Ghais Nina S, Zhang Yanmin, Grace Andrew A, Huang Christopher L-H
Physiological Laboratory, University of Cambridge, UK.
Exp Physiol. 2009 Feb;94(2):240-54. doi: 10.1113/expphysiol.2008.044669. Epub 2008 Oct 31.
The experiments explored the extent to which alterations in L-type Ca(2+) channel-mediated Ca(2+) entry triggers Ca(2+)-mediated arrhythmogenesis in Langendorff-perfused murine hearts through use of the specific L-type Ca(2+) channel modulator FPL-64716 (FPL). Introduction of FPL (1 microm) resulted in a gradual development (>10 min) of diastolic electrical events and alternans in spontaneously beating hearts from which monophasic action potentials were recorded. In regularly paced hearts, they additionally led to non-sustained and sustained ventricular tachycardia (nsVT and sVT). Programmed electrical stimulation (PES) resulted in nsVT and sVT after 5-10 and >10 min perfusion, respectively. Pretreatments with nifedipine, diltiazem and cyclopiazonic acid abolished arrhythmogenic tendency induced by subsequent introduction of FPL, consistent with its dependence upon both extracellular Ca(2+) entry and the degree of filling of the sarcoplasmic reticular Ca(2+) store. Values for action potential duration at 90% repolarization when any of these agents were applied to FPL-treated hearts became indistinguishable from those shown by untreated control hearts, in contrast to earlier reports of their altering in long QT syndrome type 3 and hypokalaemic murine models for re-entrant arrhythmogenesis. These arrhythmic effects instead correlated with alterations in Ca(2+) homeostasis at the single-cell level found in investigations of the effects of both FPL and the same agents in regularly stimulated fluo-3 loaded myocytes. These findings are compatible with a prolonged extracellular Ca(2+) entry that potentially results in an intracellular Ca(2+) overload and produces the cardiac arrhythmogenecity following addition of FPL.
这些实验通过使用特异性L型Ca(2+)通道调节剂FPL-64716（FPL），探究了L型Ca(2+)通道介导的Ca(2+)内流改变在Langendorff灌注的小鼠心脏中引发Ca(2+)介导的心律失常的程度。引入FPL（1微摩尔）导致自发跳动心脏中舒张期电活动和交替现象逐渐发展（>10分钟），并记录到单相动作电位。在有规律起搏的心脏中，FPL还会导致非持续性和持续性室性心动过速（nsVT和sVT）。程序性电刺激（PES）在灌注5 - 10分钟和>10分钟后分别导致nsVT和sVT。用硝苯地平、地尔硫卓和环匹阿尼酸预处理可消除随后引入FPL所诱导的致心律失常倾向，这与其依赖细胞外Ca(2+)内流和肌浆网Ca(2+)储存的充盈程度一致。当将这些药物中的任何一种应用于FPL处理的心脏时，90%复极化时的动作电位持续时间值与未处理的对照心脏所显示的值没有区别，这与早期关于它们在3型长QT综合征和低钾血症小鼠折返性心律失常模型中改变的报道形成对比。相反，这些心律失常效应与在对FPL和相同药物对有规律刺激的fluo-3负载心肌细胞作用的研究中发现的单细胞水平Ca(2+)稳态改变相关。这些发现与细胞外Ca(2+)内流延长一致，这可能导致细胞内Ca(2+)过载，并在添加FPL后产生心脏致心律失常性。
