727-3 Regulation of Endogenous Adenosine Improves Myocardial Functional Recovery Following Ischemia/Reperfusion Injury

Adenosine (ADO) has been shown to be cardioprotective following ischemia/reperfusion injury, but its utility is limited by profound hemodynamic side-effects. Therefore, we studied the effects of a novel ADO regulating agent, GP531 (5-amino-l- β -D-(5-benzylamino-5-deoxy-ribofuranosyl) imidazole-4-carboxamide), on functional recovery following myocardial stunning in pigs. GP531 does not bind to ADO A 1 . A 2 . or A 3 receptors, but increases local endogenous ADO concentrations, Anesthetized pigs were treated with GP531 (l or 1O ll μ /kg/min, iv) or vehicle (saline) in the presence or absence of the ADO-receptor antagonist 8-sulfophenyltheophylline (8SPT, 83 μ g/kg/min, ic), and subjected to four 8 minute periods of regional ischemia (LAD occlusion) and reperfusion. Myocardial segment shortening (SS) was monitored throughout the stunning protocol and for 2 hours following the final occlusion. Results (SS. % of baseline, * p l 0.05 vs. saline. † p l 0.05 vs. corresponding dose of GP531 alone): Treatment Baseline Occlusion 4 Reperfusion 1 hr 2 hr Saline (n = 6) 100 –15 ± 4 15 ± 2 19 ± 2 GP531 (1, n = 5) 100 –10 ± 5 39 ± 8 * 38 ± 4 * GP531 (10, n = 6) 100 –11 ± 6 47 ± 3 * 57 ± 3 * 8SPT + GP531 (10, n = 4) 100 –19 ± 5 31 ± 6 *† 30 ± 4 *† * p l 0.05 vs. saline. † p l 0.05 vs, corresponding dose of GP531 alone GP531 improved functional recovery in stunned myocardium, and this was prevented by adenosine receptor blockade with 8SPT. GP531 did not affect baseline hemodynamics or myocardial function, confirming receptor binding studies indicating that it is not a direct ADO receptor agonist. We conclude that GP531 protects the myocardium from ischemic injury in anesthetized pigs primarily via regulation of endogenous adenosine.