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

Summary 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.     

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.     

Antihypertensive assessment of two new angiotensin-converting enzyme (ACE) inhibitors: CGS 13945 and CGS 13934

CGS 13945 (1-(4-(ethoxycarbonyl)-2,4-dimethyl-2R,4R-butyryl)-2,3-dihydro-2S-indole-2-carboxylic acid) and CGS 13934 (its dicarboxylic acid derivative) are nonthiol angiotensin-converting enzyme (ACE) inhibitors which have antihypertensive properties. Acute administration of CGS 13945 lowers systolic pressure in spontaneously hypertensive rats (SHR) and sodium depletion enhances the blood pressure reduction; the acute antihypertensive effects of CGS 13934 are minimal. Acute administration of CGS 13945 or CGS 13934 also elevates plasma renin activity, especially in sodium-depleted SHR. CGS 13945 reduces systolic blood pressure of SHR in a dose-dependent manner following oral administration on each of 4 consecutive days, whereas the antihypertensive effect of CGS 13934 is not apparent until the third day of drug administration. After 3 consecutive daily doses, 30 mg/kg (PO) of CGS 13945, CGS 13934 or captopril produce equal antihypertensive effects. CGS 13945 also reduces systolic blood pressure of sodium-depleted normotensive rats. Daily oral administration of CGS 13945 to either sodium-replete or -deplete perinephritic hypertensive dogs does not appreciably affect mean arterial pressure. Results suggest that CGS 13945 must be endogenously de-esterified to the free acid form for endowment of optimal biological activity to inhibit the ACE. While the rat is apparently capable of such hydrolysis, the dog's capacity for endogenous hydrolysis appears to be quite limited.     

Effects of angiotensin converting enzyme inhibitor,perindopril, on autonomic reflexes

Summary The effect of the angiotensin converting enzyme inhibitor, perindopril, on autonomic function was assessed in a double blind, placebo controlled, crossover study in 10 normotensive males. Eight milligram of perindopril given orally lowered blood pressure without a change in heart rate. Perindopril enhanced the vagally mediated heart rate variation with deep breathing. There was no impairment of the responses to either bicycle exercise at 175 W for 5 min or isometric handgrip. The pressor response to cold was not changed and the response to the Valsalva manoeuvre was unaltered. These results suggest that the absence of tachycardia after perindopril may be in part related, as has been reported with other converting enzyme inhibitors, to enhanced cardiac parasympathetic tone. Vagomimetic action may be a property of converting enzyme inhibitors in general.     

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.     

血管紧张肽转换酶抑制药和糖尿病

血管紧张肽转换酶抑制药可增加组织对内源性和外源性胰岛素的敏感性。血管紧张肽转换酶抑制药通过扩张肾小球入球小动脉和出球小动脉、降低肾小球囊内压力 ,可延迟糖尿病肾病的发生。血管紧张肽转换酶抑制药通过降低血压、减少血管紧张肽Ⅱ的不利作用、抗血管平滑肌增殖作用、抗心力衰竭作用可减少糖尿病心血管并发症的发生。血管紧张肽转换酶抑制药尚有利于糖尿病眼部并发症、周围神经病变的治疗     

血管紧张素转化酶基因多态性不影响血管紧张素转化酶抑制剂的肾保护作用

目的 :探讨血管紧张素转化酶 (ACE)基因多态性对血管紧张素转化酶抑制剂 (ACEI)临床疗效的影响。方法 :136例原发性肾小球疾病患者 ,依ACE基因表型分为DD组 (2 4例 ) ,ID组 (71例 )和II组 (4 1例 )。给予ACEI治疗 4mo。治疗前及治疗后 1,2 ,3,4mo及停药后 1mo检测平均动脉压 (MAP)、尿蛋白量、尿白蛋白排泄率 (UAER)、肾功能、尿钠以及尿蛋白选择指数(UPSI)。结果 :3组患者治疗期间蛋白、食盐摄入量以及血肌酐、UPSI均无明显变化 ,3组之间也无明显差别 ;3组患者治疗后MAP、尿蛋白、UAER和Ccr均明显降低 ,但停药后恢复至治疗前水平 ,3组间无明显差别。结论 :ACE基因多态性不影响ACEI对肾小球疾病患者的肾保护作用     

血管紧张肽转换酶抑制药在冠心病治疗中的应用

血管紧张肽转换酶抑制药可通过改善心肌供氧耗氧平衡、改善血管内皮功能、抑制交感神经兴奋性、抑制血管平滑肌迁移和增殖、抑制血小板聚集和促进纤维蛋白溶解、抑制低密度脂蛋白氧化修饰、抑制心肌肥厚、延迟心脏重构等机制在动脉粥样硬化和冠心病的治疗中发挥重要作用     

