Antiarrhythmic efficacy of CPUY102122, a multiple ion channel blocker, on rabbits with ischemia/reperfusion injury

Background: The antiarrhythmic potential of a novel multichannel blocker CPUY102122 (CY22) was investigated in the present study. Methods: The effect of CY22 on rapid delayed rectifier potassium channel current (I-Kr) was studied using whole-cell patch clamp techniques in Chinese Hamster Ovary cells stably expressing human Ether-a-go-go-Related Gene. We further evaluated the antioxidant effects of CY22 and demonstrated the reversal of connexin down-regulation in the development of cardiac ventricular arrhythmias, which was produced using coronary ligation/reperfusion in rabbits. CY22 and Amiodarone were administered 30 min prior to the procedure. Next, electrocardiograms were recorded, protein expression of left ventricular Connexin43 (Cx43), non-phosphorylation-Cx43 (np-Cx43), Rac-1 and gp-91 [phox] were assayed using Western blot analysis, microstructural changes in the myocardium were observed and redox system activity was assayed. Results: CY22 inhibited I-Kr in a concentration-dependent manner with IC50 value of 2.8 +/- 0.8 mu mol/L. CY22 treatment significantly decreased T-wave amplitude and QTc arrhythmic scores and ameliorated the shape of the infarcted myocardium compared to the model group. CY22 decreased the serum levels of creatine kinase, lactate dehydrogenase, and myocardial levels of malondialdehyde, as well as increased superoxide dismutase activity. Cx43 expression in the left ventricle was significantly increased by CY22 treatment, which significantly decreased np-43 expression, Rac-1 activity and gp-91[phox] protein expression. Conclusions: These results indicated that CY22 has both antiarrhythmic and cardiovascular protective effects partly by blocking I-Kr the production of antioxidants and protection of Cx43. (C) 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.