Effect of blockade of angiotensin II on blood pressure, renin and aldosterone in cirrhosis

1-Sar-8-ala angiotensin II (saralasin) was infused intravenously in graded doses of from 0.1 to 10 mug/kg/min to five patients with cirrhosis and ascites after three days of restricted sodium intake. In each patient blockade of AII by saralasin produced a marked fall in blood pressure, a rise in plasma renin activity (PRA) and plasma renin concentration (PRC) and, in four of the five, a fall in plasma aldosterone (PA). The rise in PRA and PRC correlated poorly with changes in blood pressure. The effects of saralasin rapidly reversed after cessation of the infusion. Plasma volume was normal or high in each case. Three patients were mildly hypotensive in the control state, and all five were resistant to the pressor effect of infused AII. After three days of salt loading, the above effects of saralasin were diminished but not abolished. In four normal subjects, after salt depletion, saralasin infusion induced qualitatively similar but much smaller changes in blood pressure, PRA and PRC. In two cirrhotic patients without ascites, after salt depletion, saralasin infusion caused a rise in blood pressure with no significant changes in PRA, PRC or PA. These results provide evidence that in patients with cirrhosis and ascites circulating AII is active in support of blood pressure, in direct suppression of renal renin release, and in stimulation of aldosterone release.     

Correlations between blood pressure, blood volume and plasma renin during therapy with diuretics in essential hypertension. Comparison between the mineralocorticoid antagonist spironolactone and the "loop" diuretic mefruside

35 patients with benign essential hypertension were treated for 6 weeks with high doses of the mineralocorticoid-antagonist spironolactone (400 mg/day), or with the "loop-diuretic" mefruside (mean maximal dose 110 mg/day). Spironolactone caused greater reductions in blood pressure and blood volume and a more marked increase in plasma renin activity (PRA) than mefruside (p less than 0.05). It appears possible that he weaker antihypertensive effect of mefruside may relate partly to its lesser influence on circulatory volume. With both diuretics, mean decreases in blood pressure were greater in patients with low pre-therapeutic PRA than in patients with normal or high PRA. However, the diuretic-induced changes in blood pressure did not correlate with the associated variations in blood volume or PRA. Thus, the increased blood pressure sensitivity to diuretics in patients with low-renin essential hypertension did not appear to be volume or renin-dependent. Under normal conditions, the maintenance of a constant blood pressure during volume depletion may partly depend on compensatory activation of the sympathetic nervous system. Moreover, patients with low-renin essential hypertension have been found to have decreased adrenergic activity. It seems possible, therefore, that the marked blood pressure sensitivity to diuretic treatment in such patients may be the result of an impaired compensatory sympathetic response to sodium and volume depletion. Analysis of the literature suggests that the diuretic furosemide, a structural relative of mefruside, may also have less blood pressure lowering efficacy in patients with essential hypertension than the distally-acting thiazides, chlorthalidone or spironolactone. Consideration of possible differences in the blood pressure reducing potential of certain diuretics thus appears to be necessary in planning the pharmacotherapy of essential hypertension.     

The effect of saralasin (1sar-8-ala-angiotensin II) on blood pressure in patients with Cushing's syndrome

To investigate the role of the renin angiotensin system in the pathogenesis of hypertension in Cushing's syndrome two patients with hypercorticism were infused with 20 mg saralasin (1-sar-8-ala-angiotensin II) over a period of 30 minutes under constant blood pressue control. In addition, one patient with primary aldosteronism, an established form of mineralocorticoid hypertension, served as control. Neither in the two patients with Cushing's syndrome nor in the patient with primary aldosteronism could a blood pressure lowering effect of saralasin be observed. In the two patients with hypercoritcism both renin activity and plasma aldosterone increased during saralasin infusion. The patient with primary aldosteronism only showed a weak increase in plasma aldosterone concentration.     

