PRECONDITIONING PROTECTS ISCHEMIC RABBIT HEART BY PROTEIN-KINASE-C ACTIVATION

Myocardial protection in the rabbit induced by ischemic preconditionin g is thought to be adenosine receptor linked, but the signaling pathwa y responsible for the protection has yet to be identified. This study tests whether protein kinase C could be involved. Either of two inhibi tors of protein kinase C, staurosporine (50 mu g/kg) or polymyxin B (2 4 mg/kg), were administered to rabbits subjected to 30 min regional my ocardial ischemia followed by 180 min reperfusion. Half of the rabbits were preconditioned while the other half served as nonpreconditioned controls. Nonpreconditioned hearts without drug or treated with stauro sporine or polymyxin B resulted in 37.8 +/- 3.1, 40.5 +/- 2.8, and 42. 0 +/- 7.0% infarction of the risk zone, respectively. Preconditioning Limited infarct size to 7.3 +/- 2.7%. Both inhibitors blocked protecti on in preconditioned hearts with 36.2 +/- 2.7 and 40.9 +/- 2.5% of the risk zone infarcted, respectively. Activation of protein kinase C wit h 4 beta-phorbol 12-myristate 13-acetate (PMA) or with 1-oleyl-2-acety l glycerol (GAG) mimicked preconditioning in buffer-perfused hearts. P MA (0.01 nmol/min) or OAG (10 nmol/min) for 5 min was followed by 10 m in of washout. Infarct size after 30 min regional ischemia was limited in the PMA and OAG groups (6.4 +/- 1.4 and 11.7 +/- 3.3 vs. 28.0 +/- 4.5% in untreated controls) and was equipotent with ischemic precondit ioning (11.8 +/- 2.2%). Polymyxin B also blocked protection from ische mic preconditioning in the isolated heart (33.0 +/- 5.0%). Because pro tein kinase C activity is required for the preconditioned heart to be protected and because pretreatment with protein kinase C activators mi mic preconditioning, we conclude that protein kinase C is an important step in the mechanism of preconditioning.