What have we learned about inhibitors of the renin-angiotensin system?

With orally active angiotensin converting inhibitors it is now possible to block the renin-angiotensin system chronically. These agents given alone normalize blood pressure of many hypertensive patients. In the remaining, an additional salt subtraction, induced for example by diuretics, is necessary to further reduce blood pressure. In patients with congestive heart failure, angiotensin converting enzyme inhibitors increase cardiac output and exercise capacity, both acutely and chronically. Adverse reactions resulting from blockade of the renin-angiotensin system can be predicted to a large extent and therefore are most often easily avoided. Angiotensin converting enzyme inhibitors like captopril and enalapril, because of their efficacy and good acceptability are likely to become important drugs for the treatment of hypertension and congestive heart failure.     

Inflammation and atherosclerosis: the role of Renin-Angiotensin system and its inhibition

The last studies show the renin angiotensin aldosterone system plays an important role in atherosclerotic processes. Vasoconstriction and sodium and water retention, due to angiotensin II and aldosterone promote atherosclerotic processes. Theres recent evidence from animal and clinical studies to consider angiotensin II as a mediator of inflammation, which induces atherosclerotic plaque development and heart remodeling. Also angiotensin II causes endothelial dysfunction by inducing cytokine and chemokine secretion. The pharmacological blockade of the renin angiotensin system has positive influence on clinical outcomes of patients with cardiovascular diseases independently of the blood pressure lowering effect. This review summarizes studies about the role of angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists (ARA) and renin inhibitors in vascular inflammatory processes in atherosclerosis.     

Differences in first dose response to angiotensin converting enzyme inhibition in congestive heart failure: a placebo controlled study.

OBJECTIVE--To compare the first dose responses to low dose angiotensin converting enzyme inhibitors (captopril, enalapril, and perindopril) in elderly patients with stable chronic heart failure. DESIGN--Double blind, randomised, placebo controlled, parallel, group prospective study of elderly patients with stable chronic heart failure. SETTING--General hospital in-patient admissions for supervised diuretic withdrawal (24-48 hours) and the introduction of angiotensin converting enzyme inhibitor therapy. PATIENTS--48 unselected elderly (58-85 years) patients with symptomatic but stable chronic heart failure (New York Heart Association grades II-IV) confirmed by clinical history, examination, and cardiological investigations. Patients gave their written and informed consent to receive their initial treatment under double blind conditions; blood pressure was monitored and blood samples taken to measure the pharmacokinetic and neurohormonal responses. INTERVENTION--Patients were randomised to receive a daily oral dose of placebo, captopril (6.25 mg), enalapril (2.5 mg), or perindopril (2 mg). MAIN OUTCOME MEASURES--Blood pressure and heart rate responses, drug concentration, and plasma renin and ACE activities. Differences between treatment groups were analysed by analysis of variance. RESULTS--The four randomised groups of patients had similar age, severity of heart failure (NYHA class), pretreatment diuretic dosage, plasma renin activity, and serum electrolyte state. Placebo treatment caused a modest but significant diurnal fall in blood pressure. Captopril produced a significant early (1.5 hours) and brief fall in blood pressure. The blood pressure fall with enalapril was later (4-10 hours), longer lasting, and was associated with significant slowing of supine heart rate. Though perindopril produced a similar plasma ACE inhibition to that produced by enalapril, it only caused changes in blood pressure that were similar to those caused by placebo. CONCLUSIONS--This controlled study is the first to indicate a qualitative difference in the acute response to angiotensin converting enzyme inhibitors with similar structure and metabolism (that is, enalapril and perindopril). Low dose perindopril seems to be less likely to cause hypotension in patients with heart failure. The explanation for the differences is unclear but may reflect differential effects on local tissue angiotensin generation.     

Differences in first dose response to angiotensin converting enzyme inhibition in congestive heart failure: a placebo controlled study.

