METABOLIC AND ANTIOXIDANT EFFECTS OF R(+ -)-N-6-(2-PHENYLISOPROPYL)-ADENOSINE FOLLOWING REGIONAL ISCHEMIA AND REPERFUSION IN CANINE MYOCARDIUM/

Recent studies have indicated that activation of A(1)/A(2)-receptors m ay mediate metabolic adaptation of the heart to ischemia/reperfusion s tress. This study tests whether pretreatment with A(1)-selective agoni st R(-)-N-6-(2-phenylisopropyl) adenosine (R-PIA) might mimic effects of a brief period of coronary occlusion (ischemic preconditioning, IP) on energy metabolism and hydroxyl radical (OH.) formation in canine m yocardium following subsequent prolonged ischemia and reperfusion. Ana esthetized dogs were randomized to a control group subjected to 40-min occlusion of a diagonal branch of left anterior descending coronary a rtery (LAD) followed by 1-h reperfusion, or a preconditioned group (PC ) in which the same period of sustained ischemia and reperfusion was p receded by a single cycle of IP (5-min occlusion of the same LAD branc h and 10-min reperfusion), or to PIA group in which R-PIA infusion int o the same branch of LAD (0.4 mu g/kg per min during 5 min) was follow ed by 10 min of perfusion prior to sustained ischemia-reperfusion. Pre treatment with R-PIA similarly to IP reduced lactate (Lac), creatine ( Cr) and inorganic phosphate (P-i) release from myocytes into the inter stitial fluid during sustained ischemia compared to these indices in c ontrol. By the end of reperfusion, both TP and R-PIA infusion enhanced recovery of myocardial. ATP and phosphocreatine (PCr) and attenuated the total creatine (Sigma Cr = PCr + Cr) loss, an index of cell membra ne damage. A(1)-receptor activation by R-PIA, as IP, led to a signific ant reduction in OH. radical generation following reperfusion assessed by a spin trap 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO) using cardiac microdialysis. R-PIA pretreatment did not affect systemic and cardiac hemodynamic parameters. We conclude that (1) adaptive mechanisms of I P involve A(1)-receptor activation that contributes to the overall met abolic response and (2) R-PIA acts as a useful preconditioning-mimetic and anti-ischemic agent in dogs. (C) 1997 Elsevier Science B.V.