Role of Intracellular Ca 2+ in Activation of Protein Kinase C During Ischemic Preconditioning

Abstract

Background Activation of protein kinase C plays an important role in ischemic preconditioning. Given that protein kinase C is activated by an increase in the intracellular Ca 2+ concentration ([Ca 2+ ] i ) and that myocardial ischemia and reperfusion increase [Ca 2+ ] i , the effect of transient exposures to Ca 2+ on infarct size and the effect of administration of EGTA during ischemic and α 1 -adrenoceptor–mediated preconditioning on the limitation of infarct size were investigated in the canine heart. Methods and Results In open-chest dogs, 5 minutes after the completion of either three 5-minute infusions of CaCl 2 or four 5-minute infusions of the α 1 -adrenoceptor agonist methoxamine into the coronary artery, the coronary arteries were occluded for 90 minutes; this occlusion was followed by a 6-hour reperfusion in both the Ca 2+ preconditioning and methoxamine groups. Infarct sizes in the Ca 2+ preconditioning (15.8±2.3%) and methoxamine (10.1±2.2%) groups were significantly ( P <.01) smaller than in the control group (42.5±2.9%), and administration of either an inhibitor of protein kinase C (GF109203X) or an inhibitor of ecto-5′-nucleotidase (α,β-methyleneadenosine 5′-diphosphate) reduced the infarct size–limiting effect of Ca 2+ preconditioning. Administration of EGTA during ischemic or α 1 -adrenoceptor–mediated preconditioning inhibited both the infarct size–limiting effect and the activation of protein kinase C and ecto-5′-nucleotidase induced by these procedures. Conclusions [Ca 2+ ] i during ischemic and α 1 -adrenoceptor–mediated preconditioning plays an important role in the infarct size–limiting effect of these procedures by activating protein kinase C and ecto-5′-nucleotidase in the canine heart.