Eckardt L, Kirchhof P, Mönnig G, Breithardt G, Borggrefe M, Haverkamp W
Hospital of the Westfälische Wilhelms-University, Department of Cardiology and Angiology and Institute for Arteriosclerosis Research, Münster, Germany.
J Cardiovasc Pharmacol. 2000 Dec;36(6):711-21. doi: 10.1097/00005344-200012000-00005.
The exact mechanism of mechano-electrical feedback and stretch-induced arrhythmias is unknown, but the role of stretch-activated ion channels and specific calcium channels has been proposed. The aim of the present study was to test the hypothesis that stretch-activated ion channels and not calcium channels contribute to stretch-related alterations of repolarization and that these effects can be neutralized by stretch-activated channel block. We studied the interaction of acute ventricular dilatation and the stretch-activated channel blocker streptomycin and the specific calcium channel blocker verapamil in an isolated retrogradely perfused rabbit heart model in which the left ventricular size is modified by abruptly changing the volume of a fluid-filled balloon placed in the left ventricle. Acute ventricular dilatation led to a rate-dependent decrease in repolarization. The mean effective refractory period (ERP) and monophasic action potential duration (MAP90) for cycle lengths between 300 and 1,000 ms decreased from 174.2+/-9 ms and 178.9+/-7 ms to 161.6+/-11 ms and 169.7+/-5 ms, respectively. Streptomycin (80 microM) inhibited this stretch-related shortening of repolarization (ERP: 175.4+/-8 ms; MAP90: 179.7+/-8 ms, p < 0.05) but had almost no effect on already dilated ventricles. Counteraction of the observed electrophysiologic changes could only be achieved by increasing the streptomycin concentration to 200 microM. Streptomycin nearly completely suppressed stretch-related ectopic ventricular complexes. In contrast, verapamil (1 microM) had no effect on stretch-related changes in repolarization and stretch-induced arrhythmias. The present study indirectly implicates stretch-activated ion channels in the genesis of stretch-related changes in repolarization and arrhythmias. The electrophysiologic changes after ventricular dilatation to a degree that increases left ventricular pressure in a clinically relevant range can be influenced by the stretch-activated channel blocker streptomycin but not by specific calcium channel block. This may have clinically important implications for the development of new antiarrhythmic drugs.
机械电反馈和牵张诱发心律失常的确切机制尚不清楚，但已有人提出牵张激活离子通道和特定钙通道的作用。本研究的目的是检验以下假设：牵张激活离子通道而非钙通道导致牵张相关的复极化改变，且这些效应可通过阻断牵张激活通道来消除。我们在一个离体逆行灌注兔心模型中研究了急性心室扩张与牵张激活通道阻滞剂链霉素以及特定钙通道阻滞剂维拉帕米之间的相互作用，在该模型中，通过突然改变置于左心室内的充液球囊的体积来改变左心室大小。急性心室扩张导致复极化呈心率依赖性降低。在300至1000毫秒的心动周期长度下，平均有效不应期（ERP）和单相动作电位时程（MAP90）分别从174.2±9毫秒和178.9±7毫秒降至161.6±11毫秒和169.7±5毫秒。链霉素（80微摩尔）抑制了这种牵张相关的复极化缩短（ERP：175.4±8毫秒；MAP90：179.7±8毫秒，p<0.05），但对已经扩张的心室几乎没有影响。只有将链霉素浓度提高到200微摩尔才能抵消观察到的电生理变化。链霉素几乎完全抑制了牵张相关的室性异位复合波。相比之下，维拉帕米（1微摩尔）对牵张相关的复极化变化和牵张诱发的心律失常没有影响。本研究间接表明牵张激活离子通道与牵张相关的复极化变化和心律失常的发生有关。在临床相关范围内，心室扩张至增加左心室压力程度后的电生理变化可受牵张激活通道阻滞剂链霉素影响，但不受特定钙通道阻滞剂影响。这可能对新型抗心律失常药物的研发具有重要临床意义。
