Blood pressure control by the renin-angiotensin system in normotensive subjects. Assessment by angiotensin converting enzyme and renin inhibition.

BACKGROUND. The participation of the renin-angiotensin system in the control of blood pressure in normal, sodium-replete subjects is not clear. The use of a specific inhibitor of human renin should allow a better delineation of the importance of this system. METHODS AND RESULTS. Blood pressure responses were measured 1 hour after randomized, double-blind administration of the renin inhibitor Ro 42-5892 (600 mg p.o.) or the angiotensin converting enzyme inhibitor captopril (50 mg p.o.) in 20 healthy men on an ad libitum sodium diet. Effective inhibition of the renin-angiotensin system by either compound was indicated by increases of immunoreactive renin associated with an increase of angiotensin I production rate of 67.8 +/- 33.6% after captopril and a decrease of 79.5 +/- 16.4% after Ro 42-5892. Furthermore, Ro 42-5892 decreased plasma renin activity by 64%. Whereas intra-arterial diastolic (60 +/- 5.1 to 51.4 +/- 7.2 mm Hg, p less than 0.01) and mean arterial (77.7 +/- 6.0 to 71.4 +/- 8.5 mm Hg, p less than 0.001) pressures decreased after captopril, they remained unchanged after Ro 42-5892. Captopril, but not Ro 42-5892, increased forearm blood flow (2.4 +/- 0.8 versus 1.9 +/- 0.8 ml/min/100 ml, p less than 0.01) and significantly enhanced the increase of forearm blood flow to brachial artery infusions of bradykinin (0.15, 1.5, 5, 15, and 50 ng/min/100 ml; 5 minutes each) from 744 +/- 632% to 1,383 +/- 514% (p less than 0.01). Furthermore, repeat bradykinin infusions resulted in further decreases of blood pressure (from mean pressure of 71.4 +/- 8.5 to 63.2 +/- 7.6 mm Hg, p less than 0.01) only after captopril. Changes of blood pressure after captopril were unrelated to baseline plasma renin activity but correlated with captopril-induced enhancement of vasodilation to bradykinin (r = 0.68, p less than 0.05). CONCLUSIONS. The lack of blood pressure effects of renin inhibition in contrast to angiotensin converting enzyme inhibition suggests that the renin-angiotensin system does not contribute significantly to blood pressure control in normotensive, sodium-replete subjects. The hypotensive activity of angiotensin converting enzyme inhibitors may result from additional hormonal effects, for example, inhibition of bradykinin degradation and/or subsequent increases of vasodilating prostaglandins or endothelium-derived relaxing factor(s).     

Peripheral hemodynamic effects of captopril in patients with congestive heart failure

In 14 patients with severe congestive heart failure, the effects of captopril on the forearm circulation were evaluated with strain gauge plethysmography. Changes in plasma renin activity, angiotensin II, norepinephrine, epinephrine, bradykinin, prostaglandin E2, and 6-keto-prostaglandin F1 alpha concentrations were also measured. To determine whether the prostaglandins contribute to the peripheral hemodynamic response to captopril, the hemodynamic and hormonal measurements were repeated after pretreatment with indomethacin, an inhibitor of prostaglandin synthesis. Ninety minutes after administering a single dose of captopril (25 mg), mean blood pressure and venous pressure decreased (p less than 0.01 and p less than 0.05, respectively), forearm blood flow and maximum venous volume increased (p less than 0.05 for both), and forearm vascular resistance and forearm venous tone decreased (p less than 0.05 for both). Captopril also improved forearm venous distensibility (p less than 0.05). Pretreatment with oral indomethacin (50 mg) significantly blunted all of these captopril-induced hemodynamic changes. The blockage of the renin-angiotensin system by captopril was unaltered by indomethacin pretreatment. Captopril significantly increased plasma bradykinin, prostaglandin E2, and 6-keto-prostaglandin F1 alpha (p less than 0.05 for each). Indomethacin pretreatment did not affect the captopril-induced increase in bradykinin, but it did completely eliminate the increase in the prostaglandins. Plasma catecholamines did not change with captopril. These data suggest that the vasodilator prostaglandins play a significant role in captopril's peripheral vasodilative effects in congestive heart failure.     

