Allopurinol enhances adenine nucleotide levels and improves myocardial function in isolated hypoxic rat heart

Allopurinol, a competitive inhibitor of xanthine oxidase, was found to have a protective effect on ischemic myocardium. Its mechanism of action is still controversial. We used Langendorff isolated rat heart preparation to test the hypothesis that allopurinol could maintain a level of the adenine nucleotide pool (ATP, ADP, and AMP) that would protect and improve the functional activity of the heart during a period of hypoxia. Hearts were initially perfused for 30 min until steady state was attained. This was followed by 20 min of experimental perfusion divided into 5 min of control perfusion followed by 15 min of hypoxic perfusion with or without allopurinol in the perfusate. Hearts were quick-frozen and enzymatically analyzed for adenine nucleotides and creatine phosphate at the end of the hypoxic period. Left ventricular pressure, heart rate, and coronary flow were measured in all preparations. Allopurinol (0.1 mM) treated hearts had greater levels of ATP (12.3 +/- 0.8 vs. 9.3 +/- 0.8 mu mol/g dry weight; p < 0.01). This improvement occurred in the presence as well as the absence of glucose. Total adenine nucleotides improved from 17 +/- 1 to 20.3 +/- 2.4 <mu>mol/g dry weight (p < 0.01). This improvement also occurred in the presence as well as in the absence of glucose in the perfusate. It also improved cell energy state significantly in the presence as well as the absence of glucose. There was insignificant change in creatine phosphate. Allopurinol improved left ventricular pressure from 38 +/- 7% to 55 +/- 9% (p < 0.002) in the presence of glucose and from 8 +/- 3% to 27 +/- 6.3% (p < 0.001) in the absence of glucose. Coronary flow improved from 110 +/- 5% to 120 +/- 8%; (p < 0.04) in the presence of glucose. These results support the suggestion that allopurinol at 0.1 mM exerts its protective effect on rat heart during hypoxia by enhancing the adenine nucleotide pool.