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 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.     

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。     

血管紧张素转换酶抑制剂治疗慢性充血性心力衰竭有效剂量探讨

目的探讨不同剂量血管紧张素转换酶抑制剂（ACEI）卡托普利治疗慢性充血性心力衰竭（CHF）疗效。方法CHF患者56例，随机分为卡托普利高剂量组n=28，150mg／d，低剂量组n=28，25mg／d，疗程24周。观察治疗前后两组临床症状、超声心动图心功能指标并记录不良反应发生情况。结果高剂量组总有效率89．3％，明显优于低剂量组60．7％（P〈0．01），左心室功能指标每搏量（SV）、心排出量（CO）、射血分数（EF）、左室短轴缩短率（FS）治疗后与治疗前比较，高剂量组有显著改善（P〈0．01），低剂量组变化不大（P〉0．05）。结论大剂量（目标剂量）ACEI较小剂量更有效改善心功能。     

Dose-finding study of imidapril,a novel angiotensin converting enzyme inhibitor,in patients with stable chronic heart failure

Objective: To study the haemodynamic profile and tolerability of imidapril, a new long-acting ACE inhibitor, and to investigate the effect of inhibition of circulating ACE on blood pressure in patients with stable chronic heart failure. Methods: Twenty-four patients with stable, chronic heart failure (New York Heart Association (NYHA) functional Class II–III) were randomised to receive either 2.5 mg or 5 mg imidapril. Other vasodilators were withheld for ≥ 5 half-lives. Blood pressure and ACE activity were carefully monitored for 24 h after dosing. Results: Both 2.5 mg and 5 mg imidapril decreased systolic blood pressure, while diastolic blood pressure fell only after 5 mg imidapril. The two doses produced a significant and similar inhibition of circulating (serum) ACE. No serious adverse effects were observed, although symptomatic hypotension occurred in 1 patient (5 mg). The decrease in blood pressure was not related to baseline ACE activity, serum sodium or serum creatinine concentration. Conclusions: Imidapril significantly lowered systolic blood pressure and was well tolerated. The difference in the first dose response to the two doses with respect to diastolic blood pressure suggests that this haemodynamic effect of ACE-inhibition is not related to inhibition of circulating ACE. Received: 21 April 1995/Accepted in revised form: 15 December 1995     

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.     

血管紧张肽转换酶抑制剂对高血压病人心脏和大动脉的影响

目的 :评价血管紧张肽转换酶 (ACE)抑制剂对原发性高血压病人心脏和大动脉结构和功能的影响。方法 :应用二维超声、超声心动图及自动脉搏波传导速度 (PWV)测定仪观察 16例采用ACE抑制剂培哚普利治疗 (4mg ,po ,qd ;4wk后若血压 >18.6 / 12 .0kPa ,加服吲哒帕胺 2 .5mg ,po ,qd)的原发性高血压病人心脏、大动脉结构和功能的改变 ,分别在治疗前和治疗 12wk后进行上述检测。结果 :收缩压、脉压、颈动脉 股动脉PWV、颈总动脉内膜 中层厚度和左室后壁厚度在 12wk培哚普利治疗后显著降低 [分别为 (2 0 .4±s 1.4 )kPavs (18.0± 1.2 )kPa ,(7.5± 1.1)kPavs (6 .9± 1.2 )kPa ,(10 .5± 1.3)m·s- 1vs (8.6± 1.0 )m·s- 1,(0 .71± 0 .14 )mmvs (0 .5 9± 0 .14 )mm ,(10 .5± 1.0 )mmvs (9.8± 1.0 )mm ,P <0 .0 1或P <0 .0 5 ];颈总动脉横断面顺应性、容积扩张性在治疗前后无显著性差异(P >0 .0 5 )。结论 :培哚普利对心血管系统的影响不仅仅是与血压降低有关 ,药物引起动脉平滑肌松驰 ,对全身和局部肾素 血管紧张肽系统的抑制能有效地改善高血压导致的心脏、血管结构和功能的改变。     

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.     

