C1) and small (C2) arterial compliance, systemic vascular resistance (SVR), plasma renin activity (PRA), and the 24-h urinary excretion of sodium (UNaV) and aldosterone before and 1, 2, 4, and 24 h after administration of single doses of placebo, and 5, 20, and 40 mg of the ARB olmesartan medoximil to 12 unmedicated normotensive subjects. In the basal state, SVR was inversely related to UNaV (r = -0.3, P =.04); the greater the UNaV, the more vasodilated the subject. Indices of arterial compliance, both C1 (r = -0.32, P =.03) and C2 (r = -0.35, P =.02) were inversely related to the basal PRA. Renin also predicted olmesartan-induced changes in C1 (r = 0.43, P =.004) and C2 (r = 0.33, P =.04). The greater the basal PRA, the less the arterial compliance, and the more compliance improved after olmesartan. Both systolic (P =.003) and diastolic (P <.0001) BP fell significantly on olmesartan compared with placebo (MANOVA with time), and relations were observed between the basal PRA and olmesartan-induced changes in pressure (systolic BP: r = -0.414, P =.012; diastolic BP: r = -0.561 P <.0001)-the greater the initial PRA, the more olmesartan lowered BP. Furthermore, the more pressure fell, the more PRA rose reciprocally (r = -0.44, P =.007). Finally, aldosterone excretion fell (sig = 0.05) on each dose of olmesartan compared with placebo. We conclude that 1) the inverse relation of UNaV and SVR illustrates the reciprocal role of volume versus constrictor factors in maintaining normal BP; and 2) PRA is a physiologic determinant of arterial compliance in normal individuals and of the response to the ARB olmesartan. Measurement of PRA may help to predict clinical ARB responses in individual subjects.     

Systemic hemodynamic and cardiac function changes in patients undergoing orthotopic liver transplantation

The objective of this study was to determine the changes in systemic hemodynamics (systemic vascular resistance [SVR], cardiac output [CO], systemic blood pressure [SBP]) and cardiac function (pulmonary artery pressure [PAP] and pulmonary wedge pressure [PWP]) during the 96 hours following orthotopic liver transplantation (OLT) and correlate these with changes in hepatic and renal function and patient outcome. The study took place in a 12-bed medical respiratory intensive care unit in a large teaching hospital. Twenty-one patients had OLT performed over a 21.5-month period (January 1988 to October 15, 1989) for end stage liver disease (ESLD) from a variety of causes. A flow-directed right heart catheter and an indwelling arterial cannula were inserted for hemodynamic monitoring over a 96-hour postoperative period. Liver and renal function studies, total serum calcium, serum albumin, and fluid balance were determined daily. The SVR increased significantly to 12.8 +/- 0.6 U at 48 hours compared with immediate (less than 8 hours) postoperative levels (p less than 0.05) and remained elevated for 96 hours. The CO fell progressively and was significantly lower than baseline values from 64 to 96 hours. There was significant inverse correlation between the increase in SVR and the fall in CO (r = .85, p less than 0.01). The SBP was stable except for a small, but significant fall at 16 and 24 hours postoperatively. The PWP increased significantly from a baseline value of 12.5 +/- 0.9 mm Hg to 15 +/- 0.9 mm Hg at 32 hours and remained elevated through 96 hours (p less than 0.05). The serum bilirubin level fell progressively postoperatively and the prothrombin time and partial thromboplastin time (PTT) shortened significantly. Bile flow increased progressively from 107 +/- 120 ml/24 hours at the end of the first 24 hours to 188 +/- 125 ml/24 hours by 96 hours postoperatively. Five patients died from nine to 43 days postoperatively. These patients' hemodynamic parameters were not significantly different from the patients who survived. Successful OLT is associated with a rapid increase in SVR and a fall in CO without changes in SBP. These findings tend to parallel the improvement found in results of liver function tests. However, there is no correlation between the improvement in the hemodynamic state and long-term survival.     

