Plasma Converting Enzyme Activity Research Articles

Effect of a new angiotensin converting enzyme inhibitor MK 421 and its lysine analogue on the components of the renin system in healthy subjects

1 MK 421 and its lysine analogue are two new inhibitors of angiotensin converting enzyme. Ten mg of both compounds were each given p.o. to 12 normotensive volunteers to determine their effect on the various components of the renin angiotensin aldosterone system. 2 Plasma converting enzyme activity decreased to very low levels within 3 to 4 h to recover only slowly over the next 72 h. Plasma angiotensin II and aldosterone also fell but returned to baseline within 24 h, whereas plasma renin activity rose reflecting the low angiotensin II levels. 3 There was a close correlation between both angiotensin II and aldosterone levels and the logarithm of plasma converting enzyme activity demonstrating that angiotensin II and aldosterone fell only when converting enzyme activity was reduced to very low levels. 4 Mean hourly urinary sodium excretion increased markedly 6 to 10 h post-drug, while blood pressure decreased slightly. Both drugs were well tolerated. 5 Thus 10 mg of MK 421 or its lysine analogue given orally are effective and long acting angiotensin converting enzyme inhibitors.

Refractory Hypotension After Induction of Anesthesia in a Patient Chronically Treated with Angiotensin Receptor Antagonists

Refractory Hypotension After Induction of Anesthesia in a Patient Chronically Treated with Angiotensin Receptor Antagonists

Determinants of angiotensin II generation during converting enzyme inhibition.

The reaction of the renin-angiotensin system to acute angiotensin converting enzyme inhibition was investigated in a single-blind, crossover study in nine normal volunteers receiving two out of three regimens in random order: the new converting enzyme inhibitor benazepril (20 mg once or 5 mg four times at 6-hour intervals) or enalapril (20 mg). Plasma converting enzyme activity, drug levels, angiotensin I and angiotensin II, active renin, and aldosterone were measured before and 1-4 hours and 14-30 hours after drug intake. Baseline in vitro plasma converting enzyme activity was 97 +/- 15 nmol/ml/min (mean +/- SD) when Hip-Gly-Gly was used as substrate, but with carbobenzoxy-Phe-His-Leu (Z-Phe-His-Leu) or angiotensin I as substrate it was only 20 +/- 4 and 1.7 +/- 0.3 nmol/ml/min, respectively. Discriminating power at peak converting enzyme inhibition was enhanced with the two latter substrates. In vivo converting enzyme activity was estimated by the plasma angiotensin II/angiotensin I ratio, which correlated well with in vitro converting enzyme activity using Z-Phe-His-Leu as substrate (r = 0.76, n = 252). Angiotensin II levels returned to baseline less than 24 hours after drug administration, whereas in vitro and in vivo converting enzyme activity remained considerably inhibited and active renin together with angiotensin I levels were still elevated. A close linear relation was found between plasma angiotensin II and the angiotensin I/drug level ratio (r = 0.91 for benazeprilat and r = 0.88 for enalaprilat, p less than 0.001). Thus, plasma angiotensin II truly reflects the resetting of the renin-angiotensin system at any degree of converting enzyme inhibition. The ratio of plasma angiotensin II to angiotensin I represents converting enzyme inhibition more accurately than in vitro assays, which vary considerably depending on substrates and assay conditions used.

Interaction of angiotensin converting enzyme inhibition and atrial natriuretic factor.

The interaction of angiotensin converting enzyme (ACE) inhibition and atrial natriuretic factor (ANF) was investigated in six supine, sodium-replete, normal volunteers who received captopril (10 mg i.v. bolus followed by 10 mg/hr constant infusion) or vehicle superimposed on background 3-hour, constant, low-dose (1.5 pmol/kg/min) infusions of human ANF (99-126). Plasma converting enzyme activity was significantly inhibited but this had no effect on endogenous plasma ANF concentrations. ANF infusions, with or without captopril, caused similar increases in plasma ANF concentrations, and calculated metabolic clearance rates for ANF were unchanged. Similarly, blood pressure, heart rate, renal blood flow, glomerular filtration rate, and renal electrolyte excretion, including ANF-induced natriuresis, were unaffected by captopril. The combination of ANF plus captopril produced a significant increase in plasma aldosterone (79 +/- 8 vs. 60 +/- 6 pmol/l, p less than 0.05), cortisol (406 +/- 52 vs. 265 +/- 29 nmol/l, p less than 0.01), adrenaline (119 +/- 21 vs. 76 +/- 10 pg/ml, p less than 0.05), and noradrenaline (319 +/- 49 vs. 215 +/- 38 pg/ml, p less than 0.05) compared with time-matched placebo data. Converting enzyme inhibition, in the absence of major changes in blood pressure or renal blood flow, has little effect on ANF metabolism or renal bioactivity. However, ACE inhibition and ANF combined may interact to increase activity of the hypothalamo-pituitary-adrenal axis and sympathetic nervous system by unknown mechanisms.

