A physiological role of the adenosine A3 receptor: Sustained cardioprotection

• Published in: Proceedings of the National Academy of Sciences - PNAS 1998-06, Vol.95 (12), p.6995-6999
• Main Authors: Liang, B T, Jacobson, K A
• Format: Article
• Language: English
• Subjects: Adenosine - physiology; Anatomy & physiology; Animals; Biological Sciences; Cardiovascular disease; Chick Embryo; Dihydropyridines - pharmacology; Gene Transfer Techniques; Heart; Humans; Medical research; Myocardial Ischemia - physiopathology; Myocardial Ischemia - prevention & control; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Receptor, Adenosine A3; Receptors, Purinergic P1 - physiology; Ventricular Function; Xanthines - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.12.6995

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.