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The A_2a/A_2b receptor antagonist ZM-241385 blocks the cardioprotective effect of adenosine agonist pretreatment in in vivo rat myocardium

Department of Surgery, Division of Cardiothoracic Surgery, University of Kentucky College of Medicine, Lexington, Kentucky

Submitted 26 June 2006 ; accepted in final form 14 September 2006

There is increasing evidence for interactions among adenosine receptor subtypes in the brain and heart. The purpose of this study was to determine whether the adenosine A_2a receptor modulates the infarct size-reducing effect of preischemic administration of adenosine receptor agonists in intact rat myocardium. Adult male rats were submitted to in vivo regional myocardial ischemia (25 min) and 2 h reperfusion. Vehicle-treated rats were compared with rats pretreated with the A₁ agonist 2-chloro-N⁶-cyclopentyladenosine (CCPA, 10 µg/kg), the nonselective agonist 5'-N-ethylcarboxamidoadenosine (NECA, 10 µg/kg), or the A_2a agonist 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-methylcarboxamidoadenosine (CGS-21680, 20 µg/kg). Additional CCPA- and NECA-treated rats were pretreated with the A₁ antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 µg/kg), the A_2a/A_2b antagonist 4-(-2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a} {1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM-241385, 1.5 mg/kg) or the A₃ antagonist 3-propyl-6-ethyl-5[(ethylthio)carbonyl]-2-phenyl-4-propyl-3-pyridine carboxylate (MRS-1523, 2 mg/kg). CCPA and NECA reduced myocardial infarct size by 50% and 35%, respectively, versus vehicle, but CGS-21680 had no effect. DPCPX blunted the bradycardia associated with CCPA and NECA, whereas ZM-241385 attenuated their hypotensive effects. Both DPCPX and ZM-241385 blocked the protective effects of CCPA and NECA. The A₃ antagonist did not alter the hemodynamic effects of CCPA or NECA, nor did it alter adenosine agonist cardioprotection. None of the antagonists alone altered myocardial infarct size. These findings suggest that although preischemic administration of an A_2a receptor agonist does not induce cardioprotection, antagonism of the A_2a and/or the A_2b receptor blocks the cardioprotection associated with adenosine agonist pretreatment.

adenosine receptor; ischemia-reperfusion; infarct reduction

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