亲和色谱法从猪骨胶原蛋白酶解物中分离纯化血管紧张素转换酶抑制剂

目的从猪骨胶原蛋白酶解物中分离出高纯度的血管紧张素转换酶抑制剂。方法将胶原蛋白酶解物用双蒸水溶解 ,先上SephadexG 2 5柱 ,用含有 10mmol/L吡啶的 0 .6mol/L醋酸溶液洗脱 ,收集对血管紧张素转换酶有抑制作用的峰值部分冻干 ;再上血管紧张素转换酶抑制剂亲和柱洗脱 ,测定各收集管洗脱液的比抑制活力 ,收集峰值部分冻干。结果亲和色谱柱洗脱液峰值管比抑制活力达 14 5 0u/mg,为粗提液的 90 6倍 ,活力回收率为 12 .1%。结论利用亲和色谱法 ,能够从猪骨胶原蛋白酶解物中分离出高纯度的血管紧张素转换酶抑制剂。     

ACE抑制剂卡托普利对实验性围手术期心肌缺血的影响

目的:图手术期心肌缺血主要是因为应激引起冠状动脉内皮功能障碍所致,所以观察卡托普利对其影响。方法:杂种犬20只均分为4组:Ⅰ组(对照组),Ⅱ组(心肌梗塞模型组),Ⅲ组(心梗 胃大部切除术)和Ⅳ组(心梗 卡托普利 胃大部切除术)。心梗2周后行胃大部分切除术,测定Ⅲ、Ⅳ两组的基础状态、术前和术后的血流动力学指标、血浆内皮素(ET)及一氧化氮(NO)。用组织原位杂交方法观察4组非梗塞区冠脉内皮-氧化氮合酶(NOS)mRNA表达水平。结果:在Ⅲ组,手术使LV dP/dt_(max)、心脏指数(CI)及NO下降,引起LVEDP、PCWP、总外周阻力(TPR)、左室舒张压力下降时间常数(T值)和ET升高。在Ⅳ组,用卡托普利后40min,TPR下降,T值升高;手术使血流动力学指标回降,不影响其它指标。组织原位杂交示,NOS mRNA在Ⅰ组高度表达,Ⅱ组和Ⅳ组次之,Ⅲ组最低。结论:卡托普利能预防胃大部切除术引起的左室舒缩障碍和冠脉内皮功能障碍。     

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.     

Pharmacokinetics of the angiotensin converting enzyme inhibitor benazepril.HCl (CGS 14 824 A) in healthy volunteers after single and repeated administration

The pharmacokinetics of the new angiotensin converting enzyme (ACE) inhibitor benazepril.HCl were evaluated in healthy male volunteers. The single dose kinetics were established from data of 62 subjects receiving an oral 10 mg dose of the drug. The steady state kinetics were investigated in 15 subjects after once-daily oral doses of 5, 10 or 20 mg. The compound is a prodrug which, on absorption, is hydrolysed to the pharmacologically active metabolite benazeprilat. Thus, plasma concentrations and urinary excretion of parent compound and active metabolite were determined. Benazepril.HCl was rapidly absorbed (tmax = 0.5 h) and rapidly eliminated from plasma (t1/2 = 0.6 h). Only trace amounts were excreted unchanged in urine. The drug was rapidly metabolized to benazeprilat (tmax = 1.5 h). The elimination of the metabolite from plasma was biphasic. About 80 per cent of benazeprilat formed was eliminated within 24 h (t 1/2 = 2.7 h), whereas the terminal phase (t1/2 = 22.3 h) controlled a minor amount of elimination. About 17 per cent of dose was excreted in the 24-h urine as benazeprilat. The drug disposition did not change during repeated oral dosing and only small accumulation of the metabolite occurred. The accumulation ratio was 1.20 for AUC and 1.24 for urinary excretion. The effective half-life for accumulation was estimated at about 10-11 h. The comparison with other ACE inhibitors showed similarities but also marked differences with respect to the drug kinetics and excretion.     

