Casini Simona, Verkerk Arie O, van Borren Marcel M G J, van Ginneken Antoni C G, Veldkamp Marieke W, de Bakker Jacques M T, Tan Hanno L
Department of Clinical and Experimental Cardiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Meibergdreef 9, AZ 1105 Amsterdam, The Netherlands.
Cardiovasc Res. 2009 Jan 1;81(1):72-81. doi: 10.1093/cvr/cvn274. Epub 2008 Oct 1.
Cardiac voltage-gated sodium channels control action potential (AP) upstroke and cell excitability. Intracellular calcium (Ca(i)(2+)) regulates AP properties by modulating various ion channels. Whether Ca(i)(2+) modulates sodium channels in ventricular myocytes is unresolved. We studied whether Ca(i)(2+) modulates sodium channels in ventricular myocytes at Ca(i)(2+) concentrations ([Ca(i)(2+)]) present during the cardiac AP (0-500 nM), and how this modulation affects sodium channel properties in heart failure (HF), a condition in which Ca(i)(2+) homeostasis is disturbed.
Sodium current (I(Na)) and maximal AP upstroke velocity (dV/dt(max)), a measure of I(Na), were studied at 20 and 37 degrees C, respectively, in freshly isolated left ventricular myocytes of control and HF rabbits, using whole-cell patch-clamp methodology. [Ca(i)(2+)] was varied using different pipette solutions, the Ca(i)(2+) buffer BAPTA, and caffeine administration. Elevated [Ca(i)(2+)] reduced I(Na) density and dV/dt(max), but caused no I(Na) gating changes. Reductions in I(Na) density occurred simultaneously with increase in [Ca(i)(2+)], suggesting that these effects were due to permeation block. Accordingly, unitary sodium current amplitudes were reduced at higher [Ca(i)(2+)]. While I(Na) density and gating at fixed [Ca(i)(2+)] were not different between HF and control, reductions in dV/dt(max) upon increases in stimulation rate were larger in HF than in control; these differences were abolished by BAPTA.
Ca(i)(2+) exerts acute modulation of I(Na) density in ventricular myocytes, but does not modify I(Na) gating. These effects, occurring rapidly and in the [Ca(i)(2+)] range observed physiologically, may contribute to beat-to-beat regulation of cardiac excitability in health and disease.
心脏电压门控钠通道控制动作电位（AP）的上升支和细胞兴奋性。细胞内钙（Ca(i)(2+)）通过调节各种离子通道来调控AP特性。Ca(i)(2+)是否调节心室肌细胞中的钠通道尚未明确。我们研究了在心脏AP期间存在的Ca(i)(2+)浓度（[Ca(i)(2+)]）（0 - 500 nM）下，Ca(i)(2+)是否调节心室肌细胞中的钠通道，以及这种调节如何影响心力衰竭（HF）时的钠通道特性，心力衰竭是一种Ca(i)(2+)稳态受到干扰的疾病状态。
分别在20℃和37℃下，使用全细胞膜片钳技术，在对照和HF兔的新鲜分离左心室肌细胞中研究钠电流（I(Na)）和最大AP上升速度（dV/dt(max)，I(Na)的一种测量指标）。通过使用不同的移液管溶液、Ca(i)(2+)缓冲剂BAPTA和给予咖啡因来改变[Ca(i)(2+)]。升高的[Ca(i)(2+)]降低了I(Na)密度和dV/dt(max)，但未引起I(Na)门控变化。I(Na)密度的降低与[Ca(i)(2+)]的增加同时发生，表明这些效应是由于通透阻滞。因此，在较高的[Ca(i)(2+)]下，单通道钠电流幅度降低。虽然在固定的[Ca(i)(2+)]下，HF和对照之间的I(Na)密度和门控没有差异，但在HF中，刺激频率增加时dV/dt(max)的降低比对照中更大；这些差异被BAPTA消除。
Ca(i)(