Pathophysiology in malignant hypertension: with special reference to the renin-angiotensin system

Pathophysiology of malignant hypertension, of which underlying disease was essential hypertension (EHT) in 33 cases and chronic glomerulonephritis (CGN) in 26 cases, was studied with reference to the renin-angiotensin system. Plasma renin activity (PRA) was significantly higher in the EHT than in the CGN group, and angiotensin II antagonist [Sar1, Ile8]angiotensin II (AIIA) induced a significant lowering of blood pressure only in the former group. PRA was linearly correlated with both pretreatment mean blood pressure (MBP, r = 0.474, n = 29, p less than 0.01) and serum creatinine (r = 0.540, n = 29, p less than 0.01) in the EHT group but not in CGN patients, although there was an inverse correlation between PRA and serum sodium in both groups. Multiple regression analysis revealed that PRA was independently related to MBP, serum creatinine, and serum sodium in the EHT group, but not in the CGN group. These results suggest that the renin-angiotensin system plays a significant role in elevating blood pressure and deteriorating renal function in malignant hypertension derived from EHT, but it is less important in CGN related hypertension.     

Renal effects of captopril in hypertension with renal artery stenosis. Comparison between Tc-99m-DTPA scintigraphy and clearance method

In eleven hypertensive patients with renal artery stenosis, the acute renal effects of captopril were investigated using two methods: 1) the Tc99m-DTPA renography with determination of an index of renal perfusion (IP), an index of glomerular filtration (IF) and the ratio of these indices (F/P); 2) the renal hemodynamics obtained by the clearance method using a continuous infusion of I131-hippuran and I125-iothalamate for calculation of renal blood flow (RBF), glomerular filtration rate (GFR) and filtration fraction (FF). The studies were performed before and after captopril treatment. Patients were classified according to the acute response to captopril as responders (R; n = 6) and non responders (NR; n = 5). Results are as follows: (B: basal, C = captopril). (table; see text) These data confirm that captopril produced a significant decrease in F/P and FF in R whereas these indices did not change in NR; it was found that IF and GFR decreased in R whereas IF increased and GFR did not change in NR; a significant correlation was observed between delta IF and delta GFR in R (r = 0.834, p less than 0.05). These results indicate that 1) data obtained before and after captopril by renography and by clearance methods are in good correlation either in Ror in NR patients; 2) Captopril test including renography or renal hemodynamic measurements is useful for selection of R patients.     

Single administration of captopril and combined use with beta-blocker and/or thiazide diuretic in the treatment of essential hypertension.

Thirty-four patients with essential hypertension at WHO stage I or II were divided into three groups. Group I consisted of 22 cases who displayed normal renin activity (NR) or low renin activity (LR) and who received a single administration of captopril. Group II consisted of 6 cases given beta-blockers after administration of captopril. Group III consisted of 6 cases in whom beta-blocker was replaced with thiazide diuretics after administration of captopril alone. Blood pressure decreased significantly by captopril treatment alone in group I of the NR and LR subgroups (except for the diastolic blood pressure [DBP] of the NR subgroup) and fell below the target blood pressure (SBP of 165 mmHg and DBP of 95 mmHg) in 86% of the NR subgroup and 73% of the LR subgroup. Combined treatment with captopril and beta-blocker in Group II did not decrease blood pressure any lower than with captopril alone treatment and achieved the target blood pressure in only 50% of the patients. In group III, combined treatment with captopril and thiazide achieved the target blood pressure in 100% of the patients. Plasma renin activity (PRA) was increased by captopril but reduced by captopril in combination with beta-blocker. However, when beta-blocker was replaced with thiazide, PRA increased. The serum sodium concentration was significantly reduced in the LR subgroup after a single administration of captopril, but there was no other variation.     

Effect of captopril on plasma prolactin in patients with essential hypertension

The effects of the angiotensin-converting enzyme inhibitor captopril on blood pressure, heart rate, plasma prolactin, and renin activity were examined in a single-blind, placebo-controlled trial on 30 patients with essential hypertension (15 given drug, 15 placebo). Captopril, 25 mg administered orally, reduced the blood pressure and increased the plasma renin activity. Captopril decreased mean plasma prolactin from 17.5 +/- 1.4 ng/mL to 9.1 +/- 1.0 ng/mL (p less than 0.001). Significant correlation was found between captopril-induced change from control values of plasma prolactin (delta plasma prolactin) vs delta plasma renin activity (r = -0.688, p less than 0.001). These results suggest that acute administration of captopril was accompanied by a reduction in plasma prolactin and that this reduction may be of clinical significance during therapy of hypertension.     