Benazepril, an angiotensin converting enzyme inhibitor: drug interaction with salbutamol and bronchial response to histamine in normal subjects

Aims To investigate the effect of the angiotensin converting enzyme inhibitor, benazepril, on pulmonary function.
Methods We investigated the influence of benazepril, on lung function and the interaction with inhaled salbutamol (0.1 to 6.6  mg) and histamine (0.03 to 30.69  g  l⁻¹ ) in normal subjects. Benazepril 20  mg, salbutamol 8  mg, propranolol 160  mg, and placebo were given orally once daily over 10 days.
Results On day 8, there was no difference in the area under the salbutamol dose-response curves between benazepril, placebo and oral salbutamol ( P >0.05), propranolol shifted the curves to the right ( P <0.05). On day 10, histamine challenge resulted in following P D ₃₅sGaw values (geometric mean and 95% CI): with placebo 1.02 (0.95–1.09)  g  l⁻¹ , benazepril 1.04 (0.99–1.08), salbutamol 1.19 (1.13–1.25), propranolol 0.57 (0.50–0.65).
Conclusions Benazepril had no influence on baseline lung function, caused no interaction with inhaled salbutamol and the bronchial response to histamine was similar to placebo. However, our findings in normal subjects cannot be extrapolated automatically to asthmatics.     

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.     

血管紧张素转换酶抑制剂影响自发性高血压大鼠肾功能的机制

目的研究长期应用（4wk）卡托普利（30mg·kg-1）、依那普利（20mg·kg-1）和福辛普利（20mg·kg-1）3种血管紧张素转换酶抑制剂（ACEI）对自发性高血压大鼠（SHR）肾功能的影响以及与肾素-血管紧张素-醛固酮系统（RAA）、激肽释放酶-激肽系统（K-K）及前列腺素系统（PGS）的可能关系。方法测定血清及尿中的肌酐以计算肾小球滤过率、用放免法测定上述系统中有关活性物质在血浆、肾脏及尿中的浓度。结果3种ACEI均显著地降低SHR的血压。依那普利及福辛普利处理后SHR肌酐清除率分别为（370±112）及（380±110）ml·d-1，高于未处理SHR的滤过率（260±110，P＜0.05）。SHR用依那普利或福辛普利处理后血浆肾素活性及血管紧张素系Ⅰ（ATⅠ）浓度分别为（41±38）、（17±7）nmol·L-1·h-1及（12±8）、（14±10）nmol·L-1。肾脏肾素活性及ATⅠ浓度分别为（146±27）、（139±31）nmol·g-1蛋白·h-1及（85±25）、（95±23）nmol·g-1蛋白，均高于未处理组（P＜0.05）。SHR尿醛固酮排泄量在用卡托普利或依那普利处理后分别为（0.9±0.7）及（0.9±0.6）nmol·d-1，降至正常大鼠的水平，且低于未处理SHR（P＜0.05）。结论RAA在ACEI改善肾脏功能作用中起主要作用，而K-K及PGs不起重要作用。     

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.     

The acute haemodynamic effects of quinapril,a new non-sulfhydryl angiotensin converting enzyme inhibitor,in patients with severe congestive cardiac failure

Summary This study investigates the acute haemodynamic effects of Quinapril (CI-906) a new non-sulphydryl angiotensin converting enzyme inhibitor in 15 patients with refractory congestive cardiac failure. There were 14 males and 1 female mean age 59.5 years.After administration of Quinapril there was a significant reduction in mean arterial pressure (MAP) from 93.1 to 79 mmHg, systemic vascular resistance (SVR) from 1887 to 1349 dyn s cm^–5 and PCW from 27.3 to 15.3 mmHg. This was accompanied by an increase in CO from 3.7 to 4.7 l/min, cardiac index (CI) from 1.97 to 2.5 l/min/m² and Stroke volume index from 21.1 to 28.7 ml/m². There was no significant change in heart rate (HR), right atrial pressure (RAP), or pulmonary vascular resistance.The peak effect on pulmonary capillary wedge pressure (PCW) and cardiac output (CO) occurred at 75–120 min after Quinapril administration. The maximum effect on mean arterial pressure (MAP) occurred slightly later at 120–150 min. SVR and CI exhibited 2 periods of peak effects, at 90 and 180 min. This time course is very similar to that observed in studies on the acute effects of Captopril.The significant improvement in haemodynamic measurements acutely, following administration of Quinapril 5 mg orally, suggests that this drug is worthy of further study in the management of patients with refractory congestive cardiac failure, in particular its long term effects.     

新型血管紧张素转换酶抑制剂的临床应用

本文综述培哚普利、雷米普利、贝那普利、喹那普利、福辛普利等新型血管紧张素转换酶抑制剂的药物动力学特点，以及在高血压、充血性心力衰竭的临床近况、与卡托普利比较，它们大多半衰期长、作用持久、服用方便（每日１次），不良反应相似但发生率略低。预期在今后心血管疾病治疗中将发挥重要作用。