Circulating plasma prekallikrein and tissue kallikrein in normotensive and hypertensive humans: effects of angiotensin II infusion

Kinins lower blood pressure but the stimuli leading to kinin generation and their origin are less well known. We administered angiotensin II in graded infusion doses to patients with primary hypertension and normotensive controls to study the effects of on circulating kallikreins. Angiotensin II infusion did not significantly alter plasma prekallikrein or tissue kallikrein levels and the plasma levels and their changes did not correlate with blood pressure levels or changes. In the normotensive group prekallikrein levels and renin activity correlated negatively with urinary sodium and chloride excretion during basal conditions and partially during the infusion. U-tissue kallikrein concentration increased in the normotensive group. Thus, acute elevation of blood pressure induced by angiotensin II does not activate the circulating kallikrein-kinin systems. Data rather indicate that the circulating kallikrein-kinin systems may be related to alterations in volume and sodium balance and that these mechanisms may be altered in primary hypertension.     

Failures in the surgical treatment of retinal detachment. An analysis

One hundred sixteen patients underwent operation for renovascular hypertension from 1962 through 1975; 64% had aortorenal reconstruction and 36% had nephrectomy. Sixty-six percent were cured and 19% were improved. Rapid sequence intravenous pyelography, radioisotope renography, and renal arteriography were equal in ability to detect renovascular hypertension. Bilateral renal biopsy specimens had excellent prognostic value when performed in a graded semiquantitative manner. Plasma renin activity was the most consistently useful criterion for prediction of surgical cure if the following requirements were used: (1) elevated peripheral plasma renin activity, (2) elevated renin from the affected kidney, and (3) suppressed renin secretion from the contralateral kidney. An angiotensin II antagonist, saralasin acetate, used in six patients before operation in an attempt to identify those whose hypertension depended on angiotensin II activity, produced a depressor response correlating well with the surgical result.     

Nocturnal blood pressure and relation to vasoactive hormones and renal function in hypertension and chronic renal failure

The purpose of this study was to assess the blood pressure profile and to measure vasoactive hormones in patients with essential hypertension (n=61), secondary hypertension (n=32) and chronic renal failure (n=32) matched with healthy control subjects (n=35), and to study the relationship between circadian changes in blood pressure and baseline levels of vasoactive hormones and renal function. Non-invasive, automatic blood pressure measurement was performed for 24 or 48 h. Venous plasma concentrations of renin, angiotensin II, aldosterone, arginine vasopressin, atrial natriuretic peptide and endothelin were measured. The mean 24-h blood pressure was higher in all groups of hypertensive patients than in control subjects. The nocturnal blood pressure fall was preserved in essential hypertension, in contrast to secondary hypertension in which it was attenuated. In the patients with chronic renal failure the 24-h mean blood pressure was the same as in the controls. Night-time blood pressure was higher among the chronic renal failure patients than in the control group, and the nightly blood pressure fall in both diastolic and systolic blood pressure was reduced. Plasma concentrations of renin activity, arginine vasopressin, atrial natriuretic peptide, aldosterone and endothelin were significantly increased in secondary hypertension and chronic renal failure, compared to essential hypertension and control subjects. Plasma angiotensin II was increased in chronic renal failure compared to essential hypertension and controls. Estimated creatinine clearance and nightly blood pressure dips were inversely correlated in essential and secondary hypertension, i.e. with a decreasing renal function both systolic and diastolic nightly blood pressure dips were gradually attenuated. In the whole group of patients the nightly systolic and diastolic blood pressure dips were negatively correlated to basal plasma renin activity, plasma aldosterone and atrial natriuretic peptide levels, i.e. the higher the basal plasma hormone level the lower the blood pressure dip. In conclusion, patients with essential hypertension have elevated but normally configured 24-h blood pressure profiles, and patients with different kinds of secondary hypertension have elevated 24-h blood pressure profiles and attenuated nightly systolic and diastolic blood pressure falls. The more the renal function is reduced and the more the plasma levels of renin and aldosterone are increased, the more the nocturnal fall in blood pressure is reduced. It is suggested that the attenuated or absent decrease in nocturnal blood pressure in secondary renal hypertension is caused by an abnormally increased secretion of vasoactive hormones and/or by so far unknown factors released from the diseased kidney.     

