Preconditioning by mitochondrial ATP-sensitive potassium channel openers -An effective approach for improving the preservation of heart transplants

Background - Recent studies have implicated mitochondrial ATP-sensitive pot assium (K-ATP) channels in the cardioprotective effects of ischemic precond itioning. The present study used a model of prolonged cold heart storage to assess whether the mitochondrial K-ATP opener diazoxide could reproduce th e protection conferred by ischemic preconditioning. Methods and Results - Fifty-four isolated rat hearts were arrested with and stored in Celsior at 4 degrees C for 10 hours before a 2-hour reperfusion. They were divided into 5 groups. Group I hearts served as controls. In gro up 2, hearts were preconditioned by two 5-minute episodes of global ischemi a, each separated by 5 minutes of reperfusion before arrest. In group 3, he arts received a 15-minute infusion of the mitochondrial K-ATP opener diazox ide (30 mu mol/L) followed by 5 minutes of washout before arrest. In groups 4 and 5, hearts underwent a protocol similar to that used in groups 2 and 3, respectively, except that the preconditioning was preceded by a 10-minut e infusion of the mitochondrial K-ATP. Both ischemic and diazoxide precondi tioning provided a similar degree of cardioprotection demonstrated by a sig nificantly better preservation of left ventricular compliance, reduced leak age of creatine kinase, and smaller degree of myocardial edema compared wit h control hearts. These beneficial effects were abolished by 5-HD pretreatm ent. Postischemic left ventricular contractility and endothelium-dependent coronary response to 5-hydroxytryptamine and acetylcholine were not differe nt among groups. However, the endothelium-independent vasodilatory postisch emic response to papaverine was better preserved after ischemic and diazoxi de preconditioning than in the other groups. Conclusions - These data support the concept that the cardioprotective effe cts of ischemic preconditioning can be duplicated by a mitochondrial K-ATP opener and suggest that activation of these channels could be an effective means of improving the preservation of globally ischemic cold-stored hearts , as occurs during cardiac transplantation.