Plasma Converting Enzyme Activity Research Articles

Effects of captopril and enalapril on regional vascular resistance and reactivity in spontaneously hypertensive rats.

The present study compares the effects of short-term treatments with captopril and enalapril, administered in equipotent antihypertensive doses, on the regional vascular resistances and on the regional vascular responsiveness to vasopressor agents of adult spontaneously hypertensive rats (SHRs). Three groups of animals were treated by gavage with captopril (100 mg/kg), enalapril (25 mg/kg), or distilled water for 8 days. Arterial blood pressure (BP), heart rate (HR), plasma renin concentration (PRC), and plasma converting-enzyme activity (CEA) were measured. Cardiac index (CI), total peripheral resistance (PR), and organ flow distribution were determined using microspheres. Renal and mesenteric vascular responsiveness to vasopressor agents was evaluated by continuous measurement of renal and mesenteric blood flows with miniaturized pulsed Doppler flow probes. Data showed that in the anesthetized SHR the two drugs induced similar reductions in BP, PR, and HR, without affecting CI. They simultaneously produced a strong converting-enzyme inhibition as evidenced by the suppression of angiotensin I effects accompanied by a potentiation of angiotensin II responses, a reduction in CEA, and an increase in PRC. Organ flows were similarly and homogeneously increased, especially in the kidneys, in both treated groups. Norepinephrine (NE) vasoconstrictor responses were abolished in the mesenteric vascular bed by both drugs, but in the renal, NE responses although completely abolished by captopril were only partially reduced by enalapril. It thus appears that diminished vascular responsiveness to NE, especially in the case of captopril, is probably involved along with converting-enzyme inhibition in the antihypertensive action of converting enzyme inhibitors (CEI), the mechanism of the difference between captopril and enalapril remaining still speculative.

Antihypertensive Therapy with MK 4211

Nineteen hypertensive patients were treated with increasing doses of the new angiotensin-converting enzyme inhibitor MK 421. Twenty milligrams orally reduced blood pressure from 180/112 +/- 6.8/3.6 (mean +/- SEM) to 160/100 +/- 6.5/3.3 mm Hg (p less than 0.005) while heart rate increased from 75 +/- 2 to 87 +/- 3 beats/min (p less than 0.005). Plasma converting enzyme activity was still markedly reduced 24 h following 2.5, 5, 10, or 20 mg MK 421 p.o. (p less than 0.001). In nine patients treated with 20 mg b.i.d. for up to 10 months, blood pressure was controlled, with the association of hydrochlorothiazide 50 mg q.d. in five. However, 12 to 16 h following the preceding drug administration, plasma angiotensin II and aldosterone were back to base-line levels. Analysis of plasma angiotensin II-renin relationships strongly suggests that converting enzyme blockade is not complete even 4 h after 20 mg MK 421 and starts to wear off already at 12 h. Thus, MK 421 20 mg taken orally twice daily, effectively reduces blood pressure, but does not constantly suppress plasma angiotensin II and aldosterone. Whether its long duration of action makes once daily administration possible has not yet been established.

Long-term captopril therapy: evolving hemodynamic effects.

Nine patients with resistant hypertension received captopril for 12 months. Five received captopril alone, four required additional therapy. In the former, mean blood pressure fell from 109 +/- 4.2 mm Hg to 84 +/- 7.5 mm Hg (P less than 0.025) after seven days. A rise to 101 +/- 19 mm Hg was noted at six and 12 months. Total peripheral resistance fell at seven days but returned to levels above control at six and 12 months. Cardiac index was 3.21 +/- 0.55 liters/min/m2 before treatment, 3.27 +/- 0.56 liters/min/m2 at seven days, and 2.17 +/- 4.0 liters/min/m2 (P less than 0.025) at 12 months. However, forearm blood flow rose from subnormal levels during the 12 months of observation, suggesting a persistent effect on the arterioles of the extremities. Plasma converting enzyme activity was significantly reduced at seven days but was above control levels at six and 12 months. However, plasma renin activity remained elevated, and plasma aldosterone concentration was significantly reduced. The fall in mean blood pressure was not related to the change in plasma converting enzyme activity in patients receiving captopril alone (five patients) or with diuretic (two patients). In the presence of beta-adrenergic blockade and volume depletion (two patients), changes in mean blood pressure appeared to be related to changes in converting enzyme activity. The data suggest that patients with essential hypertension whose blood pressure was not adequately controlled by previous medications may initially respond to captopril with a fall in blood pressure and total peripheral resistance. However, in certain individuals, these effects diminish with time despite addition of diuretics and beta-adrenergic receptor blocking agents.

