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

Abstract

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.

• Authors: W R Tracey, W Magee, H Masamune, J J Oleynek, R J Hill
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 40 Issue 1 Pg. 138-45 (Oct 1998) ISSN: 0008-6363 [Print] England
• PMID: 9876326 (Publication Type: Journal Article)

Chemical References

• Anti-Arrhythmia Agents
• CB MECA
• Decanoic Acids
• Hydroxy Acids
• Hypoglycemic Agents
• Potassium Channels
• Receptor, Adenosine A3
• Receptors, Purinergic P1
• Xanthines
• Colforsin
• 5-hydroxydecanoic acid
• BW A1433U
• Cyclic AMP
• Adenylyl Cyclases
• Adenosine
• Glyburide

Topics

• Adenosine (analogs & derivatives, pharmacokinetics)
• Adenylyl Cyclases (metabolism)
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Binding, Competitive
• CHO Cells
• Colforsin (pharmacology)
• Cricetinae
• Cyclic AMP (metabolism)
• Decanoic Acids (pharmacology)
• Dose-Response Relationship, Drug
• Glyburide (pharmacology)
• Hydroxy Acids (pharmacology)
• Hypoglycemic Agents (pharmacology)
• Myocardial Reperfusion Injury (metabolism, pathology, prevention & control)
• Myocardium (metabolism, pathology)
• Perfusion
• Potassium Channels (drug effects, metabolism)
• Rabbits
• Receptor, Adenosine A3
• Receptors, Purinergic P1 (metabolism)
• Xanthines (pharmacology)