卡托普利对正常及肥厚大鼠心室动作电位时程的延长作用：直接作用还是对局部血管紧张素转换酶的抑制作用？

Prolongation by captopril of action potential duration in the normal and hypertrophied rat ventricle: direct action or inhibition of the local angiotensin converting enzyme?

作者信息

Ribuot C, Cardinal R, Gouin L, Moreau P, Godin D, Vermeulen M, de Champlain J, Rochette L, Nadeau R

机构信息

Research Centre, Hôpital sur Sacré-Coeur, Montreal, Québec, Canada.

出版信息

Cardiovasc Res. 1994 Feb;28(2):221-7. doi: 10.1093/cvr/28.2.221.

DOI:10.1093/cvr/28.2.221

PMID:8143304

Abstract

OBJECTIVE

The aims were: (1) to study the acute effects of captopril on the action potential characteristics of ventricular fibres from the normal rat, (2) to compare the effects of captopril with those of perindoprilat, a non-thiol angiotensin I converting enzyme (ACE) inhibitor, (3) to determine the electrophysiological properties of the peptide substrates of converting enzyme, bradykinin and angiotensin I, and (4) to investigate whether the effects of captopril occurring in the healthy heart also occur in two models of ventricular hypertrophy.

METHODS

Action potentials were recorded with the standard glass microelectrode technique in right ventricular preparations excised from rat hearts and superfused under baseline conditions and with drug containing or peptide containing Tyrode solution. Ventricular hypertrophy was induced in response to hypertension (unilaterally nephrectomised, DOCA-salt model) or 4 week old left ventricular infarction.

RESULTS

In preparations from normal rat hearts, captopril increased action potential duration in a concentration dependent fashion [EC50 = 3.5 x 10(-8) M; maximum effect = 44(SEM 5.1)% prolongation at 10(-5) M for action potential duration at 90% repolarisation, APD90]. Perindoprilat similarly caused a dose dependent increase in action potential duration, but with 100 times greater potency [EC50 = 3.1 x 10(-10) M; maximum effect = 71(11)% prolongation at 10(-5) M for APD90]. SQ 14,534, a stereoisomer of captopril with one hundredth the ACE inhibitor potency, had no significant effect on action potential duration at 10(-5) M. Angiotensin I and bradykinin caused concentration dependent prolongation of action potential, but angiotensin II (10(-6) M) had no effect. Captopril (10(-5) M) had no significant effect in the hypertrophied right ventricle from DOCA-salt hypertensive rats, but significantly increased APD90 [39(4.9)%] in right ventricular preparations from rats with 4 week old anterior left ventricular infarction.

CONCLUSIONS

In the rat, captopril prolongs action potential duration, an effect possibly due to local accumulation of bradykinin and angiotensin I.

摘要

目的

本研究旨在：（1）研究卡托普利对正常大鼠心室肌纤维动作电位特性的急性影响；（2）比较卡托普利与非硫醇类血管紧张素I转换酶（ACE）抑制剂培哚普利拉的作用效果；（3）确定转换酶的肽类底物缓激肽和血管紧张素I的电生理特性；（4）研究卡托普利在健康心脏中的作用是否也出现在两种心室肥厚模型中。

方法

采用标准玻璃微电极技术，记录从大鼠心脏切除的右心室标本在基线条件下以及用含药或含肽的台氏液灌流时的动作电位。通过高血压（单侧肾切除，DOCA-盐模型）或4周龄左心室梗死诱导心室肥厚。

结果

在正常大鼠心脏的标本中，卡托普利以浓度依赖的方式增加动作电位时程[EC50 = 3.5×10⁻⁸ M；在10⁻⁵ M时，90%复极化时动作电位时程（APD90）的最大效应为延长44（标准误5.1）%]。培哚普利拉同样引起动作电位时程的剂量依赖性增加，但效力高100倍[EC50 = 3.1×10⁻¹⁰ M；在10⁻⁵ M时，APD90的最大效应为延长71（11）%]。卡托普利的立体异构体SQ 14,534，其ACE抑制效力仅为卡托普利的百分之一，在10⁻⁵ M时对动作电位时程无显著影响。血管紧张素I和缓激肽引起动作电位的浓度依赖性延长，但血管紧张素II（10⁻⁶ M）无作用。卡托普利（10⁻⁵ M）对DOCA-盐高血压大鼠肥厚的右心室无显著影响，但在4周龄左心室前壁梗死大鼠的右心室标本中显著增加了APD90[39（4.9）%]。