ENDOGENOUS ADENOSINE REDUCES DEPRESSION OF CARDIAC-FUNCTION INDUCED BY BETA-ADRENERGIC STIMULATION DURING LOW-FLOW PERFUSION

High levels of norepinephrine in the heart are cardiotoxic resulting i n contractile dysfunction and arrhythmic activity via beta-adrenocepto r mediated mechanisms. A low now heart model perfused with physiologic al saline containing glucose and bubbled with an O-2 gas mixture was u sed to determine whether adenosine, a nucleoside with antiadrenergic p roperties, could reduce the functional manifestations of catecholamine cardiotoxicity. Isolated rat hearts were treated with dipropylcyclope ntyrxanthine (DPCPX; 0.1 mu M; A(1) receptor antagonist) to block endo genous adenosine. In DPCPX-treated hearts stimulated with isoprotereno l (ISO; 1 mu M) during 45 min of low flow (0.5 ml/min) perfusion, the recovery of contractile function (ConF) at 15 min after the restoratio n of normal flow was 64% of control (before low now) values as compare d to 110% recovery of ConF in the absence of ISO, The incidence of arr hythmias observed upon restoration of control now was increased by ISO when the action of endogenous adenosine was blocked with DPCPX. In th e absence of DPCPX both the functional depression and arrhythmias indu ced by ISO were prevented in the presence of phenylisopropyladenosine (PIA; 1 mu M; A(1) receptor agonist). At 15 min after normal flow was restored, ConF in ISO-treated hearts with PIA was 53% greater than in the absence of PIA and presence of DPCPX. This enhancement of ConF by PIA was significantly reduced by DPCPX, By 30 min after now restoratio n, these significant differences were absent. DPCPX reversed the PIA-i nduced reduction in arrhythmias observed upon restoration of normal fl ow. PIA and DPCPX alone in the absence of ISO, and ISO in the absence of PIA and DPCPX, did not result in altered ConF upon restoration of n ormal now. These findings indicate that intense beta-adrenergic stimul ation of the heart during low-flow perfusion in the absence of adenosi ne A(1) receptor activity induces contractile depression and arrhythmi city subsequent to restoration of control perfusion. It is concluded t hat endogenous adenosine protects the heart against catecholamine toxi city via stimulation of adenosine A(1) receptors. (C) 1995 Academic Pr ess Limited