Mechanisms of ranolazine pretreatment in preventing ventricular tachyarrhythmias in diabetic db/db mice with acute regional ischemia–reperfusion injury
Chung‐Chuan Chou, Hui‐Ling Lee, Gwo‐Jyh Chang, Hung-Ta Wo, Tzung‐Hai Yen, Ming‐Shien Wen, Yen Chu, Hao-Tien Liu, Po‐Cheng Chang
Abstract
Abstract Studies have demonstrated that diabetic ( db/db ) mice have increased susceptibility to myocardial ischemia–reperfusion (IR) injury and ventricular tachyarrhythmias (VA). We aimed to investigate the antiarrhythmic and molecular mechanisms of ranolazine in db/db mouse hearts with acute IR injury. Ranolazine was administered for 1 week before coronary artery ligation. Diabetic db/db and control db/ + mice were divided into ranolazine-given and -nongiven groups. IR model was created by 15-min left coronary artery ligation and 10-min reperfusion. In vivo electrophysiological studies showed that the severity of VA inducibility was higher in db/db mice than control ( db/ +) mice. Ranolazine suppressed the VA inducibility and severity. Optical mapping studies in Langendorff-perfused hearts showed that ranolazine significantly shortened action potential duration, Ca i transient duration, Ca i decay time, ameliorated conduction inhomogeneity, and suppressed arrhythmogenic alternans induction. Western blotting studies showed that the expression of pThr 17 -phospholamban, calsequestrin 2 and voltage-gated sodium channel in the IR zone was significantly downregulated in db/db mice, which was ameliorated with ranolazine pretreatment and might play a role in the anti-arrhythmic actions of ranolazine in db/db mouse hearts with IR injury.