THE OBLIGATE ROLE OF PROTEIN-KINASE-C IN MEDIATING CLINICALLY ACCESSIBLE CARDIAC PRECONDITIONING

Background. Cardiac preconditioning is an adaptation of cardiomyocytes that promotes tolerance to a subsequent ischemic insult. Adenosine re ceptor signaling is proposed as a mediator of preconditioning, but its mechanism of protection remains unknown. We hypothesized that protect ion against hypoxia-reoxygenation (H/R) injury could be conferred in a rat ventricle by adenosine-mediated protein kinase C (PKC) activation and that adenosine-mediated cardioprotection could be extended to hum an ventricular muscle. Methods, Isolated mt and human ventricular musc le (VM) strips were subjected to 30 minutes of hypoxia and 60 minutes of reoxygenation (H/R control). The VM was pretreated with 125 mu mol/ L adenosine, an adenosine antagonist ((p-Sulfophenyl) theophylline [SP T] 50 mu mol/L) and adenosine (adenosine + SPT), or with a PKC inhibit or (chelerythrine, 10 mu mol/L) and adenosine (adenosine + chelerythri ne) before H/R. Developed force (DF) and tissue creatine kinase (CK) a ctivity were assessed at end reoxygenation. Human trabeculae were obta ined from diseased explanted hearts at cardiac transplantation and wer e also subjected to H/R injury. Human VM was pretreated with adenosine (125 mu mol/L) before H/R injury. Results are expressed as mean +/- s tandard error of mean. Results. In the rat, adenosine pretreatment con ferred protection of DF against H/R injury (adenosine, 62 % +/- 6%; H/ R control, 21% +/- 2 %, p < 0.05). Adenosine + SPT or adenosine + chel erythrine eliminated the functional recovery conferred by adenosine. T his recovery of contractile function was associated with greater tissu e CK activity (adenosine, 415 +/- 40 units/gm; H/R control, 78 +/- 13 units/gm, p < 0.05). The protective effects of adenosine against H/R w ere present In the human ventricle and with recovery of DF in adenosin e (66% + 5%) and H/R control (24 % +/- 4 %), p < 0.05. Conclusions, Ad enosine, a clinically accessible agonist, induces protection against H /R injury through a PKC-mediated mechanism in the rat ventricle. Fu?th er, the protection conferred by adenosine against H/R extends to the h uman ventricle.