OBJECTIVE--To compare the first dose responses to low dose angiotensin converting enzyme inhibitors (captopril, enalapril, and perindopril) in elderly patients with stable chronic heart failure. DESIGN--Double blind, randomised, placebo controlled, parallel, group prospective study of elderly patients with stable chronic heart failure. SETTING--General hospital in-patient admissions for supervised diuretic withdrawal (24-48 hours) and the introduction of angiotensin converting enzyme inhibitor therapy. PATIENTS--48 unselected elderly (58-85 years) patients with symptomatic but stable chronic heart failure (New York Heart Association grades II-IV) confirmed by clinical history, examination, and cardiological investigations. Patients gave their written and informed consent to receive their initial treatment under double blind conditions; blood pressure was monitored and blood samples taken to measure the pharmacokinetic and neurohormonal responses. INTERVENTION--Patients were randomised to receive a daily oral dose of placebo, captopril (6.25 mg), enalapril (2.5 mg), or perindopril (2 mg). MAIN OUTCOME MEASURES--Blood pressure and heart rate responses, drug concentration, and plasma renin and ACE activities. Differences between treatment groups were analysed by analysis of variance. RESULTS--The four randomised groups of patients had similar age, severity of heart failure (NYHA class), pretreatment diuretic dosage, plasma renin activity, and serum electrolyte state. Placebo treatment caused a modest but significant diurnal fall in blood pressure. Captopril produced a significant early (1.5 hours) and brief fall in blood pressure. The blood pressure fall with enalapril was later (4-10 hours), longer lasting, and was associated with significant slowing of supine heart rate. Though perindopril produced a similar plasma ACE inhibition to that produced by enalapril, it only caused changes in blood pressure that were similar to those caused by placebo. CONCLUSIONS--This controlled study is the first to indicate a qualitative difference in the acute response to angiotensin converting enzyme inhibitors with similar structure and metabolism (that is, enalapril and perindopril). Low dose perindopril seems to be less likely to cause hypotension in patients with heart failure. The explanation for the differences is unclear but may reflect differential effects on local tissue angiotensin generation.     

Antihypertensive advantages of angiotensin II AT1 receptor antagonism

Advances in scientific research over the last century have permitted the recognition and characterization of the structure and function of an enzymatic pathway involved in cardiovascular homeostasis and blood pressure control, namely the renin-angiotensin-aldosterone system. This system may be reversibly blocked by drugs acting at different levels: renin inhibitors, angiotensin converting enzyme inhibitors and AT1 angiotensin II receptor antagonists. Lacking clinical experience with effects of AT1 angiotensin II receptor antagonists on the cardiovascular system are practically identical to those observed with angiotensin converting enzyme inhibitors. The efficacy and safety of drugs blocking the renin-angiotensin-aldosterone system in the reduction of blood pressure, the regression of cardiovascular remodeling, the prevention of progression of diabetic nephropathy to end-stage renal failure, and the prevention of cardiovascular morbidity and mortality is well established. These hemodynamic effects of AT1 angiotensin II receptor antagonists treatment are achieved with less adverse effects than with angiotensin converting enzyme inhibitors. Furthermore, the association of angiotensin converting enzyme inhibitors and AT1 angiotensin II receptor antagonists allows a more effective renin-angiotensin-aldosterone Systems blockade and improves the hemodynamic and non-hemodynamic effects. This possibility opens up new perspectives in the treatment of cardiovascular diseases, the most common cause of death at the end of the millennium in developed countries.     

Angiotensin I converting enzyme inhibitors and the renal excretion of urate

Summary Hyperuricaemia carries with it a high risk of tophi development affecting connective tissue in kidney, skin and joints, its overt clinical expression being gout. Diuretics, which are invariably prescribed in congestive heart failure and widely used for the treatment of essential hypertension, may cause hyperuricaemia and predispose to gout by inducing renal retention of urate.The angiotensin I converting enzyme inhibitors captopril and enalapril have been found to augment renal urate excretion both in normal volunteers and in hypertensive patients. Current evidence appears to indicate that the uricosuric effect of captopril and enalapril could be due to the rises in renin and angiotensin I these drugs elicit by angiotensin I converting enzyme inhibition, and/or to pharmacological actions not related, at least directly, to the renin-angiotensin-aldosterone system. Serum urate levels have been significantly reduced by monotherapy with captopril in hypertensive patients suffering from hyperuricaemia. Diuretic-induced hyperuricaemia in hypertensive patients can be prevented or counteracted by the administration of captopril and enalapril.Available clinical data support the argument that captopril and enalapril should be used as first choice drugs for the treatment of hyperuricaemic hypertensive patients. When diuretic-induced hyperuricaemia develops in patients suffering from congestive heart failure, captopril or enalapril should be added to the therapeutic regime in doses capable of countering the shift in plasma urate concentration, provided the clinical condition of the patients permits such additional pharmacological treatment.Therapy with captopril and enalapril should preferably be instituted in a gradual manner, especially in patients with hyperuricaemia, in order to prevent the precipitation of urate in the kidney and in the urinary tract.     

