Cardioprotection by orotic acid: metabolism and mechanism of action.

Abstract:

:The pyrimidine base, orotic acid (OA), improves the function of recently infarcted hearts subjected to global ischemia but its mechanism of action is unclear. Our aims were to examine (i) in normal rats, the effect of OA on pyrimidine levels in plasma, liver and heart; (ii) in rats with normal or infarcted hearts, the effect of OA on adenine nucleotide metabolism and mechanical function, before and after global ischemia. 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 OA for 2 days after coronary ligation or sham operations, and plasma and tissue pyrimidine concentrations examined. Their hearts were isolated and perfused, then subjected to 30 min of global ischemia. Mechanical function and adenine nucleotide content were assessed pre- and post-ischemia. In normal, unoperated rats, administration of 100 mg/kg OA significantly increased hepatic uracil and cytosine nucleotide concentrations, then increased plasma uridine (+124%) and cytidine (+55%), and transiently increased myocardial uracil nucleotides (+21%). Infarction significantly reduced recovery of cardiac work after global ischemia (sham=62%; infarct=26%; P<0.05), and OA treatment in infarcted hearts increased post-ischemic work by 192% (P<0.05), but not in shams. Pre-ischemic ATP was reduced in the surviving myocardium of infarcted hearts from 21.7+/-0.8 to 14.7+/-0. 7 micromol/g dry weight (P<0.001) and total adenine nucleotides (TAN) from 30.3+/-0.8 to 22.4+/-1.1 micromol/g dry weight (P<0.001). OA treatment prevented these reductions in infarcted hearts (ATP 20. 7+/-0.5; TAN, 29.1+/-0.6 micromol/g dry weight). We conclude that OA protects the infarcted heart against global ischemia by enhancing hepatic release of pyrimidine nucleosides into the plasma, which then prevent depletion of adenine nucleotides in the surviving myocardium.

journal_name

J Mol Cell Cardiol

authors

Richards SM,Conyers RA,Fisher JL,Rosenfeldt FL

doi

10.1006/jmcc.1997.0550

subject

Has Abstract

pub_date

1997-12-01 00:00:00

pages

3239-50

issue

12

eissn

0022-2828

issn

1095-8584

pii

S0022-2828(97)90550-2

journal_volume

29

pub_type

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