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

Summary 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 14824 A. 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.     

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

Summary 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.     

Effects of prolonged administration of the angiotensin converting enzyme inhibitor CGS 16617 in normotensive volunteers

Summary A new, orally active angiotensin converting enzyme (ACE) inhibitor, CGS 16617, has been evaluated in normotensive subjects during acute and prolonged administration.Single ascending doses of CGS 16617 20 to 100 mg were given to 9 normotensive volunteers at one week intervals and the changes in blood pressure, plasma ACE and renin activity were examined up to 72 h after drug intake. Also, CGS 16617 50 mg/day or placebo were given for 30 days to 8 and 6 normotensive subjects, respectively, maintained on an unrestricted salt diet. Blood pressure was measured daily in the office and ambulatory blood pressure profiles were also obtained before, during and after therapy, using the Remler M 2000 blood pressure recording system.CGS 16617 was an effective and long lasting ACE inhibitor. It did not induce a consistant change in blood pressure, but, the individual responses were very variable and several subjects experienced a clear decrease in the average of the blood pressures recorded during the daytime.     

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

Summary 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.     

Interaction between furosemide and the converting enzyme inhibitor benazepril in healthy volunteers

Summary Single oral doses of 10 mg converting enzyme inhibitor benazepril (CGS 14824A) and 40 mg furosemide were administered to 12 healthy male volunteers either separately or concomitantly. The pharmacokinetic parameters of benazepril were not influenced by coadministration of furosemide. Urinary excretion of total furosemide was significantly reduced by 10 to 20% in the presence of benazepril. This effect was considered clinically insignificant. Erect blood pressure decreased and pulse rate increased only during concomitant treatment.     

EFFECTS OF LOW DOSE INFUSION OF ATRIAL NATRIURETIC FACTOR ON ACUTE INHIBITION OF ANGIOTENSIN CONVERTING ENZYME IN NORMAL MAN

1. We have studied the effects of low dose infusions of atrial natriuretic factor (human ANF (99-126), 1.95 pmol/min per kg) on angiotensin converting enzyme (ACE) inhibitor-induced haemodynamic and hormonal changes in healthy subjects. 2. ACE inhibitor (captopril 25 mg, administered orally) was given against a background infusion of physiological saline (placebo day) or ANF (experimental day). 3. Compared with the placebo observations, ANF enhanced the fall in plasma aldosterone concentrations induced by captopril (P less than 0.05). 4. The rise of plasma renin activity following administration of ACE inhibitor which was observed during placebo infusion was abolished by ANF (P less than 0.05). 5. The responses of systemic blood pressure and heart rate to the converting enzyme inhibition were not affected by the infusion of ANF. 6. These results suggest that variations in endogenous circulating ANF may influence, in part, the response of these hormonal levels during ACE inhibition.     

CGS 13945: a new orally active angiotensin-converting enzyme inhibitor in normal volunteers

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.     

PHARMACOKINETICS OF ANGIOTENSIN CONVERTING ENZYME INHIBITION IN TISSUES FOLLOWING ORAL LISINOPRIL: STUDIES IN THE RAT USING QUANTITATIVE RADIOINHIBITOR BINDING

1. The pharmacokinetics of angiotensin converting enzyme (ACE) inhibition in plasma and tissues were measured in the rat following 10 mg/kg lisinopril given by oral gavage. 2. Specific binding of 125I-351A to ACE was measured in plasma, and homogenates of lung, aorta, kidney, testis, epididymis and brain, and used as an index of ACE activity. 3. Plasma ACE binding of 125I-351A was reduced to 5% of that in untreated rats 2 h after treatment, and returned to normal by 48 h. Kidney ACE showed a similar time course. Angiotensin converting enzyme from lung, aorta and brain was inhibited at a slower rate, and to a lesser degree. No significant inhibition of ACE was detected in epididymis or testis. 4. Individual tissues in the rat had differences in time course and degree of ACE inhibition after a single dose of lisinopril.     