Effects of enalapril in heart failure: a double blind study of effects on exercise performance,renal function,hormones, and metabolic state.

Several studies have shown symptomatic and haemodynamic improvement after the introduction of angiotensin converting enzyme inhibitors in patients with heart failure treated with diuretics. The concomitant long term effects of the new orally effective long acting angiotensin converting enzyme inhibitor, enalapril, on symptoms, exercise performance, cardiac function, arrhythmias, hormones, electrolytes, body composition, and renal function have been further assessed in a placebo controlled double blind cross over trial with treatment periods of eight weeks. Twenty patients with New York Heart Association functional class II to IV heart failure who were clinically stable on digoxin and diuretic therapy were studied. Apart from the introduction of enalapril, regular treatment was not changed over the study period; no order or period effects were noted. Enalapril treatment significantly improved functional class, symptom score for breathlessness, and exercise tolerance. Systolic blood pressure was significantly lower on enalapril treatment. Echocardiographic assessment indicated a reduction in left ventricular dimensions and an improvement in systolic time intervals. In response to enalapril, the plasma concentration of angiotensin II was reduced and that of active renin rose; plasma concentrations of aldosterone, vasopressin, and noradrenaline fell. There were significant increases in serum potassium and serum magnesium on enalapril. Glomerular filtration rate measured both by isotopic techniques and by creatinine clearance declined on enalapril while serum urea and creatinine rose and effective renal plasma flow increased. Body weight and total body sodium were unchanged indicating that there was no overall diuresis. There was a statistically insignificant rise in total body potassium, though the increase was related directly to pretreatment plasma renin (r = 0.5). On enalapril the improvement in symptoms, exercise performance, fall in plasma noradrenaline, and rise in serum potassium coincided with a decline in the frequency of ventricular extrasystoles recorded during ambulatory monitoring. Adverse effects were few. In patients with heart failure, enalapril had a beneficial effect on symptoms and functional capacity. The decline in glomerular filtration rate on enalapril may not be beneficial in early heart failure.     

Effects of enalapril in heart failure: a double blind study of effects on exercise performance, renal function, hormones, and metabolic state

Several studies have shown symptomatic and haemodynamic improvement after the introduction of angiotensin converting enzyme inhibitors in patients with heart failure treated with diuretics. The concomitant long term effects of the new orally effective long acting angiotensin converting enzyme inhibitor, enalapril, on symptoms, exercise performance, cardiac function, arrhythmias, hormones, electrolytes, body composition, and renal function have been further assessed in a placebo controlled double blind cross over trial with treatment periods of eight weeks. Twenty patients with New York Heart Association functional class II to IV heart failure who were clinically stable on digoxin and diuretic therapy were studied. Apart from the introduction of enalapril, regular treatment was not changed over the study period; no order or period effects were noted. Enalapril treatment significantly improved functional class, symptom score for breathlessness, and exercise tolerance. Systolic blood pressure was significantly lower on enalapril treatment. Echocardiographic assessment indicated a reduction in left ventricular dimensions and an improvement in systolic time intervals. In response to enalapril, the plasma concentration of angiotensin II was reduced and that of active renin rose; plasma concentrations of aldosterone, vasopressin, and noradrenaline fell. There were significant increases in serum potassium and serum magnesium on enalapril. Glomerular filtration rate measured both by isotopic techniques and by creatinine clearance declined on enalapril while serum urea and creatinine rose and effective renal plasma flow increased. Body weight and total body sodium were unchanged indicating that there was no overall diuresis. There was a statistically insignificant rise in total body potassium, though the increase was related directly to pretreatment plasma renin (r = 0.5). On enalapril the improvement in symptoms, exercise performance, fall in plasma noradrenaline, and rise in serum potassium coincided with a decline in the frequency of ventricular extrasystoles recorded during ambulatory monitoring. Adverse effects were few. In patients with heart failure, enalapril had a beneficial effect on symptoms and functional capacity. The decline in glomerular filtration rate on enalapril may not be beneficial in early heart failure.     