Incidence and pathophysiological changes in chronic two-kidney hypertension in the dog

Unilateral renal artery plication in dogs reduced renal blood flow by 80% and produced a sustained elevation in arterial pressure whereas plasma renin activity increased for only 4 days. Sodium was retained for 3 days after plication, but this response is similar to that after a sham operation. Of seven dogs studied chronically, elevated arterial pressure was sustained for 27 days or longer in six animals. In three dogs hypertension continued for 2 mo before collateral vessels developed and arterial pressure fell; ligation of these collaterals restored hypertension. Arterial pressure was unaffected by an infusion of [1-sarcosine, 8-alanine] angiotensin II in chronic hypertensive dogs on a normal sodium intake. This angiotensin antagonist lowered arterial pressure after sodium depletion, but became ineffective following rapid sodium repletion. Chronic hypertensive dogs showed normal responses to deoxycorticosterone acetate. These findings suggest that the renin-angiotensin system is not critically involved in maintenace of chronic two-kidney renovascular hypertension in the dog. The data also show that the homeostatic role played by the renin-angiotensin system in the maintenance of arterial pressure remained intact in chronic hypertension.     

Development of chronic perinephritic hypertension in dogs without volume expansion

The theory of whole body autoregulation to explain the pathogenesis of experimental renal hypertension states that hypertension is initiated in response to an early increase in salt and water retention and a subsequent elevation of the cardiac output. This hypothesis was evaluated in the present study. Dogs (n,5) were made hypertensive by wrapping the left kidney in cellophane and removing the contralateral kidney 3 wk later. One week prior to right nephrectomy, the dogs were volume depleted by placing them on a low sodium intake (less than 3 meq of sodium/day) and giving them a mercurial diuretic for the first 3 days of the diet. This superimposed sodium depletion (negative sodium balance of 137 +/- 17 meq) increased plasma renin activity 3-5 times but did not change arterial pressure or heart rate. Within 2 days after nephrectomy, the mean arterial pressure increased from the control level of 105 +/- 1 to 135 +/- 6 mmHg (P less than 0.005) and pressure remained elevated throughout an additional 4-wk period in which volume depletion was enforced. The present study suggests, therefore, that initial blood volume expansion with such possible consequences as elevated cardiac output are not essential to the pathogenesis of experimental renal hypertension.     

Carpal tunnel syndrome: reappraisal of five clinical tests

The renin-angiotensin system plays a major role in the regulation of blood pressure and sodium balance. Nitric oxide (NO) and endothelin (ET-1) are involved in the regulation of renin release and modulate the vasoconstrictive and fibrogenic effects of angiotensin II. the mechanisms that activate renin production are less effective when endogenous NO synthesis is inhibited. In the absence of NO, ET-1 prevents renin secretion. Angiotensin II stimulates the production of NO and ET-1 by endothelial cells. The vascular effects of angiotensin II are inhibited by NO reinforced by ET-1. The stimulation of ET-1 secretion could partly explain the long-term effects of angiotensin II on vascular remodelling.     

Agonist and antagonist effects of Sar1-ala8--angiotensin II in salt-loaded and salt-depleted normal man

1 Three normal subjects were infused with Sar1-ala8-angiotensin II (Saralasin, P113) whilst on a high sodium (200 mEq + normal diet) and a low sodium (10 mEq diet) intake. 2 On the high sodium intake when angiotensin II and plasma renin activity (PRA) were suppressed, P113 infusion (5-10 mug kg-1 min-1) caused a slight rise in BP and a marked drop in urine flow and sodium excretion, with a fall in glomerular filtration rate, and effective renal plasma flow. 3 On the low sodium intake, when angiotensin II and PRA were increased, P113 infusion (5-10 mugkg-1 min-1) caused no change in blood pressure, urine flow or sodium excretion. However, when P113 was infused at an incremental rate starting at 0.25 mug kg-1 min-1 there was a fall in standing BP, which was maximal at an infusion rate of 1 mug kg-1 min-1, and this fall in standing BP was largely abolished as the rate of infusion was increased to 10 mug kg-1 min -1. 4 These results show firstly that angiotension II is involved in maintaning standing blood pressure during dietary sodium depletion in normal man and secondly that P113 does have agonist as well as antagonist activity in normal man, the effect depending on the level of angiotension II and sodium intake. When looking for angiotensin II mediated hypertension it may ne important to use an incremental rate of infusion of P113 as the agonist activity of larger doses may mask its hypotensive action.     

