扎考必利对哇巴因诱发的成年大鼠心律失常的抑制作用

Inhibitory effect of zacopride on ouabain-induced arrhythmias in adult rats

目的:观察内向整流钾通道激动剂扎考必利(zacopride)对哇巴因(ouabain)诱发的成年大鼠心律失常的影响,并探讨其电生理机制。方法:利用ouabain建立成年大鼠离体和在体心律失常模型,观察zacopride对各类心律失常的作用。应用全细胞膜片钳技术,观察zacopride对大鼠单个心室肌细胞内向整流钾电流(I_(K1))、静息膜电位(RMP)及延迟后除极(DADs)的影响。结果:浓度为1μmol/L的zacopride使ouabain诱发的离体心脏期前收缩个数、室速和室颤持续时间及发生率均显著降低(P<0.05)。在麻醉大鼠,15μg/kg的zacopride使ouabain诱发的期前收缩个数、室速和室颤持续时间及发生率均显著降低(P<0.05)。Ouabain使I_(K1)明显减小(P<0.05),而0.1~10μmol/L zacopride可部分恢复甚至完全逆转ouabain对I_(K1)的抑制作用,其中1μmol/L为最大效应浓度。Ouabain使RMP减小(P<0.05),应用zacopride(0.1~10μmol/L)后,RMP呈不同程度地增大,zacopride在1μmol/L时达最大效应浓度,使RMP增大至接近正常水平。1μmol/L的zacopride可有效抑制ouabain诱发的成年大鼠心室肌细胞DADs,使其发生率由91.67%下降至12.50%(P<0.05);在灌流液中加入1μmol/L BaCl_2后,DADs再次出现。结论:内向整流钾通道激动剂zacopride对ouabain诱发的成年大鼠室性心律失常具有明显抑制作用,其机制与zacopride适度增强I_(K1)、使RMP负值增大并抑制DADs有关。

AIM:To investigate the effect of zacopride,an inward rectifier potassium channel agonist,on ouabain-induced arrhythmias in adult rats,and to explore the underlying electrophysiological mechanism.METHODS:Usingouabain to establish in vitro and in vivo arrhythmic rat m odels,the effects of zacopride on ouabain-induced arrhythmias wereobserved.The technique of whole-cell patch clamp was used to observe the effects of zacopride on inward rectifier potassiumcurrent(/Ki),resting membrane potential(R M P)and delayed afterdepolarizations(D A D s)in single rat ventricular myocyte.RESULTS:Zacopride at1jjimol/L significantly reduced total num ber of premature ventricular b e ats,and the durationand incidence of ventricular tachycardia and ventricular fibrillation induced by ouabain in rat hearts in vitro(P<0.05).In anesthetized rats,zacopride at15jjig/kg significantly reduced total num ber of premature ventricular b eats,andthe duration and incidence of ventricular tachycardia and ventricular fibrillation induced by ouabain(P<0.05)./K1wassignificantly inhibited by ouabain(P<0.05),which was partially and even completely reversed by zacopride at0.1?10|jimol/L.RMP value was significantly reduced by ouabain(P<0.05),and then increased to different levels after treatment with zacopride(0.1?10jjim o l/L).Zacopride at1jjimol/L showed its maximal effect and RMP was restored to normallevel.Moreover,zacopride at1jjimol/L m arkedly suppressed ouabain-induced DADs in single rat ventricular myocyte.The incidence of DADs decreased from91.67%to12.50%after zacopride was applied(P<0.05),and this effect was abolishedby1jjimol/L BaCl2.CONCLUSION:Inward rectifier potassium channel agonist zacopride significantly inhibitsouabain-induced ventricular arrhythmias in adult rats.The m echanism is related to increased RMP level and inhibition ofDADs by activation of/K1channel.