INHIBITION OF GLYCOLYSIS AND ENHANCED MECHANICAL FUNCTION OF WORKING RAT HEARTS AS A RESULT OF ADENOSINE A(1) RECEPTOR STIMULATION DURING REPERFUSION FOLLOWING ISCHEMIA

1 This study examined effects of adenosine and selective adenosine A(1 ) and A(2) receptor agonists on glucose metabolism in rat isolated wor king hearts perfused under aerobic conditions and during reperfusion a fter 35 min of global no-flow ischaemia. 2 Hearts were perfused with a modified Krebs-Henseleit buffer containing 1.25 mM Ca2+, 11 mM glucos e, 1.2 mM palmitate and insulin (100 mu u ml(-1)), and paced at 280 be ats min(-1). Rates of glycolysis and glucose oxidation were measured f rom the quantitative production of (H2O)-H-3 and (CO2)-C-14, respectiv ely, from [5-H-3/U-C-14]-glucose. 3 Under aerobic conditions, adenosin e (100 mu M) and the adenosine A(1) receptor agonist, N-6-cyclohexylad enosine (CHA, 0.05 mu M), inhibited glycolysis but had no effect on ei ther glucose oxidation or mechanical function (as assessed by heart ra te systolic pressure product). The improved coupling of glycolysis to glucose oxidation reduced the calculated rate of proton production fro m glucose metabolism. The adenosine A, receptor antagonist, 8-cyclopen tyl-1,3-dipropylxanthine (DPCPX 0.3 mu M) did not alter glycolysis or glucose oxidation pet se but completely antagonized the adenosine- and CHA-induced inhibition of glycolysis and proton production. 4 During aerobic reperfusion following ischaemia, CHA (0.05 mu M) again inhibit ed glycolysis and proton production from glucose metabolism and had no effect on glucose oxidation. CHA also significantly enhanced the reco very of mechanical function. In contrast, the selective adenosine A(2a ) receptor agonist, CGS-21680 (1.0 mu M), exerted no metabolic or mech anical effects. Similar profiles of action were seen if these agonists were present during ischaemia and throughout reperfusion or when they were present only during reperfusion. 5 DPCPX (0.3 mu M), added at re perfusion, antagonized the CHA-induced improvement in mechanical funct ion. It also significantly depressed the recovery of mechanical functi on pet se during reperfusion. Both the metabolic and mechanical effect s of adenosine (100 mu M) were antagonized by the nonselective A(1)/A( 2) antagonist, 8-sulphophenyltheophylline (100 mu M). 6 These data dem onstrate that inhibition of glycolysis and improved recovery of mechan ical function during reperfusion of rat isolated hearts are mediated b y an adenosine A(1) receptor mechanism. Improved coupling of glycolysi s and glucose oxidation during reperfusion may contribute to the enhan ced recovery of mechanical function by decreasing proton production fr om glucose metabolism and the potential for intracellular Ca2+ accumul ation, which if not corrected leads to mechanical dysfunction of the p ost-ischaemic myocardium.