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

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

Role of thromboxane A2 in the hypotensive effect of captopril in essential hypertension

We have previously reported that captopril stimulates thromboxane A2 synthesis in patients with essential hypertension. In the present study, the hypotensive effects of captopril and OKY-046, a selective inhibitor of thromboxane A2 synthetase, were studied in nine patients with essential hypertension to determine whether thromboxane A2 is involved in the regulation of blood pressure. A single oral dose of OKY-046 (400 mg) decreased urinary thromboxane B2 (a stable metabolite of thromboxane A2) excretion significantly (from 113 +/- 19.0 to 51.0 +/- 6.1 pg/min; p less than 0.01) and increased urinary sodium excretion significantly (from 73.0 +/- 15.3 to 113.0 +/- 14.4 microEq/min; p less than 0.01), but no change was observed in mean arterial pressure. The administration of OKY-046 (600 mg/day) for 3 days induced a significant and sustained decrease in urinary thromboxane B2 excretion, but it did not affect the mean arterial pressure. Although captopril (50 mg) alone induced a significant increase in urinary thromboxane B2 excretion (from 91.4 +/- 11.0 to 297.3 +/- 30.8 pg/min; p less than 0.001) and a significant decrease in mean arterial pressure (from 97.0 +/- 4.7 to 88.1 +/- 5.1 mm Hg; p less than 0.01), captopril in combination with OKY-046 induced a decrease both in urinary thromboxane B2 excretion (from 70.8 +/- 12.3 to 54.2 +/- 14.7 pg/min; p less than 0.01) and in mean arterial pressure (from 105.1 +/- 3.8 to 84.2 +/- 3.6 mm Hg; p less than 0.01). Thus, the hypotensive effect of captopril was potentiated by OKY-046. OKY-046 did not affect the changes in plasma renin activity and plasma aldosterone concentration and blunted urinary prostaglandin E2 and 6-keto-prostaglandin F1 alpha excretion in response to captopril. These results indicate that thromboxane A2 counteracts the hypotensive effect of captopril in patients with essential hypertension.     

Antihypertensive activity of monoclonal antibody to angiotensin II

The antihypertensive effect of monoclonal antibody to angiotensin II (MAAII) was studied in renovascular hypertensive (RVH) rats. We found that MAAII could antagonize the pressor effect of exogenous angiotensin II but not of vasopressin in vivo. Five minutes after the administration of MAAII (15 mg/kg, i.v.), plasma angiotensin II could not be detected by radioimmunoassay and the mean blood pressure (MBP) decreased in RVH rats more than in normotensive rats (delta MBP: -5.33 +/- 0.12 and -1.17 +/- 0.29 kPa, respectively, P less than 0.01). The hypotensive effect of captopril was markedly inhibited by prior administration of MAAII, while that of nitroprusside and phentolamine was not. The results suggest that the antihypertensive effect of MAAII is mainly due to its specific binding to circulating angiotensin II.     

Calcium, the renin-aldosterone system, and the hypotensive response to nifedipine

Ionic, hormonal, and blood pressure responses to a single oral dose of the calcium channel blocker nifedipine were assessed in 25 essential hypertensive subjects. When grouped according to their renin-sodium profile, low renin subjects had a greater hypotensive response to nifedipine (change in diastolic blood pressure -20.0 +/- 1.4 vs -6.4 +/- 1.0%; p less than 0.005) than did high renin hypertensive subjects. The initial level of serum ionized calcium predicted the blood pressure response to nifedipine (r = 0.70, p less than 0.001), as did the initial plasma renin activity (r = 0.65, p less than 0.005). Nifedipine induced a transient rise in serum ionized calcium (from 2.22 +/- 0.02 to 2.28 +/- 0.02 mEq/L; p less than 0.01), while plasma renin activity was consistently elevated compared with initial values at 30 (p less than 0.01), 60 (p less than 0.01), and 120 (p less than 0.05) minutes after drug administration. By comparison, plasma aldosterone levels did not rise and even declined at 30 (p less than 0.01), 60 (p less than 0.05), and 120 (p less than 0.05) minutes after nifedipine. These results suggest that low renin hypertension is more critically dependent on extracellular calcium than are higher renin forms and demonstrate that levels of serum ionized calcium, plasma renin activity, or both may predict the sensitivity of blood pressure to calcium channel blockade. Lastly, calcium may play a pivotal role in vivo in coupling renin stimulation to adrenal aldosterone responses.     

