新型β-肾上腺素能和Ikr阻滞剂厄森替利德对心肌梗死愈合的清醒犬的抗纤颤疗效。

Antifibrillatory efficacy of ersentilide, a novel beta-adrenergic and Ikr blocker, in conscious dogs with a healed myocardial infarction.

作者信息

Adamson P B, Vanoli E, Hull S S, Foreman R D, Schwartz P J

机构信息

W.K. Warren Medical Research Institute, Oklahoma City, OK 73190, USA.

出版信息

Cardiovasc Res. 1998 Oct;40(1):56-63. doi: 10.1016/s0008-6363(98)00137-0.

DOI:10.1016/s0008-6363(98)00137-0

PMID:9876317

Abstract

OBJECTIVES

IKr blockade is ineffective in preventing ventricular fibrillation elicited by the interaction between acute myocardial ischemia and elevated sympathetic activity. This depends in part on the fact that adrenergic activation offsets more than 50% of the action potential prolonging effect of IKr blockade, and thus impairs its primary mechanism of action. This study examined the antifibrillatory effect of ersentilide (CK-3579), a novel antiarrhythmic agent which combines blockade of the rapid component of the delayed rectifier potassium channel (IKr) with relatively weak beta-adrenergic blockade, in a conscious canine model of lethal arrhythmias.

METHODS

Ersentilide was tested in 19 dogs with a healed myocardial infarction (MI) undergoing two minutes of circumflex artery occlusion (CAO) during sub-maximal treadmill exercise. Epicardial monophasic action potential duration was measured before and after ersentilide in 8 anesthetized open chest dogs at baseline and during stimulation of the left stellate ganglion at constant paced heart rate.

RESULTS

In the control tests 13 of the 19 dogs had ventricular fibrillation (VF) during the exercise and ischemia test, 6 did not. During a subsequent exercise test, ersentilide prevented VF in 85% (11 of 13) of the high risk animals and showed no proarrhythmic effects in the 6 dogs without arrhythmias in the initial test. Ersentilide lowered heart rate at all levels of exercise and during acute myocardial ischemia. The antifibrillatory effect was maintained in 3 of 4 dogs in which heart rate was kept at control levels by atrial pacing. Ersentilide prolonged left ventricular monophasic action potential duration by 30% (from 179 +/- 6 ms to 233 +/- 5 ms, p < 0.001) at a 360 ms cycle length and completely prevented its shortening during sympathetic stimulation.

CONCLUSIONS

The combination of IKr and weak beta-adrenergic blockade, using ersentilide, represents a very effective and safe antiarrhythmic intervention able to overcome the limitations present in drugs devoid of any antiadrenergic effect. Such a combination may be very useful in the management of post-myocardial infarction patients at high arrhythmic risk.

摘要

目的

IKr 阻滞剂在预防急性心肌缺血与交感神经活动增强相互作用引发的心室颤动方面无效。这部分取决于肾上腺素能激活抵消了超过 50%的 IKr 阻滞剂延长动作电位的作用，从而损害了其主要作用机制。本研究在清醒犬致死性心律失常模型中，考察了新型抗心律失常药物 ersentilide（CK - 3579）的抗纤颤作用，该药物兼具延迟整流钾通道快速成分（IKr）阻滞作用和相对较弱的β - 肾上腺素能阻滞作用。

方法

在 19 只患有陈旧性心肌梗死（MI）的犬中对 ersentilide 进行测试，这些犬在次极量跑步机运动期间接受两分钟的回旋支动脉闭塞（CAO）。在 8 只麻醉开胸犬中，于基线状态以及在恒定起搏心率下刺激左星状神经节期间，测量给予 ersentilide 前后的心外膜单相动作电位时程。

结果

在对照试验中，19 只犬中有 13 只在运动和缺血试验期间发生心室颤动（VF），6 只未发生。在随后的运动试验中，ersentilide 预防了 85%（13 只中的 11 只）高风险动物的 VF，并且在初始试验中无心律失常的 6 只犬中未显示促心律失常作用。Ersentilide 在所有运动水平以及急性心肌缺血期间均降低心率。在 4 只通过心房起搏将心率维持在对照水平的犬中，有 3 只维持了抗纤颤作用。在 360 ms 的周期长度下，ersentilide 使左心室单相动作电位时程延长了 30%（从 179±6 ms 延长至 233±5 ms，p < 0.001），并完全防止其在交感神经刺激期间缩短。