Anti-arrhythmic effect of verapamil is accompanied by preservation of cx43 protein in rat heart.
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.
Department of Cardiology, Chengdu Medical College, Chengdu, PR China.
Peng
P
Zhou
Shu-Miao
SM
Zhang
Qiu-Lin
QL
Wang
Qi
Q
Wu
Mai
M
Chen
Jian-Ming
JM
Pei
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000009:adverse effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D018031:Connexin 43 / Q000378:metabolism*; D004195:Disease Models, Animal; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D014700:Verapamil / Q000008:administration & dosage / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D018031:Connexin 43; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D014700:Verapamil; D002118:Calcium