Differences in response to the peptidyldipeptide hydrolase inhibitors SQ 20,881 and SQ 14,225 in normal-renin essential hypertension

We compared vascular and hormonal responses to teprotide (SQ 20,881) and captopril (SQ 14,225) in patients with normal renin essential hypertension given a 10 mEq sodium diet. In 10 patients receiving SQ 20,881, significant changes occurred in diastolic blood pressure (DBP, -13 +/- 2.5 mm Hg), angiotensin II (-7.1 +/- 2.1 pg/ml), and plasma renin activity (PRA, +6.6 +/- 1.9 ng/ml/hr) (p < 0.01 in all cases). Twenty-one patients receiving SQ 14,225 had significant changes in mean DBP (-18 +/- 1.5 mm Hg), angiotensin II (-6.6 +/- 1.5 pg/ml), and PRA (+7.8 +/- 2.4 ng/ml/hr) (all p values < 0.01). In spite of a significantly greater hypotensive response (p < 0.02), patients receiving SQ 14,225 showed increments in PRA and decrements in angiotensin II that did not differ significantly from those seen after SQ 20,881. Moreover, there was a significant change in plasma kinins in patients receiving SQ 20,881 (+2.0 +/- 0.9 ng/ml, p < 0.01) but no change in kinins in patients receiving SQ 14,225 (0.0 +/- 0.1, ns). We conclude that there are important differences in the mechanism mediating the hypotensive response to SQ 20,881 and SQ 14,225 in normal renin essential hypertension.     

Effects of angiotensin-converting enzyme inhibition on blood pressure and plasma renin activity in essential hypertension

Oral converting enzyme inhibitor SQ14225 was administered in 11 patients with essential hypertension, in order to investigate the role of the renin-angiotensin system in the regulation of blood pressure in essential hypertension. In the sodium-repleted state (150 mEq sodium intake for 6 days) in 11 patients, converting enzyme inhibitor decreased the average mean blood pressure from 113 +/- 2 to 106 +/- 2 mm Hg (p less than 0.001). Plasma renin activity increased with sodium depletion (30 mEq sodium intake for 3 days after furosemide treatment) from 1.26 +/- 0.07 to 3.26 +/- 0.48 ng/ml/hr (p less than 0.001). In the sodium-depleted state the hypotensive effect of SQ 14225 was more pronounced (mean blood pressure 108 +/- 2 to 93 +/- 3 mm Hg). The decrease in mean blood pressure caused by the inhibitor correlated to the basal plasma renin activity (r = -0.53, p less than 0.02, n = 22 measurements). The results indicate that the renin-angiotensin system participates in the regulation of blood pressure in essential hypertension, even in the sodium-repleted state. This role of the renin-angiotensin system in blood pressure regulation becomes more crucial during sodium depletion.     

Stimulation of renin by acute selective chloride depletion in the rat.

To determine whether acute chloride depletion per se stimulates renin, we produced selective chloride depletion without sodium depletion in rats by peritoneal dialysis (PD) against 0.15 M NaHCO3 or 0.15 M NaNO3. Control rats were dialyzed against 0.15 M NaCl. Plasma renin activity (PRA) was measured before (PRA1) and 105 minutes after (PRA2) PD. Plasma volume was expanded after PD by infusion of salt-free albumin and was measured immediately after PRA2 by [131I]albumin. In experiment 1, rats were prepared on a normal diet. PRA2 (7.0 +/- 1.0 ng/ml per hr, mean +/- SEM) was increased (P less than 0.05) over PRA1 (4.7 +/- 0.7 ng/ml per hr) in Cl-depleted but not in control rats (PRA1 = 5.3 +/- 0.7, PRA2 = 6.1 +/- 0.7, P = NS). In experiment 2, to produce greater chloride depletion, all rats were prepared for 2 weeks on a low salt diet. PRA2 (47 +/- 5 ng/ml per hr) was increased as compared to PRA1 (24 +/- 2 ng/ml per hr, P less than 0.005) in the Cl-depleted group but not in the control group (PRA1 = 24 +/- 3, PRA2 = 27 +/- 6 ng/ml per hr, P = NS). Serum potassium and final plasma volume were slightly but not significantly lower than controls in these Cl-depleted rats. To exclude an additive effect of these two stimuli for renin, in experiment 2a we infused chloride-depleted rats with three times as much albumin as controls and with KHCO3, 100 mEq/liter. Despite volume expansion and potassium loading, PRA2 (41 +/- 6 ng/ml per hr) was significantly elevated as compared to PRA1 (25 +/- 4 ng/ml per hr, P less than 0.01). Since acute metabolic alkalosis also was present in all Cl-depleted renin-stimulated rats, an additional group (2b) was dialyzed against 0.15 M NaNO3; final plasma arterial pH (7.43) was not different from controls (7.42). Nevertheless, PRA2 levels again were higher (36 +/- 6 ng/ml per hr, P less than 0.05) as compared to PRA1 (23 +/- 4 ng/ml per hr). In all experiments, arterial blood pressure, glomerular filtration rate, and filtered sodium load were not different. Free water reabsorption was lower in Cl-depleted than in control rats. We conclude that acute selective chloride depletion per se is a potent stimulus for renin release.     

