Cardiovascular Research

Cardiovascular Research 1998 40(1):138-145; doi:10.1016/S0008-6363(98)00112-6
© 1998 by European Society of Cardiology

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Copyright © 1998, European Society of Cardiology

Selective activation of adenosine A₃ receptors with N⁶-(3-chlorobenzyl)-5'-N-methylcarboxamidoadenosine (CB-MECA) provides cardioprotection via K_ATP channel activation

W.Ross Tracey^a,*, William Magee^a, Hiroko Masamune^b, Joseph J. Oleynek^a and Roger J. Hill^a

^aDepartment of Cardiovascular and Metabolic Diseases, Central Research Division, Pfizer Inc., Groton, CT 06340, USA
^bDepartment of Medicinal Chemistry, Central Research Division, Pfizer Inc., Groton, CT 06340, USA

^* Corresponding author. Tel.: +1 (860) 441 1761; Fax: +1 (860) 441 5719; E-mail: w_ross_tracey@groton.pfizer.com

Objective: The aim of this study was to characterize the adenosine A₃ receptor agonist, N⁶-(3-chlorobenzyl)-5'-N-methylcarboxamidoadenosine (CB-MECA), evaluate its ability to reduce myocardial ischemia/reperfusion injury and determine the role of K_ATP-channel activation in A₃ receptor-mediated cardioprotection. Methods: Binding affinities and adenylate cyclase inhibition were examined in CHO cells expressing rabbit recombinant adenosine A₁ or A₃ receptors. Infarct size (normalized for area-at-risk;% IA/AAR) was measured in buffer-perfused rabbit hearts exposed to 30-min regional ischemia and 120 min of reperfusion. Results: CB-MECA was 100-fold selective for A₃ vs. A₁ receptors (A₃ K_i: 1 nM; A₁ K_i: 105 nM). Five-min perfusion with CB-MECA before ischemia/reperfusion elicited a concentration-dependent reduction in infarct size (EC₅₀: 0.3 nM). The CB-MECA-dependent cardioprotection (control: 58±2; CB-MECA: 21±3% IA/AAR) was unchanged by an A₁-selective concentration of the antagonist, BWA1433, but was completely prevented (P<0.05) by a nonselective (A₁/A₃) 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 A₃ receptor-selective agonist which should prove useful for elucidating A₃-dependent mechanisms in the rabbit heart. Selective stimulation of adenosine A₃ receptors with CB-MECA reduces myocardial ischemia/reperfusion injury via a mechanism which involves activation of K_ATP channels.

KEYWORDS Rabbit; Heart; Adenosine; Infarction; K_ATP channel; Preconditioning; Receptors; Reperfusion

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