Renin and aldosterone suppression in the antihypertensive action of clonidine

In 18 hypertensive patients receiving a constant (100 mEq/day) sodium diet, treatment with clonidine (0.3 mg/day for 5 days) decreased blood pressure in 11 patients with high and normal renin levels and 7 with low renin levels. The high and normal renin group had early and rapid reductions in blood pressure and plasma renin activity. In contrast, the low renin group had a more gradual hypotensive response and only a small absolute decrease in plasma renin. For all patients, pretreatment renin levels were related to the initial decrease in blood pressure but not to the reductions measured after 5 days. Thus, two mechanisms of action of clonidine are possible, one related to acute inhibition of the renin-angiotensin system in patients with high and normal renin levels and another that is independent of renin mechanisms and occurs in all hypertensive patients. In six additional patients with high renin levels induced by prior sodium depletion (10 mEq/day sodium diet), clonidine did not reduce blood pressure or renin, thus indicating that the suppressive action of this agent on renin pressor mechanisms occurs only in patients whose elevated renin levels are intrinsic to hypertension and unrelated to sodium depletion. Of the 18 patients receiving a normal sodium diet, 13 were classified as responding to treatment (decrease in both systolic and diastolic pressures of at least 10%). The five nonresponders had greater weight gain and higher values for aldosterone excretion. For all patients, there was a significant correlation between decrements in blood pressure and in aldosterone, suggesting that the countervailing effects of fluid accumulation on blood pressure in nonresponding patients resulted from a failure of aldosterone to be suppressed. Changes in aldosterone, in turn, correlated significantly with changes in renin. Thus, the antirenin effect of clonidine enhances its antihypertensive action not only by acutely ablating renin-angiotensin pressor mechanisms, but also by inhibiting aldosterone production and thereby minimizing longer-term reactive volume retention during treatment.     

Biochemical and molecular changes at the cellular level in response to exposure to environmental estrogen-like chemicals

The pharmacokinetic and pharmacodynamic properties of nonpeptide angiotensin antagonists in humans are reviewed in this paper. Representatives of this new therapeutic class share common features: lipophilia, intermediate bioavailability, high affinity for plasma proteins and liver metabolism; some have active metabolites. Angiotensin II antagonists block the blood pressure response to exogenous angiotensin II in healthy volunteers, decrease baseline blood pressure in both normal and hypertensive patients, produce a marked rise in plasma renin activity and endogenous angiotensin II and increase renal blood flow without altering glomerular filtration rate. These effects are dose-dependent, but their time course varies between the drugs owing to pharmacokinetic and pharmacodynamic differences. Additionally, the extent of blood pressure reduction is dependent on physiological factors such as sodium and water balance. The characterisation of their pharmacokinetic-pharmacodynamic relationships deserves further refinement for designing optimal therapeutic regimens and proposing dosage adaptations in specific conditions.     

Sensitivity of blood pressure and renin activation during sodium restriction

The objective of the present study was to explore the interrelationships among cumulative sodium loss, renin activation, and blood pressure changes during sodium restriction in essential hypertensive patients. Specifically, we wanted to know whether the degree of sodium sensitivity of blood pressure depends on renin activation during steady state or on initial renin activation during the first days of sodium restriction. Sixty-seven untreated essential hypertensive patients were admitted to a metabolic ward for 8 days and put on a sodium restricted diet of 55 mmol/d from the second to the last day. Urinary excretions of sodium, potassium, and creatinine were determined along with mean arterial pressure and weight during 7 days. Besides measurements in steady state condition (after 7 days), active plasma renin concentration, aldosterone, and catecholamines were also assessed during the first 3 days of sodium restriction. Analyzable data are available for 55 patients. Baseline sodium excretion and the activation of renin during the first 3 days both appeared to be predictors of total sodium loss after 7 days. Changes in blood pressure were not related to changes in sodium balance, but they were to baseline blood pressure, baseline norepinephrine, and renin activation during the early phase of sodium restriction. In addition, blood pressure appeared to fall more when the normal relationship between sodium loss and early (but not late) activation of renin was disturbed. We conclude that sodium sensitivity of blood pressure during sodium restriction is associated with a relative unresponsiveness of the renin system during the early phase of sodium loss rather than to absolute renin levels during steady state.     

