Skip Navigation

Cardiovascular Research 1998 40(1):138-145; doi:10.1016/S0008-6363(98)00112-6
© 1998 by European Society of Cardiology
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Tracey, W.R.
Right arrow Articles by Hill, R. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tracey, W.R.
Right arrow Articles by Hill, R. J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 1998, European Society of Cardiology

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

W.Ross Traceya,*, William Mageea, Hiroko Masamuneb, Joseph J. Oleyneka and Roger J. Hilla

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 KATP-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 Ki: 1 nM; A1 Ki: 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 KATP 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 KATP channels.

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


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.