Anti-Arrhythmic Effect of Verapamil Is Accompanied by Preservation of Cx43 Protein in Rat Heart

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.

Connexin 43 reduces susceptibility to sympathetic atrial fibrillation

“…Lenaerts et al reported that oxidative stress is positively correlated with the occurrence of atrial fibrillation (35). Although it is not clear how oxidative stress initiates and maintains atrial fibrillation, one possible mechanism is associated with cx43 degradation in response to calcium overload in the cytoplasm resulting from calcium overflow from sarcoplasmic reticula caused by oxidative stress, which subsequently leads to arrhythmia (36). The results of cx43 silencing experiments also indicated that cx43 serves a protective role, maintaining normal signal transduction between cardiomyocytes and reducing susceptibility to atrial fibrillation in response to oxidative stress induced by sympathetic activation.…”

Adrenomedullin Induces Cardiac Lymphangiogenesis After Myocardial Infarction and Regulates Cardiac Edema Via Connexin 43

“…As previously published, treatment of hLECs with AM increased gap junction formation, while pre-treatment with carbenoxolone (CBX), a gap junction inhibitor abrogated gap junction formation (Online Figure V) 39, 44 . Interestingly, verapamil, a drug used to treat hypertension and arrhythmias through targeting voltage-gated calcium channels, has recently been shown to have beneficial cardiovascular effects by preserving Cx43 expression 45 . Treatment of hLECs with verapamil had a very similar effect to AM and showed significant increase in gap junction formation (Figure 4a,b).…”

“…However, it has also been shown to have indirect effects on the localization and stabilization of Cx43. By inhibiting calcium influx and preserving oxygen levels in the heart with verapamil, Cx43 is stabilized during injury resulting in beneficial anti-arrhythmic phenotypes 45 . We used hLECs to show that verapamil has a similarly positive effect on the lateralization of Cx43 in lymphatics as it does in cardiomyocytes.…”

Inhibition of gap junction composed of Cx43 prevents against acute kidney injury following liver transplantation

“…From the results we obtained, we speculated that the increase in Cx43 expression might play an important role in AKI following AOLT. To explore the hypothesis, we used heptanol, a well-known inhibitor of Cx43 without hepatotoxicity as shown by others 22 and our preliminary data (Supplementary Figs. 3, 4), to alter the function of GJ composed of Cx43 (Supplementary Fig.…”