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(Circulation. 1997;96:1257-1265.)
© 1997 American Heart Association, Inc.

Articles

Role of Intracellular Ca²⁺ in Activation of Protein Kinase C During Ischemic Preconditioning

Koichi Node, MD; Masafumi Kitakaze, MD; Hiroshi Sato, MD; Tetsuo Minamino, MD; Kazuo Komamura, MD; Yoshiro Shinozaki, BE; Hidezo Mori, MD; ; Masatsugu Hori, MD

From the First Department of Medicine (K.N., M.K., H.S., T.M., K.K., M.H.), Osaka University School of Medicine, Osaka, and the Department of Physiology (Y.S., H.M.), Tokai University, Isehara, Japan.

Correspondence to Masafumi Kitakaze, MD, PhD, First Department of Medicine, Osaka University School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565, Japan. E-mail Kitakaze{at}medone.med.osaka-u.ac.jp

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 Ca²⁺ concentration ([Ca²⁺]_i) and that myocardial ischemia and reperfusion increase [Ca²⁺]_i, the effect of transient exposures to Ca²⁺ on infarct size and the effect of administration of EGTA during ischemic and 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 CaCl₂ or four 5-minute infusions of the 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 Ca²⁺ preconditioning and methoxamine groups. Infarct sizes in the Ca²⁺ 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 (,ß-methyleneadenosine 5'-diphosphate) reduced the infarct size–limiting effect of Ca²⁺ preconditioning. Administration of EGTA during ischemic or 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 [Ca²⁺]_i during ischemic and 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.

Key Words: adenosine • calcium • myocardial infarction • pathology • receptors, adrenergic, alpha

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