Kinin contribution to renal vasodilator effect of captopril in rabbit

This study was conducted to examine the role of bradykinin in the persistence of the renal vasodilator effect of captopril during angiotensin II receptor blockade. Blood pressure and renal blood flow were monitored in eight groups of pentobarbital-anesthetized rabbits. In group 4, captopril alone was administered, and it decreased blood pressure by 14 +/- 4 mm Hg and increased renal blood flow by 21 +/- 4 ml/min. After a bolus injection and a constant intravenous infusion of the imidazole derivative angiotensin II receptor antagonist DuP 753 (group 5), captopril decreased blood pressure by 9 +/- 2 mm Hg and increased renal blood flow by 8 +/- 1 ml/min (12 +/- 1% change in renal blood flow, p less than 0.05 versus group 4). In the presence of a constant intravenous infusion of saralasin (group 6), captopril decreased blood pressure by 13 +/- 5 mm Hg and increased renal blood flow by 7 +/- 2 ml/min (17 +/- 5% change in renal blood flow, p less than 0.05 versus group 4). These results did not differ from those in group 5. During a constant intrarenal arterial infusion of a B2 bradykinin receptor antagonist, DArg0, [Hyp3-Thi5,8-DPhe7]-bradykinin (BkA) (group 7), captopril decreased blood pressure by 14 +/- 4 mm Hg and increased renal blood flow by 10 +/- 4 ml/min. Combined administration of DuP 753 intravenously and BkA intra-arterially (group 8) eliminated the effect of captopril. In group 8, captopril caused insignificant changes in blood pressure and renal blood flow. The results indicate that DuP 753 and saralasin antagonize the renin-angiotensin system to a comparable extent in vivo. Although blockade of the latter system accounted for a significant part of the increase in renal blood flow caused by captopril, the remaining component was contributed by endogenous bradykinin.     

Screening of single doses of the main antihypertensive drugs at rest and during various exercise tests in patients with hypertension]

The single doses of three reference antihypertensive drugs: corinfar (20 mg), anapriline (80 mg), and hypothiazide (50 mg) were screened on day 5 of drug administration at rest and during paired isometric and dynamic exercises in comparison to placebo. There was a significant decrease in blood pressures: systolic (SBP), diastolic (DBP), and mean (MBP) (p less than 0.01-0.001) at rest and during isometric and dynamic exercises after single doses of corinfar and hypothiazide versus placebo. A single dose of anapriline resulted in a significant reduction in SBP and MBP at rest and during dynamic exercise (p less than 0.05-0.001), in DBP at rest (p less than 0.05) and in an insignificant decrease in SBP, DBP, and MBP during isometric exercise and DBP during dynamic exercise. The agents were graded in terms of the effect of placebo from the mean group and individual hypotensive effects (by each blood pressure parameter). The resting dynamic exercise failed to yield some new evidence for determining the efficacy of corinfar and hypothiazide, whereas it was informative for anapriline with regard to SBP. With respect to SBP, DBP, and MBP, isometric exercise was informative for hypothiazide.     

