Inhibition of glycolysis and enhanced mechanical function of working rat hearts as a result of adenosine A(1) receptor stimulation during reperfusion following ischaemia

1 This study examined effects of adenosine and selective adenosine A(1) and A(2) receptor agonists on glucose metabolism in rat isolated working hearts perfused under aerobic conditions and during reperfusion after 35 min of global no-flow ischaemia. 2 Hearts were perfused with a modified Krebs-Henseleit buffer containing 1.25 mM Ca2+, 11 mM glucose, 1.2 mM palmitate and insulin (100 mu u ml(-1)), and paced at 280 beats min(-1). Rates of glycolysis and glucose oxidation were measured from the quantitative production of (H2O)-H-3 and (CO2)-C-14, respectively, from [5-H-3/U-C-14]-glucose. 3 Under aerobic conditions, adenosine (100 mu M) and the adenosine A(1) receptor agonist, N-6-cyclohexyladenosine (CHA, 0.05 mu M), inhibited glycolysis but had no effect on either glucose oxidation or mechanical function (as assessed by heart rate systolic pressure product). The improved coupling of glycolysis to glucose oxidation reduced the calculated rate of proton production from glucose metabolism. The adenosine A, receptor antagonist, 8-cyclopentyl-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 inhibited glycolysis and proton production from glucose metabolism and had no effect on glucose oxidation. CHA also significantly enhanced the recovery of mechanical function. In contrast, the selective adenosine A(2a) receptor agonist, CGS-21680 (1.0 mu M), exerted no metabolic or mechanical 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 reperfusion, antagonized the CHA-induced improvement in mechanical function. It also significantly depressed the recovery of mechanical function pet se during reperfusion. Both the metabolic and mechanical effects of adenosine (100 mu M) were antagonized by the nonselective A(1)/A(2) antagonist, 8-sulphophenyltheophylline (100 mu M). 6 These data demonstrate that inhibition of glycolysis and improved recovery of mechanical function during reperfusion of rat isolated hearts are mediated by an adenosine A(1) receptor mechanism. Improved coupling of glycolysis and glucose oxidation during reperfusion may contribute to the enhanced recovery of mechanical function by decreasing proton production from glucose metabolism and the potential for intracellular Ca2+ accumulation, which if not corrected leads to mechanical dysfunction of the post-ischaemic myocardium.