Effect of captopril on the activities of angiotensin II and angiotensin converting enzyme during hypoxia induced pulmonary hypertension

To evaluate the role of angiotensin system in the development of hypoxia induced pulmonary hypertension, nine pigs (50 +/- 8 kg) were studied. A Swan-Ganz Catheter and an arterial catheter were inserted into the pulmonary artery and aorta. Pulmonary arterial pressure (PAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO) and arterial blood gases were monitoring before and after hypoxia and captopril injection (7.0 mg/kg). Plasma renin activity (PRA) and angiotensin II (ATII) were measured by RIA. Angiotensin converting enzyme (ACE) by fluorometry. Results showed during hypoxemia (PaO2 6.2 +/- 0.3 kPa, PaCO2 5.3 +/- 0.2 kPa): PAP increased from 2.4 +/- 0.2 to 3.8 +/- 0.3 kPa, (P less than 0.05) and right ventricle stroke work index (RVSWI) from 55.7 +/- 7.2 to 91.3 +/- 9.3 mJ/m2 (P less than 0.05); mean-while PRA increased from 0.6 +/- 0.2 to 1.3 +/- 0.3 mol.L-1/h (P less than 0.05) and ATII from 62.4 +/- 17.2 to 133.3 +/- 31.8 ng/L (P less than 0.01). But ACE decreased from 77.6 +/- 5.2 to 58.4 +/- 4.2 mumol.min-1/L (P less than 0.05). After Captopril injection ACE was remarkably reduced to 26.7 +/- 3.4 mumol.min-1/L (P less than 0.001) and ATII dropped to 61.9 +/- 15.5 ng/L (P less than 0.01) compared with those during hypoxemia. There was significant correlation between PAP and PRA (r = 0.564, P less than 0.01). We speculate that angiotensin system may play a part in acute hypoxia induced pulmonary hypertension and captopril inhibits the production of ATII leading to the decrease of pulmonary arterial pressure.     

Effect of age on the renin-angiotensin-aldosterone system in normal subjects: simultaneous measurement of active and inactive renin, renin substrate, and aldosterone in plasma

To investigate the effect of aging on the renin-angiotensin-aldosterone system, plasma renin substrate concentrations (PRSC); plasma total, active, and inactive renin concentrations (TRC, ARC, and IRC); PRA; and plasma aldosterone concentrations (PAC) were measured simultaneously in 60 normal subjects, 18-84 yr old. PRSC was measured by the addition of excess human renal renin. ARC and TRC after trypsin activation were measured by adding sheep renin substrate; IRC was calculated by subtracting ARC from TRC. The active renin ratio was calculated as follows: ARC/TRC X 100%. PRA and PAC were measured by RIA. There were no significant changes in PRSC, TRC, IRC, and PRA to PAC ratio with aging. Both ARC and active renin ratio fell significantly with aging (r = 0.46 and P less than 0.01; and r = 0.54 and P less than 0.01, respectively). PRA and PAC also tended to decrease with aging (r = 0.35 and P less than 0.01; and r = 0.59 and P less than 0.01, respectively). A significant positive correlation was found between PRA and ARC (r = 0.72; P less than 0.001). PRA was also correlated with PAC. In conclusion, the age-related decrease in PRA is not due to the change in PRSC, but is mainly due to the fall in ARC. Decreased conversion of inactive to active renin might be responsible in part for the reduced ARC in the elderly.     

