Infarct size reduction with the nucleoside transport inhibitor R-75231 in swine.

Abstract

Adenosine (Ado) has been reported to be cardioprotective in several models of myocardial ischemia. The nucleoside transport inhibitor R-75231 (R-75) has been reported to enhance local Ado concentrations and postischemic recovery of function, but little is known regarding its effects on myocardial infarct size. The purpose of the present study was to determine the effects of R-75 on infarct size and to measure myocardial regional Ado concentrations. Studies were conducted in pentobarbital-anesthetized swine undergoing 60 min of coronary artery occlusion and 2 h of reperfusion. Control pigs (n = 8) were compared with those receiving R-75 (0.1 mg/kg i.v.) 15 min before either occlusion (Pre R-75, n = 8) or reperfusion (Rep R-75, n = 8). Interstitial fluid (ISF) Ado, coronary venous Ado, and infarct size (% of the region at risk) were measured. In the Pre R-75 group, ISF Ado concentrations were significantly increased before and during ischemia, reaching a peak value of 71.8 +/- 8.6 microM (vs. 16.8 +/- 0.8 microM in control). ISF inosine and hypoxanthine concentrations were significantly reduced during ischemia in Pre R-75 animals. Infarct size was smaller in Pre R-75 compared with control (21.6 +/- 1.9 vs. 38.4 +/- 2.6%, P < 0.05). The Rep R-75 group had significantly elevated coronary venous Ado concentrations but no increases in ISF Ado or reduction in infarct size (33.5 +/- 3.5%). These data indicate that R-75 increases myocardial Ado and reduces infarct size when administered before coronary occlusion. The R-75-induced reduction in infarct size appears to be related to the augmentation of ISF Ado before ischemia rather than to increased plasma Ado during reperfusion.