Liang B T, Jacobson K A
Department of Medicine, Cardiovascular Division, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6995-9. 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 A3 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 A3 receptor. The protection mediated by prior activation of A3 receptors exhibits a significantly longer duration than that produced by activation of the adenosine A1 receptor. Prior exposure of the myocytes to brief ischemia also protected them against injury sustained during a subsequent exposure to prolonged ischemia. The adenosine A3 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 A1 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 A1 and A3 receptors is required to mediate the cardioprotective effect of the brief ischemia. Cardiac atrial cells lack native A3 receptors and exhibit a shorter duration of cardioprotection than do ventricular cells. Transfection of atrial cells with cDNA encoding the human adenosine A3 receptor causes a sustained A3 agonist-mediated cardioprotection. The study indicates that cardiac adenosine A3 receptor mediates a sustained cardioprotective function and represents a new cardiac therapeutic target.
心脏缺血期间释放的腺苷对心脏具有强大的保护作用。一种新发现的腺苷受体，即A3亚型，表达于心脏心室细胞上，其激活可保护心室心肌细胞在随后的缺血暴露中免受损伤。利用培养的鸡心室肌细胞模型来研究新型腺苷A3受体的心脏保护作用。由A3受体预先激活介导的保护作用持续时间明显长于腺苷A1受体激活所产生的保护作用持续时间。心肌细胞预先短暂暴露于缺血也能保护它们在随后长时间缺血暴露中免受损伤。腺苷A3受体选择性拮抗剂3-乙基5-苄基-2-甲基-6-苯基-4-苯乙炔基-1,4-(±)-二氢吡啶-3,5-二羧酸酯（MRS1191）对短暂缺血的保护作用产生双相抑制。A1受体拮抗剂8-环戊基-1,3-二丙基黄嘌呤（DPCPX）同时存在时，可将MRS1191诱导的剂量抑制曲线转变为单相曲线。两种拮抗剂同时存在可消除短暂缺血诱导的保护作用。因此，A1和A3受体的激活都是介导短暂缺血心脏保护作用所必需的。心脏心房细胞缺乏内源性A3受体，与心室细胞相比，其心脏保护作用持续时间较短。用编码人腺苷A3受体的cDNA转染心房细胞可导致A3激动剂介导的持续心脏保护作用。该研究表明，心脏腺苷A3受体介导持续的心脏保护功能，代表了一个新的心脏治疗靶点。
