Inhibition Of K(V)7 Channels Protects The Rat Against Myocardial Ischemia And Reperfusion Injury

The voltage-gated K(V)7 (KCNQ) potassium channels are activated by ischemia and involved in hypoxic vasodilatation. We investigated the effect of K(V)7 channel modulation on cardiac ischemia and reperfusion injury and its interaction with cardioprotection by ischemic preconditioning (IPC). Reverse-transcription polymerase chain reaction revealed expression of K(V)7.1, K(V)7.4, and K(V)7.5 in the left anterior descending rat coronary artery and all K(V)7 subtypes (K(V)7.1-K(V)7.5) in the left and right ventricles of the heart. Isolated hearts were subjected to no-flow global ischemia and reperfusion with and without IPC. Infarct size was quantified by 2,3,5-triphenyltetrazolium chloride staining. Two blockers of K(V)7 channels, XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone] (10 mu M) and linopirdine (10 mu M), reduced infarct size and exerted additive infarct reduction to IPC. An opener of K(V)7 channels, flupirtine (10 mu M) abolished infarct size reduction by IPC. Hemodynamics were measured using a catheter inserted in the left ventricle and postischemic left ventricular recovery improved in accordance with reduction of infarct size and deteriorated with increased infarct size. XE991 (10 mu M) reduced coronary flow in the reperfusion phase and inhibited vasodilatation in isolated small branches of the left anterior descending coronary artery during both simulated ischemia and reoxygenation. K(V)7 channels are expressed in rat coronary arteries and myocardium. Inhibition of K(V)7 channels exerts cardioprotection and opening of K(V)7 channels abrogates cardioprotection by IPC. Although safety issues should be further addressed, our findings suggest a potential role for K(V)7 blockers in the treatment of ischemia-reperfusion injury.