The haemodynamic and humoral effects of treatment for one month with the angiotensin converting enzyme inhibitor perindopril in salt replete hypertensive patients

Summary We have studied the effects of treatment for one month with perindopril, 4 or 8 mg once daily, in seven hypertensive patients. Blood pressure was lowered from 164/93 mm Hg to 145/84 mm Hg by 4 mg of perindopril and after one month remained at 142/82 mm Hg. Neither postural hypotension nor tachycardia occurred.Inhibition of plasma angiotensin converting enzyme (ACE) lasting for over 24 h was achieved and there was a significant increase in plasma renin activity (PRA).Maximum plasma concentrations of the active metabolite of perindopril, S-9780, were detected four h after oral administration.After treatment for one month there was evidence of reduced sensitivity of plasma ACE to the action of the inhibitor. The plasma concentration of S-9780 required to produce 50% inhibition of plasma ACE rose from 2.4 ng · ml^–1 following the first dose to 5.5 ng · ml^–1 after one month.     

ANGIOTENSIN CONVERTING ENZYME IN THE RAT HEART: STUDIES OF ITS INHIBITION IN VITRO AND EX VIVO

1. The pharmacokinetics of angiotensin converting enzyme (ACE) inhibition in rat heart and lung was evaluated in vitro and ex vivo. 2. Radioinhibitor [125I]-351A binding displacement was used to assess the relative potency of six ACE-inhibitors (CI906, CGS14831, S9780, 351A, MK521, SQ27519) in rat heart and lung homogenates, and estimate equilibrium association constant (Ka). 3. Following oral administration of 0.3 mg/kg of Quinapril (CI928) specific binding of [125I]-351A to ACE was measured in rat heart. 4. Ka for binding to ACE of each inhibitor was significantly higher in right and left atrium than in lung (P less than 0.05) or the right and left ventricle (P less than 0.005). These differences did not affect the degree or time course of inhibition in vivo in the rat myocardial ACE following Quinapril treatment. 5. Rank order of potency of the ACE inhibitors tested was CI906 = CGS14831 greater than S9780 greater than 351A greater than MK521 greater than SQ27519     

血管紧张素转换酶基因多态性与血管紧张素转换酶抑制剂的降压作用

目的:从基因多态性研究药效的差异。方法:选择健康志愿者99 例,未治疗的原发性高血压病人40 例,用PCR 方法检测血管紧张素转换酶(ACE) 基因的插入与缺失(I/D) 多态性, 用血管紧张素转换酶抑制剂(ACEI) 卡托普利治疗高血压病人。结果:正常人与原发性高血压患者的ACE等位基因频率及基因型频率无显著差异(P>0.05) 。卡托普利降压有效病人与无效病人ACE 基因的I/D等位基因频率及基因型频率,基因缺失型纯合子(DD)或/ 和杂合子(ID) 与非缺失型(II) 也均无显著差异(P>0.05) 。结论: ACE基因的I/ D多态性与原发性高血压的发病无关, ACEI降压作用的个体差异与ACE基因的I/D多态性无关。     

Study on pharmacokinetics of a new biliary excreted oral angiotensin converting enzyme inhibitor,temocapril (CS-622) in humans

Despite the usefulness of angiotensin converting enzyme (ACE; EC 3.4.15.1) inhibitors for patients with renal insufficiency, some hesitation has been exercised in applying ACE inhibitors to the treatment of such patients because most ACE inhibitors are excreted mainly into the urine. In this context, development of an ACE inhibitor which is excreted into the bile has been sought. The pharmacokinetic properties of the novel ACE inhibitor, temocapril hydrochloride (temocapril HCl; CS-622), were investigated in six healthy volunteers. This drug is excreted mainly into the bile in animal studies. Temocapril HCl was given in a single dose of 0.5, 1.0, and 2.0 mg, and 36, 44, and 38 per cent of the administered drug was excreted in the feces and 17, 19, and 24 per cent in the urine as the de-esterified active diacid form (the diacid metabolite) within 48 h, respectively. The plasma ACE activity was markedly inhibited. No abnormal clinical findings suggestive of side-effects were observed. Thus, from the pharmacokinetic standpoint, temocapril HCl is expected to be a useful drug for patients with renal dysfunction.     