Enalapril maleate and a lysine analogue (MK-521) in normal volunteers; relationship between plasma drug levels and the renin angiotensin system.

1 Two single doses of 10 mg each of the converting enzyme inhibitor enalapril maleate or MK-421 and of its lysine analogue (MK-521) were administered p.o. to twelve male volunteers. 2 The active diacid metabolite of MK-421 and the lysine analogue were determined by radioimmunoassay and MK-421 by the active metabolite method following in vitro hydrolysis. 3 Peak serum levels of MK-421, active metabolite and lysine analogue were reached within 1, 3 to 4, and 6 h respectively. Practically all MK-421 had disappeared from serum within 4 h. 4 A close correlation between percent inhibition of plasma converting enzyme activity and the serum concentration of active metabolite was observed ( r = 0.98, n = 171, P less than 0.001). Similarly, converting enzyme blockade as expressed by the ratio plasma angiotensin II/angiotensin I was closely correlated with serum active metabolite levels (r = 0.93, n = 15, P less than 0.001).

Effects of captopril, an angiotensin-converting enzyme inhibitor, in normotensive sodium-replete volunteers.

Captopril (SQ 14 225) was administered to normotensive, sodium-replete volunteers in order to investigate the relationships between its haemodynamic effects and effects on sympathetic activity, the renin-angiotensin-aldosterone system, and plasma-converting enzyme activity. Following the administration of captopril (25 mg) orally, mean arterial pressure fell (supine 89.1 +/- 5.9 to 81.1 +/- 3.3 mm Hg, p less than 0.01; erect 98.5 +/- 5.5 to 87.4 +/- 6.7 mm Hg, p less than 0.01) but heart rate did not change. Plasma noradrenaline rose; plasma renin activity and angiotensin I concentration rose, while angiotensin II and aldosterone fell; plasma-converting enzyme was inhibited for 6 h. The extent of blood pressure reduction and converting enzyme inhibition was closely correlated (r = 0.92, p less than 0.001). Plasma captopril concentration was directly related to converting enzyme inhibition in an in vitro study using plasma from the same subjects. In the absence of a convenient assay of captopril, converting enzyme may be used as an index of captopril concentration in the further study of kinetic and dynamic relationships.

Dissociation between in vivo and in vitro measurements of converting enzyme activity after chronic oral treatment with captopril in rats

Intraveneus administration of captopril (20 μg) produced inhibition of angiotensin I pressor responses by 70 percent and of plasma-converting enzyme activity by 72 percent. Oral treatment with captopril (50 mg/ kg/day) for 1 week inhibited angiotensin I pressor responses more (84 percent) than plasma-converting enzyme activity (23 percent). Four month oral treatment of normotensive and spontaneously hypertensive rats with captopril (50 mg/kg/day) led to a 68 and 71 percent inhibition of angiotensin I pressor responses, but produced increases in plasmaconverting enzyme activity of 123 and 94 percent, respectively. In spontaneously hypertensive rats, elevated converting enzyme activity in the medulla oblongata was measured after this treatment. It is concluded that plasma-converting enzyme activity measurements can be dissociated from the in vivo inhibition of converting enzyme. Chronic oral captopril treatment results in an induction of converting enzyme biosynthesis not only in peripheral tissue but also in the brain.

The effects of captopril on rat aortic angiotensin-converting enzyme.

Angiotensin -converting enzyme (ACE) activity was found to be present within the rat aorta using radioenzymatic techniques. Forty-two percent of the enzyme activity was localized within the tunica media. Using an equilibrium dialysis cell system that insured equal free captopril concentrations in both plasma and aorta, converting enzyme in both tissues was observed to possess similar dissociation constants for the inhibitor. Four daily intraperitoneal doses, but not a single dose, of captopril led to a persistent inhibition of aortic-converting enzyme 24 h after final drug administration. Plasma-converting enzyme activity was changed at this time. These results suggest that different pools of converting enzyme recover form captopril inhibition at different rates. The prolonged inhibition of aortic ACE is discussed in terms of drug accumulation within the vessel wall, and the effect of such accumulation on the persistent antihypertensive actions of captopril are also discussed.

Effects of the angiotensin converting enzyme inhibitor, captopril, in essential hypertension.

