INVITRO AND INVIVO CHARACTERIZATION OF AN A1-SELECTIVE ADENOSINE AGONIST, RG14202

In this report, we demonstrate that the adenosine agonist N-5'-ethyl-N 6-(cyclopentyl) adenosine-5'-uronamide (RG14202) is a vasorelaxant in porcine coronary arterial rings (EC50 = 0.37 +/-0.054 muM; n = 19). Th is vasorelaxation (VR) occurs despite RG14202 being 275-fold selective for the rat brain Al receptor. VR in response to RG14202 was attenuat ed markedly by the nonselective adenosine antagonist CGS15943, whereas 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a highly selective Al ant agonist, had only a small inhibitory effect. In contrast, the potassiu m channel blocker glybenclamide attenuated RG1 4202-induced VR markedl y (85-fold), indicating that modulation of potassium channels is likel y involved. In carotid arterial rings, RG14202 was approximately 5 tim es less potent than in the coronary artery, suggesting that this compo und may be more selective for the coronary vasculature. In anesthetize d rats, i.v. administration of RG14202 caused a significant decrease i n mean arterial pressure only at the highest dose (3 mug/kg). In compa rison, heart rate was decreased dose-dependently with maximal changes at 3 mug/kg. Both the depressor and bradycardic responses could be ant agonized with CGS15943. RG14202 increased renal, but had no effect on mesenteric or hindquarter vascular resistance. Glybenclamide pretreatm ent (20 mg/kg) did not significantly alter the effects of RG14202 on h eart rate or regional vascular resistances; however, the depressor res ponse to RG1 4202 was attenuated. In anesthetized beagles, RG1 4202 si gnificantly reduced coronary vascular resistance, but not total periph eral resistance. In summary, RG14202 is a depressor agent that reduces heart rate/cardiac output, does not decrease peripheral vascular resi stance and significantly reduces coronary vascular resistance. In vitr o, RG14202 is a potent coronary vasorelaxant which exerts at least par t of its actions through modulation of potassium channels.