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

Abstract

Lasley RD, Kristo G, Keith BJ, Mentzer RM, Jr. The A2a/A2b receptor antagonist ZM-241385 blocks the cardioprotective effect of adenosine agonist pretreatment in in vivo rat myocardium. Am J Physiol Heart Circ Physiol 292: H426 -H431, 2007. First published September 15, 2006; doi:10.1152/ajpheart.00675.2006.-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 A 1 agonist 2-chloro-N 6 -cyclopentyladenosine (CCPA, 10 g/kg), the nonselective agonist 5Ј-N-ethylcarboxamidoadenosine (NECA, 10 g/kg), or the A 2a agonist 2-[4-(2-carboxyethyl)phenethylamino]-5Ј-N-methylcarboxamidoadenosine (CGS-21680, 20 g/kg). Additional CCPA-and NECA-treated rats were pretreated with the A 1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 g/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 A 3 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 A 3 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 A2a receptor agonist does not induce cardioprotection, antagonism of the A2a and/or the A2b receptor blocks the cardioprotection associated with adenosine agonist pretreatment. adenosine receptor; ischemia-reperfusion; infarct reduction IT IS NOW WELL-RECOGNIZED that the administration of adenosine before myocardial ischemia (i.e., pretreatment) protects against both reversible and irreversible injury, an effect that appears to be mediated via the activation of cardiomyocyte A 1 and/or A 3 adenosine receptor subtypes (14, 21). The results of a very limited number of reports indicate that the administration of adenosine A 2a agonists before ischemia is not cardioprotective (1,13,32,33). However, there is now significant evidence that A 2a receptor activation during reperfusion (i.e., postconditioning) reduces myocardial infarct size (7,11,12,(35)(36)(37). The results of in vivo studies suggest that A 2a receptor postconditioning is mediated primarily via inhibition of inflammatory cell adhesion to vascular endothelial cells (7, 37). Additional reports...

Inhibiting Protease-Activated Receptor 4 Limits Myocardial Ischemia/Reperfusion Injury in Rat Hearts by Unmasking Adenosine Signaling

“…‫,ء‬ P Ͻ 0.05, treated versus control. or ischemic preconditioning (35-50%) (Yellon et al, 1992;Lasley et al, 2007). This is also the first study that has shown cross-talk between PAR4 and adenosine receptors during myocardial ischemia and reperfusion.…”

Adenosine A2A and A2B receptors are both required for adenosine A1 receptor-mediated cardioprotection

“…We (19,33) have previously reported that antagonism of adenosine A 2A and/or A 2B receptors with ZM-241385 blocked adenosine A 1 receptor agonist-mediated infarct size reduction in intact rats. Urmaliya et al (39) reported that A 1 receptormediated protection of H9c2(2-1) cells during simulated ischemia was blocked by both A 2A and A 2B receptor antagonists.…”

“…We (19,33) The purpose of this study was to determine whether the cardioprotective effects of adenosine A 1 receptor activation before ischemia and at the onset of reperfusion are modulated by A 2A and/or A 2B receptors. Experiments were conducted in isolated perfused hearts of wild-type (WT), A 2A KO, and A 2B KO mice.…”

“…Activation of A 1 and A 3 receptors before ischemia is cardioprotective (2,19,20,24,30,33,37,38,41), whereas A 2A and A 2B receptors appear to exert their effects during reperfusion (10,13,17,18,28,34,42,43). Adenosine A 3 receptor activation during reperfusion has been reported to be cardioprotective (8), but there are conflicting reports on whether A 1 receptor activation during reperfusion is beneficial (3,7,30,39,40).…”

Reduction in myocardial infarct size at 48 hours after brief intravenous infusion of ATL-146e, a highly selective adenosine A2A receptor agonist

“…On the other hand, there have also been reports showing both anti-inflammatory (8,26) and anti-infarct (1) effects of A 3 adenosine receptor activation. Nevertheless, the cardioprotective effects of adenosine during reperfusion injury appear to be mediated at least in part by A 2A receptor activation (2,13,15,18). Activation of A 2A receptors results in increased intracellular adenosine 3Ј,5Ј-cyclic monophosphate (cAMP) concentration, resulting in activation of protein kinase A and inhibition of multiple steps in the inflammatory cascade.…”