1 The effects of the orally active angiotensin converting enzyme inhibitor, captopril, were examined in 15 patients with mild or moderate essential hypertension. 2 Following initial dosing with captopril 25 mg, there was a significant fall in supine and erect blood pressure in 2 h and lasting for 6 h. There was no significant alteration of heart rate. No reduction was seen in plasma noradrenaline concentration. Maximum inhibition of plasma converting enzyme activity occurred 60 min post-dosing. 3 There was a strong positive correlation between blood pressure reduction and converting enzyme inhibition. The magnitude of the blood pressure reduction and converting enzyme inhibition following initial dosing was reflected in subsequent success with captopril monotherapy during a 12 week follow-up period. 4 It was also found that patients who did not achieve adequate blood pressure control on captopril in doses of 50 mg three times daily or less still were not controlled on a dose of 150 mg three times daily without the addition of a diuretic. 5 The risks of renal and marrow toxicity from captopril may be reduced by administering only low doses with the addition, where necessary, of a thiazide diuretic.

RHC 3659: a new orally active angiotensin converting enzyme inhibitor in normal volunteers.

1 The new converting enzyme inhibitor RHC 3659 was tested in 15 male volunteers. The study consisted of two parts: first, the ability of a single oral dose (5, 10, 20, 40 or 80 mg) to inhibit the pressor response to exogenous angiotensin I was tested with blood pressure and heart rate monitored continuously through an intraarterial catheter. A dose-related shift to the right of the pressor response curve to angiotensin I was observed with a peak occurring within 0.5 to 1 h. The pressor response to angiotensin II was unaffected. 2 In the second part, plasma renin and converting enzyme activity, angiotensin II and aldosterone were measured serially before and up to 8 h after administration of a single oral dose of RHC 3659. As expected. plasma angiotensin II and aldosterone fell within 30 min while plasma renin activity increased. Plasma converting enzyme activity was suppressed at 0.5 h in a dose-related manner with levels still below 30% of control 4 h following 80 mg of the inhibitor. 3 However, in vitro the enzyme-inhibitor complex seemed quited fragile since during storage of the plasma samples at -20 degrees C, converting enzyme activity increased significantly already within days (P less than 0.001, n = 28) and continued to rise for more than 2 months. This fragility may explain the seemingly lower potency of RHC 3659 when compared to captopril. No side effects were observed.

Effects of the oral angiotensin-converting enzyme inhibitor MK-421 in human hypertension.

1. The effects of the new oral angiotensin-converting enzyme (ACE) inhibitor MK-421 on blood pressure, plasma renin activity, angiotensin-II, aldosterone and converting enzyme activity were assessed in 16 hypertensive patients followed for 6--18 weeks. 2. After an initial titration period, maintenance doses of 2.5--40 mg once daily produced satisfactory blood pressure control in 11 and a partial but significant decrease in the remainder. 3. Treatment was associated with no change in heart rate and no orthostatic hypotension. At 24 h after the first effective dose, blood pressure was still decreased, plasma ACE was suppressed to 16% of the baseline, plasma angiotensin to 58%, aldosterone to 42%, and plasma renin activity was elevated to 228% of the baseline. 4. Magnitude of blood pressure fall was significantly correlated with the height of pretreatment blood pressure but not with baseline levels of plasma renin activity.

Plasma-converting enzyme activity does not reflect effectiveness of oral treatment with captopril

Intravenous Captopril (20 μg) in rats produced similar inhibition of the pressor responses to intravenous ANG I (70%) and of plasma-converting enzyme activity (CEA) measured fluorometrically (72%). One week oral treatment with Captopril (50 mg/kg per day) inhibited ANG I pressor responses more (84%) than plasma CEA (23%). Four-month oral treatment of normotensive and spontaneously hypertensive rats with Captopril (50 mg/kg per day) led to a 68% and 71% inhibition of the ANG I pressor responses, but to a 123% and 94% increase of plasma CEA, respectively. Thus, plasma CEA measurements can be dissociated from the in vivo inhibition of converting enzyme (CE). Chronic oral Captopril treatment induces CE biosynthesis.

Three new long-acting converting-enzyme inhibitors: relationship between plasma converting-enzyme activity and response to angiotensin I.

Three new angiotensin converting-enzyme inhibitors were given orally to 20 men in single doses ranging from 1.25 to 40 mg. Two of them induced comparable marked inhibition of both the blood pressure response to exogenous angiotensin I and plasma converting-enzyme activity. Onset of action was relatively slow, but 21 to 24 hr after drug plasma converting-enzyme activity was still clearly reduced. The third was less active. There was a close correlation between blood pressure response on administration of angiotensin I and plasma converting-enzyme activity. There were no adverse effects. These new drugs are interesting because of their long duration of action. The measurement of plasma converting-enzyme activity seems useful for monitoring efficacy of converting-enzyme blockade and compliance to therapy.

