Modulation of Adenosine Effects in Attenuation of Ischemia and Reperfusion Injury in Rat Heart

Abstract

We investigated whether xanthine oxidase-derived superoxide radical generation could be modified by interfering with adenosine transport and metabolism in reducing myocardial injury during post-ischemic reperfusion. Isolated rat hearts perfused at constant pressure were subjected to 20 min of pretreatment with test agents, followed by 40 min global ischemia and 30 min reperfusion with or without test agents. In hearts treated with adenosine deaminase inhibitor, erythro 9-(2-hydroxy-3-nonyl) adenine (EHNA), alone or together with a selective nucleoside transport blocker, p-nitrobenzylthioinosine (NBMPR), the accumulated amount of O−2· was significantly reduced [10.2±0.97, 11.6±2.4, 8.1±0.51, respectively,v31.6±2.1 (s.e.) nmol/wet g/30 min in ischemic control,P<0.01]. A positive correlation between O−2· and inosine release was observed in the initial 5 min of reperfusion in hearts treated with either EHNA or NBMPR (r=0.475,P<0.05). Furthermore, the accumulated amount of LDH release showed positive correlation with that of O−2· among the same groups (r=0.474,P<0.05). Both EHNA and NBMPR had the cardioprotective effect on the recovery of left ventricular end-diastolic pressure (LVEDP), ATP repletion, and build up of endogenous adenosine. This study suggests that : (1) adenosine metabolism can be manipulated towards the formation of O −2· during reperfusion, and it has an important bearing on the cardiac recovery of ischemic myocardium, (2) the generation of O−2· is related to only inosine release during initial reperfusion.