Immediate converting-enzyme inhibition with intravenous enalapril in chronic congestive heart failure

To test the hypothesis that intravenous enalapril is a useful pharmacologic probe of the renin angiotensin system, intravenous enalapril was administered to 9 patients with severe congestive heart failure (CHF). This produced abrupt and complete blockade of converting enzyme, with peak effect occurring at 30 minutes, as reflected by increases of plasma renin activity (from 16.8 +/- 6 to 86.6 +/- 23 ng/ml/hour) and decreases of plasma aldosterone levels (from 46 +/- 14 to 25 +/- 6 ng%) (both p less than 0.05). With reduction of angiotensin II--mediated vasoconstriction, systemic vascular resistance decreased markedly (from 1,974 +/- 233 to 1,400 +/- 136 dyne s cm-5) and cardiac index was improved (from 1.88 +/- 0.9 to 2.20 +/- 0.21 liters/min/m2) (both p less than 0.05). The time course of angiotensin II levels suggested that the lack of a cumulative effect from additive doses of intravenous enalapril was a reflection of complete inhibition of converting enzyme. One patient did not respond to enalapril; despite comparable hemodynamic severity of CHF, the renin-angiotensin system was not activated in this patient. Thus, intravenous enalapril is capable of rapid and complete inhibition of converting enzyme for the accurate assessment of angiotensin II--mediated vasoconstriction in patients with severe CHF.     

Reversible renal failure after combined treatment with enalapril and frusemide in a patient with congestive heart failure

A patient with congestive heart failure and moderate renal insufficiency developed severe reversible non-oliguric renal failure while on frusemide and enalapril. Renal failure developed when enalapril was given in the presence of pronounced sodium depletion. When positive sodium balance was restored the plasma creatinine concentration began to fall while angiotensin converting enzyme inhibition remained effective and blood pressure was stable. These observations suggest that the degree of sodium depletion plays an important role in the tendency for angiotensin converting enzyme inhibitors to induce renal failure in patients with congestive heart failure and moderate renal insufficiency. Restoration of a positive sodium balance promotes the recovery of renal function after the combined administration of angiotensin converting enzyme inhibitors and diuretics.     

Reversible renal failure after combined treatment with enalapril and frusemide in a patient with congestive heart failure.

A patient with congestive heart failure and moderate renal insufficiency developed severe reversible non-oliguric renal failure while on frusemide and enalapril. Renal failure developed when enalapril was given in the presence of pronounced sodium depletion. When positive sodium balance was restored the plasma creatinine concentration began to fall while angiotensin converting enzyme inhibition remained effective and blood pressure was stable. These observations suggest that the degree of sodium depletion plays an important role in the tendency for angiotensin converting enzyme inhibitors to induce renal failure in patients with congestive heart failure and moderate renal insufficiency. Restoration of a positive sodium balance promotes the recovery of renal function after the combined administration of angiotensin converting enzyme inhibitors and diuretics.     

