氟伐他汀拮抗溶血磷脂酰胆碱致心律失常作用的机制研究

Inhibitory effect of fluvastatin on lysophosphatidylcholine-induced ventricular arrhythmias in rats

目的探讨降脂药氟伐他汀抑制外源性溶血磷脂酰胆碱(LPC)致心律失常作用的机理。方法 20只雄性SD大鼠,随机分为LPC组和氟伐他汀处理组,应用Langendorff装置行离体心脏灌注。LPC 5μmol/L灌注5 min后冲洗30 min;氟伐他汀组先灌注10μmol/L氟伐他汀30 min,然后灌注5μmol/L LPC 5 min。细胞膜电流测定部分:采用全细胞膜片钳技术,测定LPC对大鼠心室肌细胞膜电流的影响,并观察氟伐他汀的拮抗LPC的作用。结果 LPC可引起离体心脏严重的心律失常,以短阵室速和室颤常见,氟伐他汀可基本拮抗LPC的致心律失常作用;LPC可诱发心肌细胞的巨大非选择性阳离子电流(INSC),这一作用可被氟伐他汀显著抑制;LPC诱发的INSC亦可被小分子G蛋白Rho的抑制剂和Rho激酶抑制剂所拮抗。结论氟伐他汀通过抑制LPC诱发的非选择性阳离子电流来拮抗LPC的致心律失常作用,LPC的致心律失常作用与小分子G蛋白Rho/Rho激酶信号途径有关。

Objective To investigate the effect of fluvastatin on lysophosphatidylcholine（LPC）-induced ventricular arrhythmias and its mechanism.Methods Twenty male SD rats were randomly allocated into two equal groups,namely LPC treatment group and fluvastatin pretreatment group.Langendorff apparatus was used for cardiac perfusion ex vivo with 5 μmol/L LPC for 5 min followed by washing for 30 min in LPC treatment group,and in fluvastatin pretreatment group,a 30-min perfusion with 10 μmol/L fluvastatin was administered before LPC perfusion.The LPC-induced nonselective cation current（INSC） in the ventricular myocytes was recorded using the whole-cell voltage-clamp method.Results Fluvastatin significantly inhibited LPC-induced ventricular tachyarrhythmia/fibrillation and INSC.The small G-protein Rho inhibitor（C3） and Rho-kinase inhibitor（Y-27632） in the pipette solution also suppressed LPC-induced INSC.Conclusions Fluvastatin offers cardiac protection against LPC by inhibiting LPC-induced INSC.LPC induces fatal arrhythmia via a Rho/Rho-kinase-mediated pathway.