A1 adenosine receptor antagonists block ischemia-reperfusion injury of the heart

Abstract

Background: It has been reported that A1 adenosine receptor antagonists are highly effective for the prevention and early treatment of ischemia- reperfusion injury of isolated perfused cat lung, which suggests that activation of A1 adenosine receptors is important in ischemia-reperfusion injury of the lung. In addition, preconditioning ischemia reduces ischemia- reperfusion injury of the lung and heart. Moreover, activation of A1 adenosine receptors by adenosine and selective A1 adenosine receptor agonists mimics the protective effects of preconditioning ischemia in the heart. It has been reported that prior treatment with selective A1 adenosine receptor agonists result in a rapid uncoupling of A1 adenosine receptors from signal transduction mechanisms. In the heart, these effects of A1 adenosine receptor agonists have not been reported. However, if prior treatment of ischemia of the heart with adenosine or A1 adenosine receptor agonists results in uncoupling of A1 adenosine receptors from signal transduction mechanisms that produce injury after prolonged ischemia and reperfusion. A1 adenosine receptor antagonists should provide a protective effect similar to these treatments for ischemia-reperfusion injury of the heart. Therefore, it was the purpose of these experiments to investigate the effect of selective A1 adenosine receptor antagonists on ischemia- reperfusion injury of the heart. Methods and Results: With the use of a regional infarct model in open-chest cats, the left anterior descending artery or first diagonal branch was occluded for 1 hour followed by 2 hours of reperfusion. Infarct size (area of necrosis/area at risk: AN/AR) was estimated with the use of nitroblue tetrazolium staining. The selective A1 adenosine receptor antagonists xanthine amine congener (XAC: 0.1 mg · kg- 1 · h-1), bamifylline (BAM: 10 mg · kg-1 · h-1), 1,3-dipropyl-8- cyclopentylxanthine (DPCPX: 10 μg · kg-1 · min-1) administered as continuous intravenous infusions for 1 hour before ischemia [DPCPX (I)], or DPCPX 30 μg · kg-1 · min-1 administered intravenously during 30 minutes of ischemia and 30 minutes of reperfusion [DPCPX(1/R)] significantly (P<.05) reduced AN/AR from 52.2±3.8% (control, n=5) to 23.4±6.6% (XAC, n=5), 34.9±3.6% (BAM, n=5), 15.9±2.9% [DPCPX(I), n=5], or 13±3.2% [DPCPX (I/R), n=5). Conclusions: A1 adenosine receptor antagonists significantly reduce ischemia-reperfusion injury of the heart. A1 adenosine receptor antagonists may be useful for the prevention or early treatment of ischemia- reperfusion injury of the heart after coronary artery bypass graft surgery or cardiac transplant surgery and during or after angioplasty or thrombolytic therapy of the heart.