Vascular renin-angiotensin system in two-kidney, one clip hypertensive rats

The possible role of the renin-angiotensin system in the maintenance of hypertension in two-kidney, one clip hypertensive rats was studied. Plasma renin activity rose rapidly and markedly in association with the elevation of blood pressure and then decreased gradually, although blood pressure remained high. Renin activity in the lung, aorta, and mesenteric artery also increased with the development of hypertension and then decreased in a way similar to that of plasma renin activity at the chronic stage of hypertension. Plasma angiotensin converting enzyme activity did not change significantly until 16 weeks after unilateral renal artery clipping, whereas vascular angiotensin converting enzyme activity significantly increased at the chronic, but not the acute, stage of hypertension. In chronically renal hypertensive rats, 1-sarcosine, 8-isoleucine angiotensin II or enalapril, an angiotensin converting enzyme inhibitor, lowered the blood pressure and enalapril also lowered the angiotensin converting enzyme activity of vascular tissues. The constrictor effect of angiotensin I was greater in isolated arteries from chronically hypertensive rats than in those from age-matched normotensive rats. These results suggest that the vascular renin-angiotensin system plays an important role in the maintenance of two-kidney, one clip hypertension. Elevated vascular angiotensin converting enzyme activity appears to increase local production of angiotensin II, which results in vasoconstriction by acting directly and indirectly through adrenergic nerves on vascular smooth muscle.     

Comparison of the effects of losartan and enalapril on clinical status and exercise performance in patients with moderate or severe chronic heart failure

Objectives. This study assessed the feasibility of an efficacy trial comparing angiotensin-converting enzyme inhibition and angiotensin II receptor antagonism in heart failure. Patients with moderate or severe heart failure whose condition had previously been stabilized by treatment with a converting enzyme inhibitor were randomly assigned to receive enalapril or losartan. The study was designed to detect any signs of clinical deterioration during double-blind treatment.Background. Losartan is a specific, nonpeptide angiotensin II receptor-1 antagonist with a vasodilator hemodynamic profile similar to that of converting enzyme inhibitors. Although therapy with specific receptor blockade has certain theoretic advantages over nonspecific converting enzyme inhibition, demonstration of a comparable therapeutic effect in patients with congestive heart failure will require a major effort comparing two active agents.Methods. One hundred sixty-six patients with stable heart failure in New York Heart Association functional class III or IV and an ejection fraction ≤35% were included in a multicenter, double-blind, parallel, enalapril-controlled trial. After a 3-week stabilization period with optimal therapy, including digitalis, diuretic drugs and a converting enzyme inhibitor, patients were randomly assigned to 8 weeks of therapy with losartan, 25 mg/day (n = 52); losartan, 50 mg/day (n = 56); or enalapril, 20 mg/day (n = 58). Patients were assessed with frequent clinical and laboratory evaluation and exercise testing.Results. No significant differences between groups in terms of changes in exercise capacity (6-min walk test), clinical status (dyspnea-fatigue index), neurohumoral activation (norepinephrine, N-terminal atrial natriuretic factor), laboratory evaluation or incidence of adverse experience were observed.Conclusions. The results suggest that losartan and enalapril are of comparable efficacy and tolerability in the short-term treatment of moderate or severe congestive heart failure. A trial designed to compare the efficacy, tolerability and effect on mortality of long-term angiotensin II receptor blockade with converting enzyme inhibition is both feasible and ethically responsible.     

Pilot study of combined blockade of the renin-angiotensin system in essential hypertensive patients

BACKGROUND: Additive hemodynamic effects of combined blockade of the renin-angiotensin system by an angiotensin I converting enzyme inhibitor and an angiotensin II antagonist have been observed in sodium-depleted normotensive volunteers and in patients with congestive heart failure. OBJECTIVE: To investigate whether the same additive hemodynamic effects occur in patients with hypertension and to verify the safety of such an approach. DESIGN: Multicenter, randomized, double-blind, parallel-group, pilot study. PATIENTS: 177 patients with mild-to-moderate hypertension [diastolic blood pressure (DBP): 95-115 mmHg after a 4-week placebo run-in period] were included in the study. INTERVENTION: Combination therapy consisting of 50 mg losartan daily and 10 mg enalapril daily was administered for 6 weeks. The effects of this therapeutic regimen was compared with similar groups of patients who received either 50 mg losartan daily or 10 mg enalapril daily. MAIN OUTCOME MEASURES: 24-hour ambulatory mean DBP and clinic DBP measured at trough after 6 weeks of treatment. RESULTS: 24-hour ambulatory mean DBP did not significantly differ between treatment groups although the combination tended to lower BP more. The combination therapy was more effective on clinic DBP measured at trough than was losartan by 3.2 mmHg [confidence interval (95%, CI) 0.7-5.7 mmHg, P = 0.012], and more effective than enalapril by 4.0 mmHg (95% CI, 1.5-6.4 mmHg, P = 0.002). In a subgroup of 28 patients, higher plasma active renin and angiotensin I levels during blockade by the combination therapy were observed. This finding confirmed that the combination of the two agents inhibited the renin-angiotensin system to a greater extent than did either agent alone. CONCLUSION: A combination of 10 mg enalapril daily and 50 mg losartan daily safely induces a supplementary, although modest, fall in clinic DBP in patients with mild-to-moderate essential hypertension.     