Laminectomy for spinal cord compression from metastatic tumor

The blood pressure response to graded infusions of angiotensin II was assessed under control conditions and following short term (16 hour) indomethacin treatment utilizing normal men equilibrated on a constant diet of normal sodium and potassium content. Although basal mean blood pressure was unchanged, the increase in blood pressure with all rates of angiotensin II infusion ranging from 200 to 1000 ng/min was significantly greater with indomethacin treatment. Pre-infusion body weight and plasma renin activity were similar under the two conditions. These results suggest that prostaglandins modulate the systemic vasoconstrictor effects of angiotensin II.     

A study on the pathogenesis of hyporeninemia in diabetics

Hyporeninemic hypoaldosteronism has mainly been described in patients with diabetes mellitus. In order to elucidate the mechanisms of hyporeninemia in diabetic patients, the author studied the response of active renin concentration (ARC) and inactive renin concentration (IRC) to the administration of captopril or sodium depletion in patients with diabetes mellitus and glomerulonephritis and in normal subjects. The diabetic patients were separated into four groups: Group 0, diabetic patients without neuropathy or nephropathy; Group I, those with neuropathy without nephropathy; Group II, those without neuropathy with nephropathy; Group III, those with neuropathy and nephropathy. Diabetic patients with some complications had slightly lower plasma active renin levels than those without complications. The mean increase in plasma active renin after captopril (delta ARC) and sodium depletion was lower in group I than in group 0, and there was no difference between group II and group 0. There was no correlation between delta ARC and creatinine clearance (Ccr) in diabetes mellitus. Plasma prorenin was higher in group I than in group 0, and there was no difference between group II and group 0. No significant change of prorenin after captopril was observed in all groups, but the mean increase in plasma inactive renin after sodium depletion was slightly higher in groups I and III than in groups 0 and II. ARC/IRC was significantly lower in group I than in group 0, and there was no difference between group II and group 0. There was no correlation between ARC/IRC and Ccr in diabetes mellitus, but significant correlation between ARC/IRC and postural change in systolic blood pressure. In three diabetic patients with hyporeninemic hypoaldosteronism, the postural fall in systolic blood pressure was significant, and ARC/IRC was significantly low, but IRC was not high. These results suggest that autonomic dysfunction is a major factor in an impairment of the processing of prorenin to active renin in diabetic patients, and severe autonomic dysfunction may impair the biosynthesis of prorenin in patients with hyporeninemic hypoaldosteronism.     

The renin-angiotensin-aldosterone system in hypertensive subjects. I-Analytical study of 124 patients (author's transl)

An analytical study of the renin-angiotensin-aldosterone system was made in 124 individuals with essential hypertension, aged from 25 to 55 years. The results obtained, with rigorous control to posture and sodium balance, indicate the existence of a number of subgroups of hypertensive subjects related to their renin activity and plasma aldosterone in the upright position. This classification thus makes possible comparison with patients suffering from secondary hypertension.     

Non-traumatic brain abscess

Serotonin and abnormal serotonergic activity (both central and peripheral) may play a role in pathogenesis of essential hypertension. Serotonin acts chiefly via three types of receptors namely S1, S2 and S3 serotonergic receptors. Besides being vasoactive, it has some inotropic and chronotropic properties and also affects blood rheology. It has stimulating effect on renin and aldosterone secretion. The action of other vasoactive substances like norepinephrine and angiotensin II are amplified. All these physiological effects of serotonin strongly support the hypothesis that it may be involved in hypertension. The advent of serotonin antagonists in lowering blood pressure has further substantiated this hypothesis.     