Routine heparin therapy inhibits adrenal aldosterone production

While heparin-induced aldosterone deficiency has been sporadically reported, it is not known whether heparin always inhibits aldosterone production to a variable extent or if this is an idiosyncratic effect, nor is the mechanism underlying the phenomenon known. We have examined plasma aldosterone, PRA, and aldosterone to renin activity ratios in 20 patients before, during and after treatment with heparin. Aldosterone cell during heparin treatment from 73.5 +/- 20.5 to 36.8 +/- 11.2 pg/ml (P less than 0.05) and rose after its withdrawal to 94.8 +/- 37.1 p/ml (P less than 0.05). PRA rose with heparin treatment from 2.8 +/- 1.0 to 6.1 +/- 1.6 ng/ml . h (P less than 0.05) and fell to 2.4 +/- 0.5 ng/ml . h (P less than 0.05) when the drug was withdrawn. Aldosterone to renin activity ratios, which are indices of aldosterone responsiveness to angiotensin, fell from 59.5 +/- 1.7 to 25 +/- 14.9 (P less than 0.01) with heparin treatment and rose after withdrawal of the drug to 58.5 +/- 24.9 (P less than 0.01). There was a significant small fall in serum sodium levels with the introduction of heparin, but none of the patients developed clinical mineralocorticoid deficiency. Although heparin consistently perturbs aldosterone production in the glomerulosa cell, this effect is not clinically significant when normal adjustments can be made in the generation of angiotensin. However, where limitations in the renin-angiotensin-aldosterone axis exist, e.g. in diabetes mellitus, mineralocorticoid insufficiency may be precipitated by heparin.     

Plasma levels of atrial natriuretic factor in mild to moderate hypertensives without signs of left ventricular hypertrophy: correlation with the known duration of hypertension

The relationship between plasma atrial natriuretic factor (ANF), blood pressure (BP), age, plasma renin activity (PRA) and urinary sodium excretion was studied in 64 normal subjects (mean age 48.7 +/- 2.1 yrs; BP: 126.5 +/- 1.6/79.5 +/- 0.9 mmHg) and in 104 untreated uncomplicated essential hypertensives (50.8 +/- 1.1 yrs; BP: 164.7 +/- 1.6/105.2 +/- 0.6 mmHg). ANF was measured by radioimmunoassay after extraction on C18 columns. ANF was significantly higher in the hypertensives than in the normal subjects (37.1 +/- 1.2 vs 29.7 +/- 1.5 pg/ml, P less than 0.01). In normals plasma ANF was significantly correlated with age (r = 0.72, P less than 0.001), Na excretion (r = 0.42, P less than 0.001) and PRA (r = -0.71, P less than 0.001) whereas in the hypertensives ANF plasma levels correlated only with systolic (r = 0.46, P less than 0.001) and diastolic (r = 0.51, P less than 0.001) BP. In addition in hypertensive patients, by multivariate linear regression analysis, a significant correlation was found between age, known duration of hypertension and plasma ANF. The partial correlation coefficient between duration of hypertension and plasma ANF was highly significant (r = 0.80, P less than 0.001). These findings suggest that in essential hypertension the level of arterial BP is a main determinant of the ANF plasma values offsetting the ability of other physiological factors to regulate plasma ANF levels.     

Effects of graded renal artery constriction on blood pressure, renal artery pressure, and plasma renin activity in Goldblatt hypertension

One-kidney, one clip (1K1C) and two-kidney, one clip (2K1C) Goldblatt hypertension was produced in rats by placing 0.30, 0.25, or 0.20 mm silver clips on the left renal artery. Mean arterial pressure (MAP) and plasma renin activity (PRA) were measured in conscious rats 24 to 28 days after clipping. The MAP in control rats (n = 38) was 116 +/- 1 mm Hg (mean +/- SEM). The 0.30, 0.25, and 0.20 mm clips produced MAPs of 133 +/- 2, 161 +/- 5, and 189 +/- 5 mm Hg, respectively, in 1K1C rats, and 123 +/- 2, 129 +/- 3, and 172 +/- 5 mm Hg in 2K1C rats (n = 17-20). When 1K1C and 2K1C groups were compared, MAP was significantly greater in 1K1C rats at all clip sizes. No treatment group's PRA was different than control (4.8 +/- 0.4 ng AI/ml/hr), except for the 0.20 mm 2K1C rats (16.2 +/- 3.1 ng AI/ml/hr). Renal artery pressure (RAP) was measured in another series of experiments and was not different from control in all but the 0.20 mm 1K1C rats. With identical clip sizes, 2K1C rats showed smaller pressure gradients than 1K1C across the clips: 0.30 mm, 8.5 +/- 1.7 vs 10.7 +/- 1.9 mm Hg; 0.25 mm, 16.5 +/- 1.2 vs 42.1 +/- 7.5 mm Hg; 0.20 mm, 51 +/- 5.3 vs 79.1 +/- 5.7 mm Hg (n = 8-12). Therefore, both the increase in MAP and the pressure gradient across the clip were greater in the 1K1C rats at every clip size.(ABSTRACT TRUNCATED AT 250 WORDS)