Pharmacological Demonstration of the Additive Effects of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Antagonism in Sodium Depleted Healthy Subjects

A blockade of the hemodynamic and tissue effects of angiotensin II (Ang II) more complete than that presently achieved with usual daily doses of angiotensin converting enzyme (ACE) inhibitors or type 1 Ang II receptor antagonists has potential advantages and risks. Therefore, it is worthwhile to investigate the biological and the hemodynamic effects of the simultaneous blockade of the renin-angiotensin system (RAS) at the two sites where it can be currently achieved, ACE and type 1 Ang II receptors. To investigate this issue, 2 double-blind randomized crossover studies were performed in a model of mild sodium depletion in normotensive volunteers. They ingested single oral doses of captopril 50 mg, losartan 50 mg, their combination or matched placebos, and in a second study, single oral doses of enalapril 10 mg, enalapril 20 mg and the combination of losartan 50 mg with enalapril 10 mg. The combination captopril 50 mg and losartan 50 mg had additive effects on blood pressure fall and renin release in sodium-depleted normotensive subjects. When compared to enalapril 10 mg and the doubling of its dose, the combination of losartan 50 mg and enalapril 10 mg significantly increased both the area under the time curve of mean blood pressure fall and plasma active renin levels. It did not further decrease plasma aldosterone levels. The conclusion is that a more complete blockade of the RAS can be achieved by concomitant administration of an type 1 Ang 11 receptor antagonist and an ACE inhibitor.     

Is There a Place on the Shelf for Aliskiren?

Increased renin-angiotensin-aldosterone system (RAAS) activity contributes to target-organ damage and increases cardiovascular risk by elevating blood pressure (BP) and through direct effects on the heart, kidneys, brain, and vascular endothelium. Pharmacologic blockade of RAAS effectively reduces BP and limits or reverses various forms of target-organ damage, including cardiac heart failure, coronary artery disease, chronic kidney disease, and left ventricular hypertrophy. Direct renin inhibitors selectively inhibit human renin and have a therapeutic potential similar to angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. Aliskiren is the only orally active direct renin inhibitor that has been approved for the treatment of hypertension and has been shown to have favorable effects on target-organ damage. It effectively reduces BP and has favorable effects on heart failure and proteinuria in diabetic patients. Additional outcome trials are needed to establish the role of this new class of antihypertensive medication in preventing cardiovascular outcomes.     

New angiotensin converting enzyme inhibitors. Their role in the management of hypertension

The introduction of orally active angiotensin converting enzyme (ACE) inhibitors has revolutionized the treatment of hypertensive disorders and provided an effective alternative for the management of congestive heart failure (CHF). By interfering with the formation of angiotensin II, the active agent of the renin system, ACE inhibitors block the system's vasoconstrictive and sodium-retaining effects, with a consequent reduction in systemic blood pressure. The net effect is improved blood flow and reduced cardiac work. Thus, ACE inhibitors are likely to improve cardiac work capacity and quality of life. Their mechanism of action differs markedly from that of traditional antihypertensive agents which lower blood pressure while reducing cardiac output and blood flow. Since the primary action of ACE inhibitors is to block the renin system, a dramatic response to monotherapy suggests a large renin factor while the lack of a response suggests a low-renin state more amenable to treatment with a diuretic or calcium antagonist. Because of their many attributes, ACE inhibitors are increasingly used as first-line therapy for the treatment of hypertension or CHF. The prototype orally active ACE inhibitor, captopril, is a sulfhydryl compound with a good safety profile at the recommended dosages but reported toxicity at higher dosages. Second-generation ACE inhibitors (eg, enalapril and quinapril) are more potent sulfhydryl-free esters with a greater affinity for the converting enzyme. These newer agents are pro-drugs requiring ester hydrolysis to form the active free acid compound.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of vascular wall renin: intracellular and extracellular mechanism