Pharmacokinetics of temocapril hydrochloride,a novel angiotensin converting enzyme inhibitor,in renal insufficiency

Summary The pharmacokinetics of temocapril hydrochloride, a novel prodrug-type angiotensin-I converting enzyme (ACE) inhibitor, has been studied in patients with mild (Group II) to severe (Group III) renal insufficiency in comparison with subjects with normal renal function (Group I).The pharmacokinetic parameters of the active diacid metabolite, including C_max, AUC and half-life (t_1/2), showed only slight changes between the three groups: AUC (0–) was significantly larger in Group III than Group I, and t1/2 tended to be prolonged in Group III, but the change was not significant.The urinary recovery of the diacid was significantly decreased in Group III. (Group I, 28.1 %, Group II, 21.6 %, Group III, 12.8 %). Compared with other ACE inhibitors, which are mainly excreted through the kidney, the plasma concentration of the active diacid metabolite was hardly influenced by renal function. It was speculated that lowering of the dose of temocapril might be recommended only in patients with severe renal insufficiency.     

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。     

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.     

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.     

血管紧张素转换酶抑制剂治疗阿尔茨海默病的效果

目的观察血管紧张素转换酶抑制剂(ACEI)治疗阿尔茨海默病(AD)痴呆患者的精神行为症状、认知功能损害的效果。方法 52例AD痴呆患者口服盐酸卡托普利治疗12周,采用神经精神科问卷(NPI)评定患者的精神行为症状变化,采用简易智能状态检查量表评定患者的认知功能变化。结果治疗12周后,除情感淡漠外,NPI各项因子得分显著下降(P<0.05),NPI总分下降81.47%(P<0.05);照顾者的苦恼程度也随着患者精神行为症状的改善而降低;治疗前后患者的认知功能无显著性差异(P>0.05)。结论盐酸卡托普利可以明显改善AD痴呆患者的精神行为症状,但对患者的认知功能损害无明显疗效。     

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。     

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.     

培哚普利对慢性缺氧高二氧化碳大鼠肺血管重建的影响

目的 探讨培哚普利对常压慢性缺氧高二氧化碳性肺动脉高压及肺血管重建的影响。方法 47只SD大鼠随机分为：对照组（A）、缺氧高二氧化碳处理4wk组（B1）、培哚普利治疗4wk组（B2）、缺氧高二氧化碳处理8wk组（C1）、培哚普利治疗8wk组（C2)。采用常压低氧高二氧化碳肺动脉高压大鼠模型,观察肺动脉平均压（mPAP),血浆血管紧张素Ⅱ（AngⅡ） 及肺小血管平滑肌外膜、内膜超微结构的变化,以及培哚普利对以上变化的影响。结果 缺氧高二氧化碳使mPAP,AngⅡ上升,超微结构发生变化,培哚普利治疗4wk组mPAP,AngⅡ下降,平滑肌超微结构病变减轻。培哚普利治疗8wk组,平滑肌超微结构病变与对照组相似。结论 提示缺氧高二氧化碳使肺血管重建,且与AngⅡ有关;培哚普利能在一定程度上能减轻肺血管重建。     

Effects of direct cedrol inhalation into the lower airway on autonomic nervous activity in totally laryngectomized subjects

Aims

Previous studies reported that Cedrol (odorant) inhalation (CI) induced changes in autonomic balance and baroreceptor sensitivity (BRS) in both healthy subjects and anosmic patients. This suggests that Cedrol may act on the lower airway, and that the pulmonary system may exert an inhibitory influence on the cardiovascular system.

Method

To test the above possibility, vaporized Cedrol (64.0 ± 7.7 10⁻⁹m) or blank air was directly inhaled through the lower airway from a hole in the trachea, but not through the upper airway, using totally laryngectomized subjects. During the experiment, ECG, systolic (SBP) and diastolic (DBP) blood pressures were measured. Sympathetic and parasympathetic nervous activity was estimated by spectral analyses of variability in these parameters (heart rate variability (HRV), SBP variability (SBPV) and DBP variability (DBPV)). BRS was computed from transfer gain between SBP and the R-R interval of the ECG.

Results

SBP and DBP significantly decreased during CI, although there were no significant differences in HR and respiratory rate. BRS significantly increased during CI. The low frequency components of SBPV and DBPV (indices for sympathetic activity) significantly decreased during CI, while high frequency components of HRV (an index for parasympathetic activity) significantly increased.

Conclusions

The present experiment using totally laryngectomized patients replicated the similar results in healthy subjects who inhaled Cedrol through the nose, suppression of sympathetic outflow and increase in parasympathetic outflow. These results demonstrated that Cedrol acts on the lower airway and pulmonary system, and suggest a new target for drug therapy of hypertension.

What is already known about this subject

• Relationships between smell sensation and autonomic changes have been studied extensively.
• However, the possibility that odorants may also act on the lung and lower airway remains unknown.