Plasma Angiotensin-(1-8) Octapeptide Measurement to Assess Acute Angiotensin-Converting Enzyme Inhibition with Captopril Administered Parenterally to Normal Subjects

The blood pressure (BP), heart rate (HR), and humoral effects of single intravenous (i.v.) doses of the angiotensin-converting enzyme (ACE) inhibitor captopril was investigated in five normotensive healthy volunteers. Each subject received at 1-week intervals a bolus dose of either captopril (1, 5, and 25 mg) or its vehicle. The study was conducted in a single-blind fashion, and the order of treatment phases was randomized. The different doses of captopril had no acute effect on BP and HR. They induced a dose-dependent decrease in plasma ACE activity and plasma angiotensin II levels. The angiotensin-(1-8) octapeptide was isolated by solid-phase extraction and high-performance liquid chromatography (HPLC) prior to radioimmunoassay (RIA). All three doses of captopril reduced circulating angiotensin II levels within 15 min of drug administration. Only with the 25-mg dose was the angiotensin II concentration below the detection limit at 15 min and still significantly reduced 90 min after drug administration. Simultaneous and progressive decreases in plasma aldosterone levels were observed both with ACE inhibition and during vehicle injection, but the relative fall was more pronounced after captopril administration. No adverse reaction was noticed. These results demonstrate that captopril given parenterally blocks the renin-angiotensin system in a dose-dependent manner. Only with the dose of 25 mg was the inhibition of plasma-converting enzyme activity and the reduction of plasma angiotensin II sustained for at least 1 1/2 h.

Repeated Administration of the Converting Enzyme Inhibitor Cilazapril to Normal Volunteers

Summary: Cilazapril 1.25 and 5.0 mg p.o. q.d. was administered in double-blind fashion to two groups of six normal volunteers on 8 consecutive days. Blood pressure, heart rate, and plasma converting enzyme activity were measured each day prior to drug administration and up to 72 h after the last dose. Plasma renin activity, blood angiotensin I, plasma angiotensin II, and aldosterone as well as plasma cilazaprilat levels were determined on the first and the last day of active treatment at times 0, 4, and 24 h. The drug was very well tolerated by all volunteers. At 4 h postdrug, plasma converting enzyme activity was reduced in dose-dependent fashion on the first and the eighth day; plasma cilazaprilat levels were also clearly dose dependent. Nevertheless, 24 h postdrug cilazaprilat levels were similar on the first and last day of drug administration, and plasma converting enzyme activity was also stable throughout the 8 days. The various components of the renin-angiotensin system responded in the usual fashion. These results provide strong evidence that cilazapril is a very potent and highly effective converting enzyme inhibitor. Doses well below 5 mg/day will probably suffice for therapeutic efficacy. These data also confirm the hypothesis formulated in the preceding article, i.e., that there is no accumulation of the drug with repeated administration despite its long pharmacological half-life (t½).

Repeated Administration of the Converting Enzyme Inhibitor Cilazapril to Normal Volunteers

Cilazapril 1.25 and 5.0 mg p.o. q.d. was administered in double-blind fashion to two groups of six normal volunteers on 8 consecutive days. Blood pressure, heart rate, and plasma converting enzyme activity were measured each day prior to drug administration and up to 72 h after the last dose. Plasma renin activity, blood angiotensin I, plasma angiotensin II, and aldosterone as well as plasma cilazaprilat levels were determined on the first and the last day of active treatment at times 0, 4, and 24 h. The drug was very well tolerated by all volunteers. At 4 h postdrug, plasma converting enzyme activity was reduced in dose-dependent fashion on the first and the eighth day; plasma cilazaprilat levels were also clearly dose dependent. Nevertheless, 24 h postdrug cilazaprilat levels were similar on the first and last day of drug administration, and plasma converting enzyme activity was also stable throughout the 8 days. The various components of the renin-angiotensin system responded in the usual fashion. These results provide strong evidence that cilazapril is a very potent and highly effective converting enzyme inhibitor. Doses well below 5 mg/day will probably suffice for therapeutic efficacy. These data also confirm the hypothesis formulated in the preceding article, i.e., that there is no accumulation of the drug with repeated administration despite its long pharmacological half-life (t1/2).

