Adenosine receptor subtypes and cardioprotection

Brief ischemia prior to a sustained period of ischemia reduces myocardial i nfarct size, a phenomenon known as preconditioning. A cardiac ventricular m yocyte model has been developed to investigate the role and signaling mecha nism of adenosine receptor subtypes in cardiac preconditioning. A 5-min exp osure of cardiac myocytes to simulated ischemia, termed preconditioning isc hemia, prior to a subsequent 90-min period of ischemia protected them again st injury incurred during the 90-min ischemia. Preconditioning ischemia pre served ATP content, reduced percentage of cells killed, and decreased relea se of creatine kinase into the medium. Activation of the adenosine A(1) rec eptor with CCPA or the A(3) receptor with IB-MECA can replace preconditioni ng ischemia and mimic the protective effect of preconditioning ischemia. Bl ockade of the A(1) receptor with its selective antagonist DPCPX or of the A (3) receptor with the A(3) selective antagonist MRS1191 during the precondi tioning ischemia resulted in only a partial attenuation of the subsequent p rotection. Incubation with both DPCPX and MRS1191 or with the nonselective antagonist 8-SPT during the preconditioning ischemia completely abolished t he protective effect of preconditioning ischemia. The K-ATP channel opener pinacidil caused a large activation of the K-ATP channel current and was ab le to precondition the myocyte. The K-ATP channel antagonist glibenclamide blocked the cardioprotective effect of preconditioning ischemia when it was included during myocyte exposure to the preconditioning ischemia, indicati ng that K-ATP channel is a requisite effector in mediating preconditioning. A receptor-mediated stimulation of phospholipase C or phospholipase D,with consequent activation of protein kinase C and K-ATP channel, appears to be the signaling mechanism linking adenosine A(1) and A(3) receptors to the i nduction of preconditioning. A model of how ischemic preconditioning is tri ggered and mediated is proposed. Evidence is accumulating to support its va lidity. Drug Dev. Res. 45:394-401; 1998. (C) 1998 Wiley-Liss, Inc.