THE CARDIOPROTECTIVE EFFECTS OF R-75231 AND LIDOFLAZINE ARE NOT CAUSED BY ADENOSINE A(1) RECEPTOR ACTIVATION

The goal of this study was to determine the cardioprotective profile f or the nucleoside transport inhibitor -bis(4-fluorophenyl)pentyl]-1-pi perazinylacetamide trihydrochloride-2,5 hydrate (R 75231) in isolated rat hearts and whether its protective effects are caused by adenosine Al activation. R 75231 increased time to contracture during global isc hemia in a concentration-dependent manner (EC(25) = 2.6 mu M) that was comparable to the structurally related compound lidoflazine (EC(25) = 1.2 mu M). R 75231 caused only modest improvements in reperfusion con tractile function, whereas it profoundly reduced LDH release. The card ioprotective effects of R 75231 were accompanied by preischemic negati ve inotropy with modest bradycardic effects. Adenosine also increased time to contracture, although it was not very potent (EC(25) > 300 mu M), and this effect was accompanied by significant preischemic bradyca rdia without measurable negative inotropic activity. Both the preische mia bradycardia and increase in ischemic time to contracture with aden osine were abolished completely by the Al blocker 8-cyclopentyl-1,3-di propylxanthine. The adenosine-induced increase in time to contracture was reversed partially by glybenclamide. Neither the pre- nor postisch emic effects of R 75231 were abolished by 8-cyclopentyl-1,3-dipropylxa nthine or glybenclamide, except for the preischemic bradycardia. Simil ar results were observed for lidoflazine. Thus, the cardioprotective e ffects of R 75231 are not mediated by adenosine A(1) receptor activato n and, thus, probably are not caused by its activity as a nucleoside t ransport inhibitor. It may be acting as a calcium antagonist in this m odel.