ADENOSINE RECEPTOR ANTAGONISTS BLOCK ISCHEMIA-REPERFUSION INJURY OF THE HEART

Background It has bean reported that A(1) adenosine receptor antagonis ts are highly effective for the prevention and early treatment of isch emia-reperfusion injury of isolated perfused cat lung, which suggests that activation of A(1) adenosine receptors is important in ischemia-r eperfusion injury of the lung. In addition, preconditioning ischemia r educes ischemia-reperfusion injury of the lung and heart. Moreover, ac tivation of A(1) adenosine receptors by adenosine and selective A(1) a denosine receptor agonists mimics the protective effects of preconditi oning ischemia in the heart. It has been reported that prior treatment with selective A(1) adenosine receptor agonists results in a rapid un coupling of A(1) adenosine receptors from signal transduction mechanis ms. In the heart, these effects of A(1) adenosine receptor agonists ha ve not been reported. However, if prior treatment of ischemia of the h eart with adenosine or A(1) adenosine receptor agonists results in unc oupling of A(1) adenosine receptors from signal transduction mechanism s that produce injury after prolonged ischemia and reperfusion, A(1) a denosine receptor antagonists should provide a protective effect simil ar to these treatments for ischemia-reperfusion injury of the heart. T herefore, it was the purpose of these experiments to investigate the e ffect of selective A(1) adenosine receptor antagonists on ischemia-rep erfusion injury of the heart. Methods and Results With the use of a re gional 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 A(1) adenosine receptor antagonists xanthine amine congener (XAC; 0.1 mg . kg(-1). h(-1)), bamifylline (BAM; 10mg . kg(-1). h(-1)) , 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 10 mu g . kg(-1). min(-1) ) administered as continuous intravenous infusions for 1 hour before i schemia [DPCPX (I)], or DPCPX 30 mu g . kg(-1). min(-1) administered i ntravenously during 30 minutes of ischemia and 30 minutes of reperfusi on [DPCPX (I/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]. Co nclusions A(1) adenosine receptor antagonists significantly reduce isc hemia-reperfusion injury of the heart. A(1) adenosine receptor antagon ists may be useful for the prevention or early treatment of ischemia-r eperfusion injury of the heart after coronary artery bypass graft surg ery or cardiac transplant surgery and during or after angioplasty or t hrombolytic therapy of the heart.