Effects of Single Doses of the Converting Enzyme Inhibitor Cilazapril in Normal Volunteers

The new converting enzyme inhibitor cilazapril, or RO 31-2848, was evaluated in 14 healthy male volunteers. In a pilot study in two subjects, the inhibiting capacity of single oral doses of 5 and 10 mg on the pressure and heart rate response to exogenous angiotensin I was assessed. Both doses reduced the blood pressure response to angiotensin I to 10% of control within 45 min and for the 4 h tested. In the main study, 12 volunteers each received two single oral doses of cilazapril at a 2-week interval, and plasma converting enzyme and renin activity, blood angiotensin I, plasma immunoreactive angiotensin II and aldosterone were measured serially. Single doses of 1.25, 2.5, 5, and 10 mg of cilazapril were tested in groups of six subjects each. All doses inhibited plasma converting enzyme activity by 90% for at least 8 h and induced the expected pattern of changes of the renin-angiotensin-aldosterone system. Only slight dose-dependent variations in the effect were observed. Basic heart rate and blood pressure were not altered by any of the doses, which all were well tolerated. These data suggest that cilazapril is a very potent and long-acting new converting enzyme inhibitor.

Effect on blood pressure and the renin-angiotensin system of repeated doses of the converting enzyme inhibitor CGS 14824A

A new, orally active angiotensin converting enzyme (ACE) inhibitor, CGS 14824A, was evaluated in 12 healthy male volunteers. Two groups each of 6 volunteers were given 5 or 10 mg once daily p.o. for 8 days. Four hours after the first and the last morning doses, plasma angiotensin II, aldosterone and plasma converting enzyme activity had fallen, while blood angiotensin I and plasma renin activity had risen. Throughout the study, more than 90% inhibition of ACE was found immediately before giving either the 5 or 10 mg dose and 50% blockade was still present 72 h following the last dose. Based on the determination of ACE, there was no evidence of drug accumulation. No significant change in blood pressure or heart rate was observed during the course of the study. CGS 14824A was an effective, orally active, long-lasting and well tolerated converting enzyme inhibitor.

Perindopril, Converting Enzyme Blockade, and Peripheral Arterial Hemodynamics in the Healthy Volunteer

The effects of three doses (4, 8, and 16 mg) of perindopril, a new angiotensin I converting enzyme inhibitor, on systemic blood pressure, heart rate, brachial and carotid artery flow and diameter (assessed by the pulsed Doppler technique), forearm vascular resistance, plasma converting enzyme and renin activities, and plasma aldosterone were investigated in the normal volunteer and compared with those of a placebo over a 24-h period following oral drug intake in a double-blind, crossover trial. Perindopril dose-dependently decreased plasma converting enzyme activity, an effect that peaked at 3-4 h and persisted up to at least 48 h. Plasma renin activity increased for 12 h and plasma aldosterone was slightly decreased. Systemic blood pressure and heart rate were not drug-affected but perindopril dose-dependently augmented brachial and carotid artery flow, indicating an increase in peripheral arterial compliance. These vasodilating effects, which lasted up to 10 h after drug intake, affected both large arteries and arterioles, the latter being more sensitive, however, and were more marked in the muscular resistance vessels.

Perindopril, Converting Enzyme Blockade, and Peripheral Arterial Hemodynamics in the Healthy Volunteer

Summary: The effects of three doses (4, 8, and 16 mg) of perindopril, a new angiotensin I converting enzyme inhibitor, on systemic blood pressure, heart rate, brachial and carotid artery flow and diameter (assessed by the pulsed Doppler technique), forearm vascular resistance, plasma converting enzyme and renin activities, and plasma aldosterone were investigated in the normal volunteer and compared with those of a placebo over a 24-h period following oral drug intake in a double-blind, crossover trial. Perindopril dose-dependently decreased plasma converting enzyme activity, an effect that peaked at 3–4 h and persisted up to at least 48 h. Plasma renin activity increased for 12 h and plasma aldosterone was slightly decreased. Systemic blood pressure and heart rate were not drug-affected but perindopril dose-dependently augmented brachial and carotid artery flow, indicating an increase in peripheral arterial compliance. These vasodilating effects, which lasted up to 10 h after drug intake, affected both large arteries and arterioles, the latter being more sensitive, however, and were more marked in the muscular resistance vessels.

