SELECTIVE ACTIVATION OF ADENOSINE A(3) RECEPTORS WITH -6-(3-CHLOROBENZYL)5'-N-METHYLCARBOXAMIDOADENOSINE (CB-MECA) PROVIDES CARDIOPROTECTION VIA K-ATP CHANNEL ACTIVATION

Objective: The aim of this study was to characterize the adenosine A, receptor agonist, N-6-( 3-chlorobenzyl)-5'-N-methylcarboxamidoadenosin e (CB-MECA), evaluate its ability to reduce myocardial ischemia/reperf usion injury and determine the role of K-ATP-channel activation in A(3 ) receptor-mediated cardioprotection. Methods: Binding affinities and adenylate cyclase inhibition were examined in CHO cells expressing rab bit recombinant adenosine A(1) or A(3) receptors. Infarct size (normal ized for area-at-risk; % IA/AAR) was measured in buffer-perfused rabbi t hearts exposed to 30-min regional ischemia and 120 min of reperfusio n. Results: CB-MECA was 100-fold selective for A(3) vs. A(1) receptors (A(3) K-i: 1 nM; A(1) K-i: 105 nM). Five-min perfusion with CB-MECA b efore ischemia/reperfusion elicited a concentration-dependent reductio n in infarct size (EC50: 0.3 nM). The CB-MECA-dependent cardioprotecti on (control: 58+/-2; CB-MECA: 21+/-3% IA/AAR) was unchanged by an A(1) -selective concentration of the antagonist, BWA1433, but was completel y prevented (P<0.05) by a nonselective (A(1)/A(3)) concentration (55+/ -6% IA/AAR). The K-ATP channel inhibitors, glibenclamide and 5-HD, had no effect on control infarct size, yet significantly (P<0.05) blunted the CB-MECA-dependent cardioprotection (glibenclamide: 49+/-6; 5-HD: 58+/-4% IA/AAR). Conclusions: CB-MECA is a novel 100-fold A(3) recepto r-selective agonist which should prove useful for elucidating A(3)-dep endent mechanisms in the rabbit heart. Selective stimulation of adenos ine A(3) receptors with CB-MECA reduces myocardial ischemia/reperfusio n injury via a mechanism which involves activation of K-ATP channels. (C) 1998 Elsevier Science B.V. All rights reserved.