CHARACTERIZATION OF ANGIOTENSIN CONVERTING ENZYME FROM RAT TISSUE BY RADIO-INHIBITOR BINDING STUDIES

1. Angiotensin converting enzyme (ACE) derived from rat lung, aorta, epididymus, brain, kidney and plasma was characterized by radio-inhibitor (¹²⁵I-MK351A) binding studies. Under optimal binding conditions at equilibrium ¹²⁵I-MK351A bound to ACE was displaced from ACE in a concentration related manner by unlabelled MK351A. 2. MK351A binding site concentration for each tissue and equilibrium dissociation constant (K_D) was estimated by Scatchard analysis of binding data. Binding sites/mg protein was greatest in lung and least in brain. The K_D for kidney ACE was significantly higher than that of lung, aorta, epididymus or brain ACE (P<0.005; t-test, d.f. = 10). 3. ¹²⁵I-MK351A bound to ACE prepared from lung and kidney was displaced in a concentration dependent manner by SQ20881, SQ14225, MK422, and Ro31–3113–000. Concentration of ACE inhibitor required to displace 50% of bound ¹²⁵I-MK351A (DD₅₀) was consistently higher for kidney-derived ACE than lung-derived ACE. 4. The differences in radio-inhibitor binding characteristics of ACE from different rat tissues suggests that the enzyme active site may not be identical in all organs.     

Antihypertensive mechanism of action of the novel angiotensin converting enzyme inhibitor benazepril. Effect on isolated vascular preparations

Benazepril (CGS 14824A HCl) is a new prodrug type angiotensin converting enzyme (ACE) inhibitor. The active form is considered to be benazeprilat, a diacid hydrolyzed compound. Benazepril and benazeprilat inhibited the contraction induced by exposure with angiotensin I, not angiotensin II, in the isolated rabbit aorta. The ACE inhibiting activity of benazeprilat was 1000 times more potent than that of benazepril in this experiment. Benazepril as well as benazeprilat and captopril exerted little influence on norepinephrine, serotonin and high K(+)-induced contraction or bradykinin-induced relaxation in isolated blood vessel preparations, thus angiotensin II synthesis inhibition seemed to be the main cause for its vasodilation. Benazepril, unlike benazeprilat or captopril showed considerable influence on prostaglandin (PG)-induced responses at higher concentrations. The vasocontraction induced by PGF2 alpha was competitively antagonized at 10(-5)-10(-4) mol/l, while vascular responses induced by PGE1, PGE2 or PGI2 was inhibited at 3 x 10(-4) mol/l of benazepril. Although these influences on PGs might not contribute much to its vasodilatory mechanism, the action seemed interesting in relation to cough induction, a known side effect of ACE inhibitors in the market. Benazepril has two asymmetric carbon atoms, thus four optical isomers are possible, SS (benazepril), SR (CGP 14'829A), RS (CGP 42'454A), RR (CGP 42'456A). The SS configuration was the most potent for antagonizing angiotensin I-induced vasocontraction, which seemed to be the best fitted for the ACE molecule.     

Effect of benazepril hydrochloride on cardiac hypertrophy in spontaneously hypertensive rats.

To study the effects of a novel angiotensin I converting enzyme inhibitor (ACEI) on hypertension-induced cardiac hypertrophy, benazepril hydrochloride (CGS 14824 A, CAS 86541-74-4) at the dose of 3 and 10 mg/kg/d p.o. was administered to spontaneously hypertensive rats from 4 to 16 weeks of age. In addition to suppression of developing blood pressure, benazepril hydrochloride reduced both the wet weights of whole heart and left ventricle dose-dependently and significantly. Benazepril hydrochloride had no effect on hydroxyproline concentration and content or protein concentration in the left ventricle, whereas is reduced the total protein content dose-dependently. Serum ACE activity was significantly reduced at 10 mg/kg/d of benazepril hydrochloride, but renin activity, aldosterone and noradrenaline concentration in serum were not changed. From the microscopic findings of the left ventricle, benazepril hydrochloride reduced the myocardial hypertrophy significantly. From these results, benazepril hydrochloride seems to suppress the increase in volume load by acting through the renin-angiotensin-aldosterone system, and dose not seem to cause a significant reflex of catecholamine which often occurs with peripheral vessels dilation. Thus, benazepril hydrochloride may be expected to suppress cardiac hypertrophy in patients with hypertension.     

