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Abstract
The present study was to test the hypothesis that anti-arrhythmic properties of verapamil may be accompanied by preserving connexin43 (Cx43) protein via calcium influx inhibition. In an in vivo study, myocardial ischemic arrhythmia was induced by occlusion of the left anterior descending (LAD) coronary artery for 45 min in Sprague-Dawley rats. Verapamil, a calcium channel antagonist, was injected i.v. into a femoral vein prior to ischemia. Effects of verapamil on arrhythmias induced by Bay K8644 (a calcium channel agonist) were also determined. In an ex vivo study, the isolated heart underwent an initial 10 min of baseline normal perfusion and was subjected to high calcium perfusion in the absence or presence of verapamil. Cardiac arrhythmia was measured by electrocardiogram (ECG) and Cx43 protein was determined by immunohistochemistry and western blotting. Administration of verapamil prior to myocardial ischemia significantly reduced the incidence of ventricular arrhythmias and total arrhythmia scores, with the reductions in heat rate, mean arterial pressure and left ventricular systolic pressure. Verapamil also inhibited arrhythmias induced by Bay K8644 and high calcium perfusion. Effect of verapamil on ischemic arrhythmia scores was abolished by heptanol, a Cx43 protein uncoupler and Gap 26, a Cx43 channels inhibitor. Immunohistochemistry data showed that ischemia-induced redistribution and reduced immunostaining of Cx43 were prevented by verapamil. In addition, diminished expression of Cx43 protein determined by western blotting was observed following myocardial ischemia in vivo or following high calcium perfusion ex vivo and was preserved after verapamil administration. Our data suggest that verapamil may confer an anti-arrhythmic effect via calcium influx inhibition, inhibition of oxygen consumption and accompanied by preservation of Cx43 protein.
Highlights
Ischemic heart disease-induced ventricular tachyarrhythmia is the main cause of sudden cardiac death [1,2]
Effect of Verapamil on Ischemia-induced Arrhythmias In order to ascertain the anti-arrhythmic property of verapamil, SD rats were subjected to 45 min of ischemia
This is based on the following observations: 1) myocardial ischemia and high concentration of extracellular Ca2+ may trigger intracellular calcium overload, leading to decrease of Cx43 protein, which favors the occurrence of cardiac arrhythmias and 2) anti-arrhythmic effects of verapamil were abolished by heptanol, a Cx43 uncoupler, or Gap 26, a Cx43 channels inhibitor, and accompanied by protection of Cx43 protein against ischemic insults via inhibiting L-type calcium channels. 3) verapamil reduced heart rate, ventricular contractility, and blood pressure, it should exhibit anti-arrhythmic effects through inhibition of oxygen consumption
Summary
Ischemic heart disease-induced ventricular tachyarrhythmia is the main cause of sudden cardiac death [1,2]. It is well documented that myocardial ischemia may lead to intracellular calcium overload, resulting in cardiac arrhythmias. Calcium channel blocking by calcium channel antagonists such as verapamil may prevent cardiac arrhythmias. It has been demonstrated that calcium overload may induce uncoupling of connexin (Cx43), which contributes to the occurrence of cardiac arrhythmia [4,5,6]. No reports in the literature have documented the effect of calcium channel blockage by verapamil on Cx43 protein; study on Cx43, a new therapeutic target against cardiac arrhythmias, may provide new insight for the understanding of calcium channel blockage. Cx43-deficient mice have been demonstrated to exhibit accelerated onset and enhanced incidence of ventricular arrhythmias induced by ischemia [6]. Cx43 may serve as a promising target in the treatment of cardiac arrhythmias
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