A physiological role of the adenosine A(3) receptor: Sustained cardioprotection

Adenosine released during cardiac ischemia exerts a potent, protective effect in the heart. A newly recognized adenosine receptor, the A(3) subtype, is expressed on the cardiac ventricular cell, and its activation protects the ventricular heart cell against injury during a subsequent exposure to ischemia. A cultured chicken ventricular myocyte model was used to investigate the cardioprotective role of a novel adenosine A(3) receptor. The protection mediated by prior activation of A(3) receptors exhibits a significantly longer duration than that produced by activation of the adenosine A(1) receptor. Prior exposure of the myocytes to brief ischemia also protected them against injury sustained during a subsequent exposure to prolonged ischemia. The adenosine A(3) receptor-selective antagonist 3-ethyl 5-benzyl-2-methyl-6-phenyl-4-phenylethynyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS1191) caused a biphasic inhibition of the protective effect of the brief ischemia. The concomitant presence of the A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) converted the MRS1191-induced dose inhibition curve to a monophasic one. The combined presence of both antagonists abolished the protective effect induced by the brief ischemia. Thus, activation of both A(1) and A(3) receptors is required to mediate the cardioprotective effect of the brief ischemia. Cardiac atrial cells lack native A(3) receptors and exhibit a shorter duration of cardioprotection than do ventricular cells. Transfection of atrial cells with cDNA encoding the human adenosine A(3) receptor causes a sustained A(3) agonist-mediated cardioprotection. The study indicates that cardiac adenosine A(3) receptor mediates a sustained cardioprotective function and represents a new cardiac therapeutic target.