CARDIOPROTECTION BY OROTIC-ACID - METABOLISM AND MECHANISM OF ACTION

The pyrimidine base, erotic acid (OA), improves the function of recent ly infarcted hearts subjected to global ischemia but its mechanism of action is unclear, Our aims were to examine (i) in normal rats, the ef fect of OA on pyrimidine levels in plasma, liver and heart; (ii) in ra ts with normal or infarcted hearts, the effect of OA on adenine nucleo tide metabolism and mechanical function, before and after global ische mia, To investigate the metabolism of OA, normal rats received 100 mg/ kg OA, and changes in plasma and tissue concentrations of pyrimidines were examined. The effects of OA were also studied in rats receiving O A for 2 days after corollary ligation or sham operations, and plasma a nd tissue pyrimidine concentrations examined, Their hearts were isolat ed and perfused, then subjected to 30 min of global ischemia. Mechanic al function and adenine nucleotide content were assessed pre-and post- ischemia. In normal, unoperated rats, administration of 100 mgikg OA s ignificantly increased hepatic uracil and cytosine nucleotide concentr ations, then increased plasma uridine (+/-124%) and cytidine (+55%), a nd transiently increased myocardial uracil nucleotides (+21%). Infarct ion significantly reduced recovery of cardiac work after global ischem ia (sham=62%; infarct=26%; P<0.05), and OA treatment in infarcted hear ts increased post-ischemic work by 192% (P<0.05), but not in shams. Pr e-ischemic ATE was reduced in the surviving myocardium of infarcted he arts from 21.7+/-0.8 to 14.7+/-0.71 mu mol/g dry weight (P<0.001) and total adenine nucleotides (TAN) from 30.3 +/- 0.8 to 22.4 +/- 1.1 mu m ol/g dry weight (P<0.001). OA treatment prevented these reductions in infarcted hearts (ATE 20.7 +/- 0.5; TAN, 29.1 +/- 0.6 mu mol/g dry wei ght). We conclude that OA protects the infarcted heart against global ischemia by enhancing hepatic release of pyrimidine nucleosides into t he plasma, which then prevent depletion of adenine nucleotides in the survivingmyocardium. (C) 1997 Academic Press Limited.