CARDIOPROTECTION WITH A NOVEL ADENOSINE REGULATING AGENT MEDIATED BY INTRAVASCULAR ADENOSINE

Adenosine is cardioprotective in models of myocardial stunning and inf arction, but the precise compartment within the heart in which adenosi ne elicits its cardioprotective effects has not been determined. The g oals of the present study were to (i) investigate the effects of a nov el adenosine regulating agent, GP531 amino-1-beta-D-(5-benzylamino-5-d eoxyribofuranosyl on posts ischemic myocardial function, and (ii) exam ine the contribution of endogenous adenosine in the intravascular and interstitial compartments in mediating the beneficial effects. Pigs we re instrumented for measurement of myocardial segment shortening, and for sampling of coronary venous blood and myocardial interstitial flui d for determination of adenosine concentration. Myocardial dysfunction was induced by 4 x 8 min coronary occlusions, and recovery of regiona l function was monitored for 2 h. In control pigs, function recovered to 24 +/- 2% of baseline after 2 h. Treatment with GP531 improved func tional recovery to 55 +/- 3%. GP531-mediated cardioprotection was prev ented by adenosine receptor blockade with 8-sulfophenyltheophylline (2 3 +/- 2%). GP531 did not affect basal adenosine levels, but caused a 2 -fold greater increase in vascular adenosine concentration with ischem ia (54.6 +/- 10.6 vs. 28.1 +/- 8.0 mu M in controls, P < 0.05). In con trast, the interstitial adenosine concentration was not significantly different in treated vs. untreated control pigs (9.4 +/- 3.9 vs. 15.0 +/- 1.3 mu M in controls). These data indicate that (1) GP531 improves recovery of myocardial function following ischemia-reperfusion injury via an adenosine receptor-dependent mechanism, and (2) the cardioprot ection is associated with increased intravascular, but not interstitia l, adenosine concentration during ischemia. Therefore, we conclude tha t cardioprotection elicited by GP531-enhanced endogenous adenosine is dependent on an intravascular site of action. (C) 1997 Elsevier Scienc e B.V.