Angiotensin-converting enzyme inhibition and prostaglandins

To determine whether prostaglandins contribute to the depressor response of angiotensin-converting enzyme inhibitors, plasma prostaglandin levels were measured by radioimmunoassay in normo- and hypertensive subjects on both sodium-restricted and sodium-loaded diets before and after captopril administration. On the sodium-restricted diet, the hypotensive response to captopril was accompanied by significant increments in the metabolite of prostaglandin E2 (PGE2-M) and bradykinin and by significant decrements in angiotensin II. The high sodium diet suppressed the response of the renin-angiotensin and kinin systems to captopril but the hypotensive response persisted. Furthermore, the decrease in blood pressure correlated significantly with increments in prostaglandin E2-metabolite. Prostaglandin synthesis was then inhibited in the sodium-restricted hypertensive patients by pretreatment with indomethacin. This maneuver completely eliminated the captopril-induced prostaglandin E2-metabolite increment without changing bradykinin or angiotensin II responses but significantly attenuating the hypotensive response. Finally, when patients were studied on a high sodium intake, similar effects were observed except now indomethacin completely abolished the blood pressure response to captopril. These studies therefore support the hypothesis that increased production of vasodilator prostaglandins in a major mediator of the hypotensive response to captopril. Whether the change in prostaglandin release is a direct effect of the drug or secondary to increased kinin levels is uncertain.     

Long-term treatment of chronic heart failure by an inhibitor of angiotensin converting enzyme

We studied the hemodynamic, echocardiographic, phonomechanographic and hormonal changes during acute (25 mg) and chronic (6 months--75 to 225 mg/day) treatment of 10 patients with congestive cardiac failure due to cardiomyopathy with dilatation with SQ 14 225 (Captopril). The following changes were observed after the single dose: an increase in cardiac output (p less than 0,001), in stroke volume (p less than 0,01), a reduction in heart rate (p less than 0,01), in peripheral resistance (p less than 0,001) and pulmonary capillary pressure (p less than 0,001). There were no significant changes in end systolic or end diastolic left ventricular internal diameter. Plasma renin activity increased (p less than 0,001); there was a concurrent fall in serum aldosterone (NS): the plasma concentration of converting enzyme decreased (p less than 0,001). There was a correlation between the increase in peripheral resistance under basal conditions and the basal plasma renin activity (R = 0,72, p less than 0,02). The decrease in peripheral resistance after captopril also correlated with basal plasma renin activity (R = 0,89, p less than 0,01). After six months continuous therapy, the hemodynamic effect was sustained and was accompanied by a significant symptomatic improvement. Left ventricular internal end systolic and end diastolic diameters decreased (p less than 0,01 and p less than 0,01 respectively). The pre-ejectional period decreased (p less than 0,05). Serum aldosterone fell significantly (p less than 0,001) as did plasma renin activity (p less than 0,01); the serum level of converting enzyme remained low with respect to its initial value. These results show that captopril may be useful in severe cardiac failure without tolerance during long-term administration. No renal or hematological toxicity was observed in this group of patients.     

Effects of a competitive antagonist of bradykinin on blood pressure and renal blood flow in anesthetized rats

To examine a possible role of endogenous bradykinin in the regulation of blood pressure (BP) and renal blood flow (RBF), a newly synthesized competitive antagonist of bradykinin (B4147) was studied in anesthetized rats. Also, the question of whether the hypotensive effect of the converting enzyme inhibitor, captopril, is mediated partly by an accumulation of endogenous bradykinin was considered. The intravenous infusion of B4147 (25 micrograms/min) inhibited the depressor effect of exogenous bradykinin (0.5 microgram, i.v.) by 69%. After an intravenous injection of B4147 at doses of 25, 50 and 100 micrograms, BP increased and RBF decreased in a dose-dependent fashion. The increase in BP was not blocked by pretreatment with an angiotensin II antagonist (1-Sar-8-Ile angiotensin II; 20 micrograms/kg per min) or an alpha 1-blocker (prazosin; 0.1 mg/kg). The administration of captopril (1 mg/kg) decreased mean BP from 110 +/- 3.5 to 71 +/- 1.9 mmHg (P less than 0.001). However, the injection of B4147 (50 micrograms) after the administration of captopril elicited an increase in BP of 43% of the initial decrease induced by captopril. These results suggest that the effects of B4147 on BP and RBF are not mediated through angiotensin II or sympathetic alpha 1-stimulation. Endogenous bradykinin could contribute to the maintenance of BP and RBF in anesthetized rats, probably counter-balancing the vasoconstrictor mechanisms. It is also suggested that bradykinin may partly participate in the acute hypotensive effect induced by the converting enzyme inhibitor captopril.     

A randomized placebo-controlled trial of combined early intravenous captopril and recombinant tissue-type plasminogen activator therapy in acute myocardial infarction.