Greater blood pressure-lowering effect of the renin inhibitor EMD 58265 than an angiotensin-converting enzyme inhibitor in two-kidney one-clip Goldblatt rabbit

1. Renin inhibitors may be more advantageous than either angiotensin-converting enzyme (ACE) inhibitors or angiotensin (Ang) antagonists in blocking the renin-angiotensin system (RAS) because they do not allow accumulation of either AngI or AngII in plasma. 2. Effects of i.v. administration of two human renin inhibitors (EMD 58265 and U 71038) were compared with the ACE inhibitor enalaprilat on mean blood pressure (BP), renal blood flow (RBF) and plasma AngI and AngII in the anaesthetized two-kidney one-clip Goldblatt rabbit. 3. At doses of 2-2.5 mg/kg, i.v., EMD 58265 and 5-10 mg/kg, i.v., U 71038, both drugs decreased BP approximately 10 mmHg more than enalaprilat (2-4 mg/kg, i.v.) when given either before or after the ACE inhibitor. None of the three agents had any significant effect on RBF in the face of the lowered BP; however, renal vascular resistance was decreased. A higher dose of enalaprilat (10 mg/kg, i.v.) had no further effect on BP than the lower doses but did cause a marked increase in RBF. 4. Both renin inhibitors markedly decreased plasma AngI, but the high basal level of AngII was less consistently and only modestly affected. Enalaprilat, in either the low dose range or at the high dose, was also not effective in significantly decreasing AngII. 5. The results indicate that renin inhibition in the rabbit with a high circulating AngII level is more effective in lowering BP than ACE inhibition. A high dose of the ACE inhibitor may be required to block the intrarenal RAS, which may account for the increase in RBF.     

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).     

Reactive hyperreninemia is a major determinant of plasma angiotensin II during ACE inhibition.

The new ACE inhibitor trandolapril was administered to normal volunteers at daily doses of 0.5, 2, and 8 mg for 10 days. Twenty-one volunteers, aged 21-30 years, were included in the study. To randomly selected groups of seven subjects, each dose was administered in a single-blind fashion. None of the doses induced a consistent fall in blood pressure. Angiotensin-converting enzyme activity (ACE) was measured in vitro using three different synthetic substrates (i.e., Hip-Gly-Gly, Z-Phe-His-Leu, or angiotensin I). Although the degree of ACE inhibition assessed with the three methods varied widely, all methods clearly indicated dose-dependent ACE inhibition. These in vitro results were confirmed by measuring ACE inhibition in vivo using the ratio of plasma angiotensin II (ANG II) to blood angiotensin I (ANG I). The dose-dependent ACE inhibition was paralleled by a dose-dependent rise in active renin and blood angiotensin I levels, most evident on day 10. In contrast, plasma ANG II levels on day 10 were not different whether the volunteers received 0.5 or 8 mg trandolapril. Thus, whereas increasing doses of this new ACE inhibitor progressively enhanced the blockade of ACE activity, this was not reflected by additional reductions of plasma ANG II levels. The progressive enhancement of ACE inhibition seemed to be offset by the accentuation of the compensatory rise in renin and ANG I, which was still partially converted to ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of captopril (SQ 14, 225) on the renin-angiotensin-aldosterone system in normal rats

High doses of captopril (SQ 14, 225) (120-160 mg/kg/day) were administered orally to normal rats, and the effects on the renin-angiotensin-aldosterone system were observed. Plasma angiotensin converting enzyme (ACE) activity was elevated significantly on the 3rd, 7th and 30th days of captopril administration. ACE activity in the lung and the kidney was significantly decreased on the 1st day then gradually increased, becoming significantly higher than that of controls by the 30th day. Plasma renin activity (PRA) was significantly elevated on the 1st day and remained at a high level until the 30th day. Renal renin content was found to be significantly lower on the 1st and 3rd days. Plasma aldosterone concentration was not affected by captopril treatment, whereas serum potassium concentration was found to be significantly lower on the 1st, 3rd and 30th days. It is suggested that besides its inhibitory action on ACE, captopril has a direct or indirect stimulating action on ACE production as well as on renin release.     

Emerging markers in cardiovascular disease: Where does angiotensin‐converting enzyme 2 fit in?

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