Captopril and the maintenance of blood pressure after sinoaortic denervation in the rabbit.

1. At a dose of 1 mg/kg intravenously, captopril lowered blood pressure in conscious rabbits, that had undergone denervation of sinoaortic baroreceptors, but had no effect on heart rate. In sham-operated controls, this dose caused only an increase in heart rate. 2. In the same experiments, captopril caused a substantial inhibition of plasma angiotensin converting enzyme (CE) activity of rapid onset and gradual decline over 2 to 3 h. The time course of recovery of blood pressure and plasma CE activity were similar. 3. Saralasin, by intravenous infusion, lowered blood pressure in sinoaortic rabbits but to a smaller extent than captopril. 4. The fall in blood pressure observed after captopril is not dependent on the integrity of baroreceptor afferents.

Converting enzyme inhibition during chronic angiotensin II infusion in rats. Evidence against a nonangiotensin mechanism.

Interpretation of results obtained with angiotensin-converting enzyme inhibition in hypertensive patients has been obscured by the possibility of nonangiotensin-mediated mechanisms, particularly rats, we have compared the effects of converting enzyme inhibition (CEI) by oral captopril administration to those of dextrose. In this setting of constant angiotensin II levels, any apparent effects of CEI must be mediated by a nonangiotensin-related mechanism. Angiotensin II infusion at 30 ng/min increased mean blood pressure by an average of 22 mm Hg. Following 7 days of CEI, effective blockade of converting enzyme was established both by a 10-fold elevation of vasodepressor sensitivity to exogenous bradykinin and a markedly decreased plasma converting enzyme activity. On the ninth day of angiotensin II infusion, mean arterial pressure, heart rate, and plasma renin activity were not different between CEI and dextrose-treated groups. Similarly, blockade of angiotensin II by saralasin induced a comparable fall in blood pressure in both groups. Metabolic studies also revealed no long-term differences in water and food intake, weight change, or sodium and potassium metabolisms. These findings suggest that, in the continued presence of angiotensin II, there is no detectable hemodynamic or metabolic effect of chronic converting enzyme inhibition, and therefore that bradykinin plays little or no role in its long-term antihypertensive action.

Responses of blood pressure and angiotensin-converting enzyme activity to acute captopril administration in normotensive and hypertensive rats.

The purpose of these experiments ws to determine the dose of captopril which resulted in essentially complete blockade of tissue and plasma converting enzyme activity (CEA) and to correlate the effect of this dose of inhibitor on blood pressure and CEA in a number of normotensive and hypertensive rat models. Oral administration of captopril (0.3-10 mg/kg) induced a dose-related attenuation of CEA in plasma freshly drawn from normotensive conscious rats. After storage at -20 or 4 C before assay, both captopril-treated and untreated plasmas displayed markedly greater CEA. The converting enzyme inhibitor induced a parallel shift to the right of angiotensin I-induced blood pressure responses, reaching a 100-fold displacement of dose-dependent responses in the presence of 10 mg/kg captopril. Sixty minutes after oral administration of 10 mg/kg captopril, plasma CEA was blocked completely in all normo- and hypertensive models studied. This dose of the inhibitor reduced blood pressure in the sodium-deplete normotensive rat, the spontaneously hypertensive rat, and the initial phase two-kidney, one-clip Goldblatt rat but not in the sodium-replete normotensive rat, the spontaneously hypertensive rat, the mineralocorticoid hypertensive rat, or the chronic phase of two-kidney, one-clip Goldblatt rat. It is concluded that acute administration of captopril at a dose which results in complete blockade of plasma converting enzyme and severe attenuation of tissue converting enzyme reduces blood pressure in animals with high PRA but not in animals in which the PRA is low. (Endocrinology 108: 536, 1981)

