光学对映体CK - 4000(S)和CK - 4001(R)对除颤及增强电击诱导的动作电位时程延长的影响。

Effects of optical enantiomers CK-4000(S) and CK-4001(R) on defibrillation and enhancement of shock-induced extension of action potential duration.

作者信息

Beatch G N, Dickenson D R, Tang A S

机构信息

Division of Cardiology, University of Ottawa Heart Institute, University of Ottawa, Ontario, Canada.

出版信息

J Cardiovasc Electrophysiol. 1995 Sep;6(9):716-28. doi: 10.1111/j.1540-8167.1995.tb00448.x.

DOI:10.1111/j.1540-8167.1995.tb00448.x

PMID:8556192

Abstract

INTRODUCTION

Class III antiarrhythmics have been reported to lower defibrillation threshold (DFT); however, the mechanism(s) of this effect is unknown. Recent evidence suggests that DFT strength DC shocks may terminate reentrant arrhythmias through prolongation of action potential duration and refractory periods. Since Class III antiarrhythmic drugs prolong repolarization, we examined the hypothesis that these drugs enhance shock-induced action potential duration extension (APDE), which might contribute to lowering of DFT.

METHODS AND RESULTS

In order to investigate the specificity of drug effects on action potential repolarization following a shock, an optical enantiomer with mixed beta-blocking and Class III effects (CK-4000) and its enantiomer with "pure" Class III antiarrhythmic effects (CK-4001) were compared against placebo in a canine defibrillation model (n = 8 per group). At the 3 mg/kg dose, the enantiomers nonstereoselectively lowered DFT voltage by 19 +/- 15% (CK-4000, P < 0.05 compared to placebo) and 25 +/- 12% (CK-4001, P < 0.05 compared to placebo), indicating that Class III antiarrhythmic actions alone were sufficient for this effect. Similarly, CK-4000 and CK-4001 at 3 mg/kg enhanced APDE (P < 0.01 compared to placebo) by 20 +/- 11% and 24 +/- 17%, respectively. APDE prolongation significantly correlated with reduction in DFT voltage for both CK-4000 (r = -0.55, P < 0.03) and CK4001 (r = -0.63, P < 0.01). At 3 mg/kg, the enantiomers stereoselectively prolonged action potential duration (APD75) by an average of 37 +/- 14% (CK-4000, P < 0.001) and 23 +/- 14% (CK-4001, P < 0.001), and ventricular effective refractory period (VERP) by 38 +/- 15% (CK-4000, P < 0.01) and 27 +/- 13% (CK-4001, P < 0.05). Prolongations of APD75 and VERP did not correlate with reductions of DFT in individual dogs.

CONCLUSIONS

These results show that Class III antiarrhythmics and DFT strength shocks additively delay repolarization, which suggests that drug enhancement of APDE may contribute to their effects on DFT.

摘要

引言

据报道，Ⅲ类抗心律失常药物可降低除颤阈值（DFT）；然而，这种效应的机制尚不清楚。最近的证据表明，DFT强度的直流电休克可能通过延长动作电位持续时间和不应期来终止折返性心律失常。由于Ⅲ类抗心律失常药物可延长复极化，我们检验了这样一种假说，即这些药物可增强休克诱导的动作电位持续时间延长（APDE），这可能有助于降低DFT。

方法与结果

为了研究药物对休克后动作电位复极化影响的特异性，在犬除颤模型中（每组n = 8），将具有β受体阻滞和Ⅲ类混合效应的光学对映体（CK - 4000）及其具有“纯”Ⅲ类抗心律失常效应的对映体（CK - 4001）与安慰剂进行比较。在3mg/kg剂量下，这两种对映体非立体选择性地使DFT电压降低了19±15%（CK - 至000，与安慰剂相比P < 0.05）和25±12%（CK - 4001，与安慰剂相比P < 0.05），表明仅Ⅲ类抗心律失常作用就足以产生这种效应。同样，3mg/kg的CK - 4000和CK - 4001分别使APDE增强了20±11%和24±17%（与安慰剂相比P < 0.01）。CK - 4000（r = -0.55，P < 0.03）和CK4001（r = -0.63，P < 0.01）的APDE延长均与DFT电压降低显著相关。在3mg/kg时，这两种对映体立体选择性地使动作电位持续时间（APD75）平均延长了37±14%（CK - 4000，P < 0.001）和23±14%（CK - 4001，P < 0.001），使心室有效不应期（VERP）延长了38±15%（CK - 4000，P < 0.0）和27±13%（CK - 4001，P < 0.05）。APD75和VERP的延长与个体犬DFT的降低无关。