Inhibitors of angiotensin-converting enzyme, renin and angiotensin II receptor lower the blood pressure of spontaneously hypertensive rats (SHRs) used as a model of essential hypertension. Since their plasma renin levels were normal or subnormal, renin in the vascular tissue was considered to play a key role in the maintenance of the hypertension. To clarify the source and localization of vascular renin in SHRs, the effects on blood pressure of antirenin antibodies, the converting enzyme inhibitors delapril and enalapril, and the angiotensin II receptor antagonist DuP 753 were examined in intact and bilaterally nephrectomized SHRs and their normotensive controls. The efficient hypotensive action of the renin antibody indicated that renin of the renal origin is a dominant factor. The gradual but complete disappearance of the antihypertensive action of these inhibitors of the renin-angiotensin system upon bilateral nephrectomy indicated the importance of membrane-associated renin of the renal origin and angiotensin-converting enzyme in the maintenance of the spontaneous hypertension.     

First dose hypotension with enalapril and prazosin in congestive heart failure

Since the introduction of angiotensin converting enzyme inhibitors into the adjunctive treatment of patients with congestive heart failure, cases of severe hypotension, especially on the first day of treatment, have occasionally been reported. To assess the safety of the angiotensin converting enzyme inhibitor enalapril a multicenter, open, randomized, prazosin-controlled trial was designed comparing the incidence and severity of symptomatic hypotension on the first day of treatment. Trial medication was 2.5 mg enalapril or 0.5 mg prazosin. Subjects were 1210 inpatients with New York Heart Association functional class (I)/II and III who were not adequately compensated with digitalis and/or diuretics. In the group receiving enalapril, 3 patients (0.5%) experienced severe hypotension on day 1 and 28 patients (4.7%) moderate hypotension. In those given prazosin, 15 patients (2.6%) experienced severe hypotension and 60 patients (10.3%) moderate hypotension. The difference is statistically significant (P less than or equal to 0.000012). All patients recovered. It was concluded that treatment of patients suffering from congestive heart failure New York Heart Association functional class (I)/II or III with enalapril is comparably well tolerated.     

Estimating renin participation in hypertension: superiority of converting enzyme inhibitor over saralasin.

This study was designed to examine more closely the differences in blood pressure responses in hypertensive patients to two agents which block the renin-angiotensin system. Accordingly, 39 seated patients received under the same conditions both saralasin, an octapeptide competitive antagonist of angiotensin II, and the nonapeptide converting enzyme inhibitor, SQ20881, which blocks the generation of angiotensin II from angiotensin I. A second component of the study involved administration of these agents in 10 addtional studies in anephric subjects. Although both agents produced maximal responses in blood pressure that correlated well with each other (p less than 0.001) and with the pretreatment plasma renin levels (p less than 0.001), analysis of the results by renin subgroups revealed significant differences. Thus, both drugs lowered the diastolic pressures of patients with high renin levels, but but converting enzyme inhibitor produced changes of greater amplitude (p less than 0.05). In contrast, saralasin was consistently pressor in both patients with low renin levels and anephric patients in whom converting enzyme blockade preduced no significant changes in blood pressure. Another impressive disparity in the responses to the two agents occurred in the group with normal renin levels in whom saralasin produced either neutral or pressor responses (mean change was +2.0 +/- 1.5 standard error of the mean (SEM) per cent control diastolic pressure) whereas the converting enzyme inhibitor consistently induced depressor responses (mean change was -10.2 +/- 1.2 per cent, p less than 0.001). Altogether, the results suggest that converting enzyme inhibitor tests for angiotensin II-dependent blood pressure with more sensitivity than the partial agonist saralasin. Moreover, it is unlikely that the differences between the responses to the two agents were due to bradykinin accumulation, since depressor responses to converting enzyme inhibitor were not observed in the patients with low renin levels and the anephric patients.