What this study adds

• The present results provide the first evidence that the lung and lower airway exert an inhibitory influence on the cardiovascular system in response to Cedrol (odorant) in the air under physiological conditions.

     

AngⅡ受体阻断剂与ACEI对肾性高血压大鼠血以及血浆和组织AngⅡ含量变化的影响

目的明确血管紧张素转换酶抑制剂(ACEI)卡托普利与血管紧张素Ⅱ(AngⅡ)受体阻断剂洛沙坦二类药物的药效和作用特点。方法本实验采用①离体血管环微量生物反应测定法检测AngⅡ引起的血管收缩反应;②建立两肾一夹型高血压大鼠模型;利用颈动脉插管法和鼠尾测压计检测血压,观测急性与慢性血压的变化;③用放射免疫法检测高血压大鼠血浆与肾组织中的AngⅡ含量。结果①离体血管环实验:AngⅡ能引起剂量依赖性的血管收缩反应,卡托普利(0.1 mg/kg)对低剂量AngⅡ收缩反应有轻度的抑制效应;随着外源性AngⅡ量增多,其抑制血管收缩作用明显减弱。同样条件下洛沙坦却能完全抑制AngⅡ所引起的血管收缩反应。②在体急性降压实验:最大有效剂量的卡托普利使模型鼠的平均动脉压由(18.4±3.9)kPa降为(8.7±1.2)kPa,降压幅度达到9.6 kPa,之后给洛沙坦最大降压有效剂量(2 mg/kg),血压未再下降;改变给药顺序,平均动脉压由(16.8±1.1)kPa降为(11.4±2.4)kPa,降压幅度为5.30 kPa,然后给最大有效降压剂量的卡托普利,血压持续降为(9.3±1.8)kPa,幅度达2.12 kPa,差异具有明显的统计学意义(P<0.05)。③慢性降压实验:高血压大鼠模型给予实验因素干预后,卡托普利组平均动脉压由(18.9±2.5)kPa降为(11.8±1.6)kPa,洛沙坦平均动脉压由(19.7±2.4)kPa降为(11.7±2.0)kPa,降压幅度分别为7.19 kPa和7.93 kPa,与对照组比较差异无统计学意义。④放射免疫实验:血浆中AngⅡ含量卡托普利组为(376±72)ng/L,明显低于对照组的(526±77)ng/L,而洛沙坦组为(1 036±159)ng/L,明显高于对照组(P<0.01),二者差异具有统计学意义。肾组织中AngⅡ含量,卡托普利组(392±81)pg/g,较对照组的(431±80)pg/g降低8.9%,洛沙坦组为(294±86)pg/g,较对照组降低32.4%(P<0.05)。结论①洛沙坦是通过阻断AngⅡ受体而发挥作用,而卡托普利只能够减少内源性AngⅡ的生成,离体状态下药效弱于洛沙坦。②急性在体实验卡托普利的最大降压效应强于洛沙坦;慢性在体实验二者药效差异无统计学意义。③长期作用下,肾组织的AngⅡ水平对调节血管张力起主要的作用,血浆中AngⅡ辅助起作用。     

Renal excretion of an angiotensin I converting enzyme inhibitor (SA-446) in dogs

Summary The renal excretory mechanism of an orally active inhibitor of angiotensin converting enzyme (SA-446) was examined in anesthetized dogs. Parenteral administration of this compound resulted in production of constant levels of about 2 mg/l in the plasma (P_SA) and the urine concentration was 726±200 mg/l, a level significantly higher than that in the plasma. Renal clearance of SA-446 (C_SA) was 2.24±0.34 ml/g·min and was significantly higher than GFR. The clearance ratio (C_SA/GFR) of over 1.0 was indicative of a net tubular secretion. Administration of probenecid resulted in a significant rise in P_SA and in a significant decrease in urinary excretion but with no change in the plasma protein binding ratio. C_SA decreased significantly from 2.24±0.34 to 0.71±0.14 ml/g·min. The inhibotory action of SA-446 (0.02 mg/kg, i.v.) on the pressor response to angiotensin I disappeared at about 50 min, this action being maintained for about 2 h in the probenecid pretreated dog.Since probenecid is a competitive inhibitor of organic anion secretory transport, our results show the net tubular secretion of SA-446, via organic anion transport systems. Prolongation of the action of SA-446, as induced by probenecid may be due to the increase of plasma concentration, by the inhibition of tubular secretion.     

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。