Effects of varying sodium intake on blood pressure and renin-angiotensin system in subtotally nephrectomized rats

In rats in which the renal mass had been reduced by 70 per cent, the effects of varying sodium intake on blood pressure, serum electrolytes, renin-angiotensin system, and some other parameters that were modified simultaneously were studied. Within 4 weeks, a high sodium diet (750 mEa. per kilogram) resulted in marked hypertension, whereas a standard sodium diet (150 mEq. per kilogram) elevated the blood pressure only slightly. A low sodium diet (less than 0.2 mEq. per kilogram) prevented the rise in blood pressure. In the hypertensive group, the hematocrit values were markedly decreased, indicating the expansion of extracellular and intravascular spaces. The compensatory renal hypertrophy was accelerated by the high sodium diet and retarded during restriction. During low sodium intake, the serum concentration of sodium was diminished and that of potassium elevated. During the high sodium diet, the sodium concentration was unchanged, but the potassium concentration was decreased. Subtotal nephrectomy diminished the plasma angiotensin II concentration, and the renin content of the kidney remnant was lower than that of the kidneys from control animals. Sodium restriction stimulated the renin angiotensin system markedly, whereas high sodium intake suppressed it. After subtotal nephrectomy, elevation of blood pressure, renal hypertrophy, and suppression of the renin-angiotensin system are closely related to sodium intake.     

Comparison of blood pressure and angiotensin responses to the renin inhibitor Ro 42-5892 and the angiotensin converting enzyme inhibitor enalapril in essential hypertension

OBJECTIVE: To compare the responses of angiotensin II (Ang II) and blood pressure to the renin inhibitor Ro 42-5892 and the angiotensin converting enzyme (ACE) inhibitor enalapril. SUBJECTS: Eight non-sodium-restricted patients with mild-to-moderate essential hypertension. DESIGN: A single-blind crossover study. Ro 42-5892 (600 mg orally, once a day) and enalapril (20 mg orally, once a day) were given for 8 days before detailed investigations were carried out. METHODS: Ambulatory blood pressure was measured directly for 24 h by the Oxford technique on three occasions. Off-treatment and on day 8 of treatment with Ro 42-5892 and with enalapril. Ang II was measured by radioimmunoassay after separation by high-performance liquid chromatography. RESULTS: Plasma renin activity and Ang II were lowered by 83% [95% confidence interval (CI) 61-105] and 68% (95% CI 49-87), respectively, 0.5-1 h after Ro 42-5892, but after only 3 h values had returned to baseline. Unlike this rapid and short-term suppression of Ang II, the maximal antihypertensive response to Ro 42-5892 (fall in blood pressure 12.9/9.0 mmHg) occurred only after 6 h. Blood pressure returned to baseline after 8 h. In response to enalapril, Ang II was maximally suppressed by 63% (95% CI 32-94) after 2 h and by 83% (95% CI 76-90) after 8 h. Despite early maximal Ang II suppression, the maximal antihypertensive response to enalapril occurred only after 12 h (fall in blood pressure 25.3/16.3 mmHg). With this compound a significant antihypertensive effect was still present 24 h after dosing. CONCLUSIONS: Compared with enalapril at 20 mg once a day, repeated oral administration of a single dose of Ro 42-5892 at 600 mg caused only short-term suppression of Ang II and blood pressure. Suppression of Ang II and reduction in blood pressure were temporally dissociated, both with the ACE inhibitor and the renin inhibitor. This implies that the blood pressure lowering effect of these inhibitors is caused partly by Ang II suppression outside the circulation.     

The effects of an angiotensin blocker (saralasin) on kidney function in dehydrated sheep

Saralasin, an angiotensin II analogue and receptor blocker, was infused at 7 and 15 micrograms . min-1 into dehydrated conscious Merino ewes. This caused mean arterial blood pressure, cardiac output, heart rate and renal vascular resistance to fall, and central venous pressure to rise. Renal plasma flow was unaffected but there were significant reductions in glomerular filtration rate, filtration fraction, urine flow, sodium and potassium excretion, solute clearance and solute-free water reabsorption. It is suggested that saralasin produced these effects by inhibiting endogenous angiotensin II activity, and in particular by causing a reduction in renal post-glomerular resistance. This in turn caused a fall in glomerular filtration rate and filtration fraction. While saralasin might have had effects on renal tubular function and perhaps on vasopressin secretion, the observed effects on renal function can be explained by the decrease in glomerular filtration rate and filtration fraction.