The adjunctive use of intravenous captopril with tissue plasminogen activator early during acute myocardial infarction offers theoretic advantages of diminishing left ventricular volume, preventing ventricular dilation and improving patient survival. To test the safety and efficacy of combined early administration of intravenous captopril and recombinant tissue-type plasminogen activator (rt-PA), 38 patients treated with rt-PA 3 +/- 0.3 h (mean +/- SE) after the onset of myocardial infarction were randomized to intravenous followed by oral captopril or placebo therapy. They underwent cardiac catheterization with measurement of hemodynamic variables and left ventricular function and determination of serum renin, angiotensin and aldosterone levels on days 1 and 7. Oral administration of the selected agent was continued for 3 months along with other antianginal medications, including nonangiotensin-converting enzyme inhibitor vasodilators. Repeat measurements of left ventricular function were obtained before hospital discharge and at 3 months. There were no significant differences in baseline clinical characteristics between groups. One patient in the captopril-treated group became hypotensive during intravenous therapy, requiring discontinuation of treatment. Compared with the placebo-treated group, the captopril-treated group had significant reductions at day 7 in left ventricular end-diastolic pressure (22.5 +/- 1.5 versus 16.3 +/- 1.6 mm Hg, p less than 0.01) and mean systemic arterial pressure (93.6 +/- 3.3 versus 86.2 +/- 2.7 mm Hg, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of captopril on arterial pressure, systemic hemodynamics and renin activity in the blood plasma of rats with spontaneous hypertension

An angiotensin-I-converting enzyme, captopril, was administered since birth onward to normotensive (NR) and spontaneously hypertensive rats (SHR). It produced a marked hypotensive effect in SHR only. Cardiac output and circulating blood volume were similar in intact and experimental animals, NR and SHR alike. Captopril considerably increased plasma renin activity in NR and SHR.     

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.     

Long-term converting-enzyme inhibition as a guide to surgical curability of hypertension associated with renovascular disease

Converting-enzyme inhibition as a guide to the hypotensive response to be expected from surgery was evaluated in 27 hypertensive patients with renovascular disease. Blood pressure averaged 163 +/- 5/102 +/- 2 mm Hg (mean +/- standard error of the mean) during converting-enzyme inhibition with captopril, 518 +/- 29 mg daily for 2.8 +/- 0.3 months, and stabilized at a similar level of 165 +/- 4/104 +/- 3 mm Hg during 5.0 +/- 0.6 months of postoperative follow-up, when no medication was administered. Postoperative pressure, both systolic (r = +0.53; p = 0.004) and diastolic (r = +0.55; p = 0.003), was correlated with blood pressure during converting-enzyme inhibition. In addition, multiple regression analysis identified systolic pressure during converting-enzyme inhibition as the only significant (p less than 0.01) predictor of postoperative systolic pressure. Diastolic pressure during converting-enzyme inhibition (p less than 0.05) in conjunction with circulating renin (p less than 0.05) and renin suppression from the contralateral kidney (p less than 0.01) explained up to 53% of the postoperative diastolic pressure. Therefore, blood pressure during long-term converting-enzyme inhibition may be useful as a predictor of the postoperative blood pressure in hypertensive patients with renovascular disease.     

Converting Enzyme Inhibition in Mild and Moderate Essential Hypertension. II

ABSTRACT. In 24 patients with mild/moderate essential hypertension, we studied the effects of captopril with/without hydrochlorothiazide (Htz) on blood pressure, the renin-angiotensin system, blood bradykinin concentration (BBK), plasma volume, exchangeable sodium and glomerular filtration. Daily captopril doses of 75 and 150 mg were equally effective in reducing the blood pressure. Addition of Htz caused further blood pressure reductions. Nineteen patients attained a diastolic blood pressure ≤90 mmHg. Angiotensin converting enzyme inhibition with captopril led to a fall in plasma concentrations of angiotensin II (PAII) and renin substrate, and an increase in plasma concentrations of renin and angiotensin I. Patients starting with Htz had a higher PAII and subsequently a larger fall in blood pressure on captopril than untreated patients. BBK remained unchanged, indicating that the hypotensive action of captopril does not involve an accumulation of circulating kinin. Body fluid volumes and renal function were not affected by the various treatment regimens.