Renin-angiotensin system, converting-enzyme inhibition and kidney function in aging female rats.

The age-related changes in the renin-angiotensin system were investigated in normotensive 3-, 10-, 20-, and 30-mo-old female Wistar rats. Plasma renin concentration and immunofluorescent renal renin index remained constant from 3 to 10 mo, then decreased as the animals become older, whereas plasma concentration of renin substrate diminished slightly between 10 and 20 mo and plasma converting-enzyme activity was not modified with age. Acute inhibition of converting-enzyme activity by intravenous administration of 0.1 mg/100 g body wt S 9780 (the diacid form of S 9490) was followed by a 7- to 8-mmHg decrease in arterial pressure and a concomitant 10-12% increase in inulin and p-aminohippuric acid (PAH) clearance in the 10- and 20-mo-old rats. On the other hand, neither glomerular filtration rate, PAH clearance nor arterial blood pressure were affected by converting-enzyme inhibition in the 30 mo-old rats. These results indicate that the activity of the renin-angiotensin system is progressively reduced with age and suggest that angiotensin II does not play an important role in the maintenance of blood pressure and kidney hemodynamics in normotensive female senescent rats.

Perindopril, a New Converting Enzyme Inhibitor: Systemic and Regional Hemodynamics and Sympathoinhibitory Effects in Spontaneously Hypertensive Rats

The effects of a new converting enzyme inhibitor, perindopril (5 mg/kg p.o. q.d. for 8 days), on systemic and regional hemodynamics, as well as its interferences with the sympathetic nervous system at the cardiovascular level, were investigated in nonbinephrectomized and in binephrectomized spontaneously hypertensive rats (SHRs). Perindopril abolished plasma converting enzyme activity and lowered arterial blood pressure (BP) without affecting heart rate. Cardiac index (microspheres) was not drug affected; thus, the reduction in BP was due to a decrease in total peripheral resistance which was shown to be homogenous, since all investigated vascular resistances were reduced to the same extent. In nonbinephrectomized, pithed SHRs, perindopril decreased BP and renal and hindlimb vascular resistances (pulsed Doppler). In addition, perindopril exerted a sympathoinhibitory effect as evidenced by (a) a reduction in the systemic vasopressor and regional vasoconstrictor responses to the alpha 1-adrenoceptor agonist, cirazoline, and especially to the alpha 2-adrenoceptor agonist UK 14.304; and (b) a decrease in the systemic pressor and in the hindlimb vasoconstrictor responses to spinal cord stimulation. In binephrectomized, pithed SHRs, perindopril no longer decreased BP; however, whereas its sympathoinhibitory effect versus alpha-adrenoceptor agonists was abolished, that versus spinal cord stimulation persisted. These results indicate that (a) perindopril lowers BP in SHRs by a renal-dependent mechanism; (b) perindopril exerts in SHRs a sympathoinhibitory effect versus alpha-adrenoceptor agonists and spinal cord stimulation; (c) the sympathoinhibitory effect of perindopril versus alpha-adrenoceptor agonists is postjunctional and kidney dependent; and (d) the sympathoinhibitory effect of perindopril versus spinal cord stimulation is possibly prejunctional in its mechanism and does not require the presence of the kidneys.

Impact of Captopril on Hemodynamic and Hormonal Effects of Nitroprusside

The impact of oral captopril, 2 mg . kg-1, on the dose and on the hemodynamic and hormonal effects of nitroprusside was studied in seven patients (Group II). A comparable group (Group I, n = 7) received nitroprusside alone. In both groups, nitroprusside produced comparable decreases in mean arterial pressure, systemic vascular resistance, and right atrial pressure; cardiac output increased because of a significant change in heart rate. Although plasma renin activity increased significantly (compared with control values) in both groups, it was greater (p = 0.01) through the operative period in patients pretreated with captopril. Plasma aldosterone concentration increased in Group I (p = 0.01) but decreased in Group II (p = 0.01). Plasma catecholamine concentrations increased (p = 0.01) with nitroprusside alone but were unchanged in captopril-treated patients. Plasma converting enzyme activity was markedly inhibited (p = 0.001) by captopril. Following cessation of nitroprusside infusion in Group I, rebound hypertension occurred in conjunction with a significant (p = 0.01) increase in systemic vascular resistance; it was associated with elevated plasma renin activity, catecholamines, and aldosterone concentrations. In contrast, captopril-treated patients showed no rebound hemodynamic changes. Nitroprusside dose was less (p = 0.01) with captopril pretreatment (2.1 +/- 0.3 vs. 4.8 +/- 0.9 microgram . kg-1 . min-1). Thus, captopril is a useful adjunct to nitroprusside-induced hypotension.

