title: Cardioprotection with a novel adenosine regulating agent mediated by intravascular adenosine.
abstract: Adenosine is cardioprotective in models of myocardial stunning and infarction, but the precise compartment within the heart in which adenosine elicits its cardioprotective effects has not been determined. The goals of the present study were to (i) investigate the effects of a novel adenosine regulating agent, GP531 (5-amino-1-beta-n-(5-benzylamino-5-deoxyribofuranosyl) imidazole-4-carboxamide), on post-ischemic myocardial function, and (ii) examine the contribution of endogenous adenosine in the intravascular and interstitial compartments in mediating the beneficial effects. Pigs were instrumented for measurement of myocardial segment shortening, and for sampling of coronary venous blood and myocardial interstitial fluid for determination of adenosine concentration. Myocardial dysfunction was induced by 4 x 8 min coronary occlusions, and recovery of regional function was monitored for 2 h. In control pigs, function recovered to 24 +/- 2% of baseline after 2 h. Treatment with GP531 improved functional recovery to 55 +/- 3%. GP531-mediated cardioprotection was prevented by adenosine receptor blockade with 8-sulfophenyltheophylline (23 +/- 2%). GP531 did not affect basal adenosine levels, but caused a 2-fold greater increase in vascular adenosine concentration with ischemia (54.6 +/- 10.6 vs. 28.1 +/- 8.0 microM in controls. P < 0.05). In contrast, the interstitial adenosine concentration was not significantly different in treated vs. untreated control pigs (9.4 +/- 3.9 vs. 15.0 +/- 1.8 microM 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 cardioprotection is associated with increased intravascular, but not interstitial, adenosine concentration during ischemia. Therefore, we conclude that cardioprotection elicited by GP531-enhanced endogenous adenosine is dependent on an intravascular site of action.
authors.affiliation: Department of Cardiovascular Pharmacology, Gensia, Inc., San Diego, CA 92121, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Kurz
authors.forename: D A
authors.initials: DA
authors.lastname: Bullough
authors.forename: C J
authors.initials: CJ
authors.lastname: Buggé
authors.forename: K M
authors.initials: KM
authors.lastname: Mullane
authors.forename: M A
authors.initials: MA
authors.lastname: Young
mesh_terms: D000241:Adenosine / Q000378:metabolism / Q000494:pharmacology*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003853:Deoxyribonucleosides / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D013552:Swine; D013556:Swine, Miniature
chemical_list: D002316:Cardiotonic Agents; D003853:Deoxyribonucleosides; C103214:GP 531; D000620:Aminoimidazole Carboxamide; D000241:Adenosine