McCabe Christopher, Hicks Martin N, Kane Kathleen A, Wainwright Cherry L
Department of Physiology & Pharmacology, University of Strathclyde, Glasgow, UK.
Br J Pharmacol. 2005 Sep;146(1):118-28. doi: 10.1038/sj.bjp.0706304.
The aims of this study were to determine if endothelin-1 (ET-1) under normal and ischaemic conditions exhibits a direct arrhythmogenic effect that is independent of its ability to cause coronary vasoconstriction, and to determine the contribution of the ET(A) and ET(B) receptor subtype. ET(A/B) (with ET-1) and ET(A) (ET-1 in the presence of BQ-788) receptor activation resulted in a significant reduction in both epi- and endocardial monophasic action potential duration (MAPD(90)). ET(A) receptor activation reduced both epi- and endocardial effective refractory period (ERP). This MAPD(90) and ERP shortening were associated with a reduction in coronary flow, myocardial contractility and induction of ventricular fibrillation (VF) during ERP measurement. The ET(B) agonist sarafotoxin (S6c) had no marked, or concentration-dependent, effect on MAPD(90), ERP, myocardial contractility or induction of arrhythmias. Neither ET-1 nor S6c, given prior to coronary artery occlusion, significantly changed the ischaemia-induced dispersion of MAPD(90), ERP or the % incidence of VF. In conclusion, neither ET(A) nor ET(B) receptor stimulation has a direct arrhythmogenic effect in isolated rabbit hearts under normal or ischaemic conditions. The ET-1-induced arrhythmogenic effect observed in nonischaemic hearts is likely to be the result of the associated coronary vasoconstriction caused by ET(A) receptor stimulation resulting in myocardial ischaemia.
本研究的目的是确定在正常和缺血条件下，内皮素-1（ET-1）是否表现出独立于其引起冠状动脉血管收缩能力的直接致心律失常作用，并确定ET(A)和ET(B)受体亚型的作用。ET(A/B)（与ET-1一起）和ET(A)（在BQ-788存在下的ET-1）受体激活导致心外膜和心内膜单相动作电位时程（MAPD(90)）均显著缩短。ET(A)受体激活降低了心外膜和心内膜的有效不应期（ERP）。这种MAPD(90)和ERP的缩短与冠状动脉血流减少、心肌收缩力降低以及ERP测量期间室颤（VF）的诱发有关。ET(B)激动剂沙拉新（S6c）对MAPD(90)、ERP、心肌收缩力或心律失常的诱发没有明显的或浓度依赖性的影响。在冠状动脉闭塞前给予ET-1或S6c，均未显著改变缺血诱导的MAPD(90)、ERP离散度或VF发生率。总之，在正常或缺血条件下，ET(A)和ET(B)受体刺激在离体兔心中均无直接致心律失常作用。在非缺血心脏中观察到的ET-1诱导的致心律失常作用可能是ET(A)受体刺激导致冠状动脉血管收缩进而引起心肌缺血的结果。