Haemodynamic and pharmacological effects of the converting enzyme inhibitor CGS 14824A in normal volunteers

The converting enzyme inhibitor CGS 14824A was evaluated in 15 healthy male volunteers. First, the efficacy of a single 5 or 10 mg oral dose in antagonizing the pressor response to exogenous angiotensin I was tested in 2 subjects. Blood pressure and heart rate were monitored continuously through an intra-arterial catheter. CGS 14824A 5 mg reduced the response to angiotensin I within 75 min to 50%, and 10 mg within 1 h to less than 25%, and for a period of more than 4 h. Subsequently, plasma renin and converting enzyme activity, plasma angiotensin I, angiotensin II and aldosterone were measured serially before and up to 72 h following oral administration of 2, 5, 10 or 20 mg CGS 14824A to groups of 5 volunteers. Plasma converting enzyme activity fell to well below 10% of baseline within 1 h after administration of 5 mg or more CGS 14824A. Within 2 h following 2 mg p.o., a similarly low level was reached. Twenty four hours following the 20 mg dose, plasma converting enzyme activity was still below 10%. As expected, plasma renin activity and angiotensin I rose while angiotensin II and aldosterone fell following the 2 mg dose. This pattern of effects was enhanced by increasing the dose. Nonetheless, 24 h after the 20 mg dose, plasma angiotensin II and aldosterone had returned to their baseline levels. No side-effects occurred. Thus, in normal volunteers, CGS 14824A was an effective, potent and long acting converting enzyme inhibitor.

The effect of the converting enzyme inhibitor HOE 498 on the renin angiotensin system of normal volunteers.

The converting enzyme inhibitor HOE 498 was evaluated in 12 normotensive male volunteers aged 21 to 26. The efficacy of single 5, 10 or 20 mg oral doses in blocking the pressor response to exogenous angiotensin I was tested in 3 of the subjects. All 3 doses of HOE 498 reduced the pressor response to exogenous angiotensin I to below 50% of control within 1,5 h following administration of the drug. Plasma renin and converting enzyme activity, blood angiotensin I, as well as plasma angiotensin II and aldosterone were measured serially before and up to 72 h following oral administration of a single dose of 2.5, 5, 10 or 20 mg of HOE 498 to groups of 5 volunteers each. As expected, blood angiotensin I levels and plasma renin activity rose while plasma converting enzyme activity, plasma angiotensin II and aldosterone concentration fell after administration of the drug. While the dose of 2.5 mg did not reduce plasma converting enzyme activity below 20% of control, the higher doses all resulted in plasma converting enzyme inhibition exceeding 90%. No side-effects were observed. It is concluded that in normal volunteers HOE 498 is an effective potent and long-acting converting enzyme inhibitor. Based on these preliminary findings it is expected that 5 mg HOE 948 will turn out to be adequate for therapeutic use.

Influence of chronic renal failure on captopril pharmacokinetics and clinical and biological effects in hypertensive patients.

The pharmacokinetic parameters of unchanged plasma captopril and the kinetics of the drug effects on plasma converting enzyme activity (PCEA), plasma renin activity (PRA), plasma aldosterone (PA) and mean blood pressure (MBP) were studied over 24 h after oral administration in three groups of hypertensive patients: with normal renal function (group 1, plasma creatinine less than 110 mumol/l, n = 10), with moderate chronic renal failure (group 2, 135 less than plasma creatinine less than 450 mumol/l, n = 10) and with severe chronic renal failure (group 3, plasma creatinine greater than 500 mumol/l, n = 10). Renal impairment had no effect on plasma captopril Cmax, CLtot and relative bioavailability (AUC). In contrast, captopril kel decreased while T1/2 increased progressively from group 1 to group 3. PCEA blockade (T1/2 and AUC) was increased significantly and proportionally to the degree of renal impairment. However, there were no differences between the three groups regarding captopril-induced modifications of PRA and PA. Although the maximal reduction in MBP was identical in the three groups, the overall antihypertensive effect (AUC) of captopril increased significantly and progressively from group 1 to group 3, especially in duration. There was no correlation between basal plasma creatinine values and unchanged captopril relative bioavailability (AUC) and between unchanged captopril relative bioavailability (AUC) and the drug effects (AUC) on PCEA, PRA, PA and MBP. However there was a correlation between basal plasma creatinine values and plasma captopril T1/2, PCEA blockade (AUC) and overall antihypertensive effect (AUC). The apparent discrepancy between the lack of effects of chronic renal failure on plasma unchanged captopril bioavailability and its potentiating effects on PCEA blockade and MBP reduction may be accounted for by the renal impairment-induced accumulation of captopril metabolites.

