Xie Lai-Hua, Sato Daisuke, Garfinkel Alan, Qu Zhilin, Weiss James N
Cardiovascular Research Laboratory, Department of Medicine (Cardiology), David Geffen School of Medicine at the University of California, Los Angeles, California 90095, USA.
Biophys J. 2008 Sep 15;95(6):3100-10. doi: 10.1529/biophysj.108.130955. Epub 2008 Jun 6.
Beat-to-beat alternation in the cardiac intracellular Ca (Ca(i)) transient can drive action potential (AP) duration alternans, creating a highly arrhythmogenic substrate. Although a steep dependence of fractional sarcoplasmic reticulum (SR) Ca release on SR Ca load has been shown experimentally to promote Ca(i) alternans, theoretical studies predict that other factors are also important. Here we present an iterated map analysis of the coordinated effects of SR Ca release, uptake, and leak on the onset of Ca(i) alternans. Predictions were compared to numerical simulations using a physiologically realistic AP model as well as to AP clamp experiments in isolated patch-clamped rabbit ventricular myocytes exposed to 1), the Ca channel agonist BayK8644 (100 nM) to increase SR Ca load and release fraction, 2), overexpression of an adenoviral SERCA2a construct to increase SR Ca uptake, and 3), low-dose FK506 (20 microM) or ryanodine (1 microM) to increase SR Ca leak. Our findings show that SR Ca release, uptake, and leak all have independent direct effects that promote (release and leak) or suppress (uptake) Ca(i) alternans. However, since each factor affects the other by altering SR Ca load, the net balance of their direct and indirect effects determines whether they promote or suppress alternans. Thus, BayK8644 promotes, whereas Ad-SERCA2a overexpression, ryanodine, and FK506 suppress, Ca(i) alternans under AP clamp conditions.
心脏细胞内钙离子（Ca(i)）瞬变的逐搏交替可驱动动作电位（AP）时程交替，从而形成高度致心律失常的基质。尽管实验表明肌浆网（SR）钙离子释放分数对SR钙离子负荷有强烈依赖性，可促进Ca(i)交替，但理论研究预测其他因素也很重要。在此，我们对SR钙离子释放、摄取和漏出对Ca(i)交替起始的协同作用进行了迭代映射分析。将预测结果与使用生理逼真的AP模型进行的数值模拟以及在分离的膜片钳记录的兔心室肌细胞中进行的AP钳实验进行了比较，这些细胞分别暴露于1）钙离子通道激动剂BayK8644（100 nM）以增加SR钙离子负荷和释放分数，2）腺病毒SERCA2a构建体的过表达以增加SR钙离子摄取，以及3）低剂量FK506（20 microM）或ryanodine（1 microM）以增加SR钙离子漏出。我们的研究结果表明，SR钙离子释放、摄取和漏出都有独立的直接作用，可促进（释放和漏出）或抑制（摄取）Ca(i)交替。然而，由于每个因素通过改变SR钙离子负荷来影响其他因素，它们直接和间接作用的净平衡决定了它们是促进还是抑制交替。因此，在AP钳条件下，BayK8644促进Ca(i)交替，而腺病毒SERCA2a过表达、ryanodine和FK506则抑制Ca(i)交替。