SHORT TERM RESPONSE AND DONG TERM MANAGEMENT WITH CAPTOPRIL IN SEVERE HYPERTENSION (HT) OF CHILDREN

Short term response to single dose of Captopril has been studied in 15 severe HT children at least 24 h after cessation of anti HT drugs. Blood pressure (BP) fell significantly (p < 0,001) PRA rose (p < 0,01) plasma aldosterone fell (p < 0,02) in the 6 first hours. Sequential measurement of plasma converting enzyme activity (PCEA) in 6 cases shows significant inhibition. Decrease in PCEA does not constantly parallel the decrease of BP suggesting intervention of other (s) mechanism (s). A positive poor correlation was found between fall of BP and increase of PRA (r = 0,45), a negative one was found between fall of BP and inuline distribution volume (r = 0,52). Long term treatment with Captopril (7days to 12 months, average 101 days) has been performed in 10 patients with resistant HT. 4 of them had a chronic renal failure (mean inulin clearance 25 ml/mn/1.73 sq.m) and 3 were haemodialysed. Maximal dosage was 200 mg/1.73 sq/m/day ; low salt diet was maintained. BP was normalized in 9 cases. In the last patient partially uncontrolled BP and dialysis hypotensions led to bilateral nephrectomy. In one patient with graft artery stenosis Captopril induced a dramatic fall of BP and a consecutive acute reversible tubulopathy leading to cessation of the drug. 5 patients are still treated ; GFR improved in 2 cases. No “allergic” side effect has been observed. Since this side effect is dose related it is fully recommended to obtain the lowest dosage by associating salt depletion.

Plasma converting enzyme activity (C.E.A.) : An index of plasma levels of captopril?

Captopril (1 and 4 mg/kg) was administered intravenously to rabbits and plasma converting enzyme measured using a radioenzymatic technique. Captopril inhibited plasma converting enzyme activity in a dose and time dependent manner, which correlated well with the degree and duration of blockade of the pressor response to angiotensin I (1 μ/kg), but to a lesser extent with the potentiation of the vasodepressor action of bradykinin (80 ng/kg). Plasma converting enzyme activity may be a useful guide to the plasma levels of captopril and its active metabolites, and in the absence of a suitable method for measurement of the drug itself may assist in optimising therapy and elucidating the drug's action.

Discrepancy between antihypertensive effect and angiotensin converting enzyme inhibition by captopril.

Captopril, an inhibitor of angiotensin converting enzyme, was administered twice daily to 13 hypertensive patients for a mean period of 9 weeks. Continuous blood pressure control in the ambulatory patients was established with a portable blood pressure recorder. Notwithstanding, in eight patients with normal renal function, plasma converting enzyme was found to resume normal activity before administration of the morning dose of captopril. Only in 5 patients with impaired renal function did some blockade of plasma converting enzyme persist for more than 12 hours. Measured plasma converting enzyme activity seemed to reflect total conversion of angiotensin I, including conversion in the pulmonary vascular bed, since changes in its activity were closely paralled by changes in plasma aldosterone levels. Bradykinin accumulation seems unlikely when converting enzyme and thus, presumably, kininase II has resumed normal activity. Captopril administration does not seem to alter plasma epinephrine or norepinephrine levels. Blood pressure reduction in the face of normal angiotensin converting enzyme activity is probably due to hyporesponsiveness of the arterioles to pressor hormones, which may be due to specific renin-related and/or nonspecific effects of captopril.

Orally active angiotensin‐converting enzyme inhibitor (SO 14,225) as a treatment for essential hypertension.

1 Captopril (SQ14,225), an orally active inhibitor of angiotensin-converting enzyme, was administered to nine patients with essential hypertension. Plasma renin activity (PRA) was low in four, 'normal' in three and high in two patients. 2 In the hospital, captopril alone induced a significant drop in BP from 165 +/- 6/106 +/- 2 to 140 +/- 5/90 +/- 1 mmHb (P less than 0.001). PRA increased concomitantly (P less than 0.05), whereas plasma-converting enzyme activity (P less than 0.005) and plasma aldosterone (P less than 0.05) were reduced. 3 Six patients underwent chronic ambulatory therapy with captopril for a mean of 16 +/- 3 weeks. After discharge from the hospital, BP remained normalized but in five out of six patients this required additional diuretic therapy. 4 The results suggest that captopril alone or combined with diuretic therapy provides a new, efficient and well tolerated tool to treat patients with essential hypertension independently of their PRA level. It may turn out to be more effective in lowering BP than beta-adrenoceptor-blocking agents.

Plasma Angiotensin Converting Enzyme Activity in Mother and Fetus*

Plasma converting enzyme activity was measured by a spectre-photometric technique inplasma taken from normal mothers and fetuses at term during elective cesarean section or at spontaneous vaginal delivery. Plasma converting enzyme activity in the fetus was within the normal range for non-pregnant adults and for pregnant women undergoing spontaneous vaginal delivery. Fetalconverting enzyme activity was the same whether delivery was accomplished by cesarean section or by the vaginal route, but maternal converting enzyme activity was significantly elevated at cesarean section compared with spontaneous delivery. These data are compatible with the thesis that fetal plasma converting enzyme is, at least in part, derived from extrapulmonary sources and that plasma conversion is not affected by the events that initiate labor or fetal respiration. The increment in maternal converting enzyme activity at cesarean section has not been adequately explainedbut may be due to the effects of anesthesia.II levels.