Captopril: pharmacokinetics, antihypertensive and biological effects in hypertensive patients.

The kinetics of captopril plasma levels and of the drug-induced plasma converting enzyme activity (PCEA), plasma renin activity (PRA) and diastolic blood pressure (DBP) modifications were studied over 24 h after oral administration of captopril, 1 mg/kg, to ten hypertensive patients. Free unchanged captopril pharmacokinetic parameters were: t1/2, alpha: 0.45 +/- 0.06 h; tmax: 0.98 +/- 0.13 h; Cmax: 1.31 +/- 0.20 mg l-1; t1/2,z: 0.66 +/- 0.13 h; V: 0.614 +/- 0.104 1 kg-1 and CLtot: 0.690 +/- 0.082 l h-1 kg-1. At 6 h captopril was no longer detectable in plasma. The onset of PCEA inhibition and of DBP decrease closely followed the rise of captopril's plasma levels, while that of PRA increase was delayed. In contrast, while captopril rapidly disappeared from plasma, its biological and antihypertensive effects were long-lasting. The lack of correlation between the relative bioavailability of captopril and the induced reduction in DBP (evaluated by the corresponding AUCs) suggests that free unchanged captopril plasma monitoring is not an adequate indicator of hypertensive patients' potential responsiveness to captopril's blood pressure lowering effects.

A potent converting enzyme inhibitor CGS 13928C. Drug profile in normal volunteers.

The converting enzyme inhibitor CGS 13928C was evaluated in 15 healthy male volunteers. First the efficacy of a single oral dose of 0.5, 1, 2 or 5 mg in antagonizing the pressor response to exogenous angiotensin I was tested with continuous monitoring of the blood pressure and heart rate by an intraarterial catheter. CGS 13928C 1, 2 and 5 mg consistently reduced the response to angiotensin within 2 to 3 h and for a period exceeding the 4 h of monitoring. The 2 mg dose was hardly more effective than 1 mg and 5 mg did not further enhance the blockade. Subsequently, plasma renin and converting enzyme activity, angiotensin I, angiotensin II and aldosterone were measured serially before and up to 72 h following oral administration of either 1 mg (n = 7) or 2 mg (n = 8) CGS 13928C. As expected, plasma renin activity and angiotensin I rose, while plasma converting enzyme activity, angiotensin II and aldosterone fell following both doses of the drug. No side-effects occurred. In normal volunteers CGS 13928C is an effective and extremely potent, orally active converting enzyme inhibitor.

CGS 13945

The new converting enzyme inhibitor CGS 13945 was evaluated in 14 male volunteers. The study consisted of two parts. First, the capacity of a single oral dose (10, 20, 50, 100, 250, or 500 mg) to inhibit the pressor response to exogenous angiotensin I was tested, with blood pressure and heart rate monitored continuously through an intra-arterial catheter. The 250-mg and particularly the 500-mg dose markedly reduced the pressor response to angiotensin I within 1/2 h and for a period exceeding 4 h. There was a close correlation between the pressor response to angiotensin I and plasma converting enzyme activity. In a second part, plasma renin and converting enzyme activity, angiotensin I and II, and plasma aldosterone were measured serially before and up to 48 h after oral administration of either 250 or 500 mg of CGS 13945 to six volunteers each. As expected, plasma renin activity and angiotensin I levels rose, while plasma converting enzyme activity and angiotensin II and aldosterone levels fell within 1/2 h. Twenty-four hours following administration of 500 mg CGS 13945, plasma converting enzyme had not quite returned to base line. No side effects were observed. CGS 13945 seems less potent than previously studied converting enzyme inhibitors, but equally effective and relatively long acting.