title: Mechanism of cardioprotective effect of orotic acid.
abstract: The pyrimidine base, orotic acid (OA), markedly improves the function of recently infarcted hearts subjected to global ischemia. The mechanism of cardiac action of OA is unclear, but it has been proposed that OA acts by correcting a relative deficiency of nucleotide precursors required for RNA synthesis in the stressed myocardium or by improving myocardial energy supply. The aim of this study was to investigate the mechanism of action of OA by (1) determining whether a high dose of OA can raise the concentration of pyrimidine metabolites in plasma, liver, and heart; (2) examining the effects of OA on adenine nucleotide (AN) concentrations in normal and infarcted hearts, before and after global ischemia; and (3) determining the effect of uridine, an important metabolite of OA, on myocardial energy metabolism. Three studies were performed: (1) The time course of changes in tissue and plasma concentrations of pyrimidine compounds was examined in unoperated rats after the administration of 100 mg/kg OA. (2) Rats were given OA (30 mg/kg/d) for 2 days after experimental infarction, and tissue and plasma pyrimidine concentrations were examined; the hearts were removed for perfusion in the isolated working rat heart model (37 degrees C), subjected to 30 minutes of global ischemia, and recovery of function was assessed. AN content was assessed in the noninfarcted myocardium before and after ischemia. Isolated hearts were subjected to 30 minutes of hypoxic perfusion and the effect of adding 17 microM uridine to the perfusate was examined. Study 1 showed that OA administration produced an increase in hepatic uridine and cytidine, followed by increased plasma uridine and cytidine (cytidine, +55%, P < 0.001; uridine, +124%, P = 0.011). Myocardial uracil nucleotides increased temporarily after 4 hours (+21%, P < 0.01). In infarcted hearts after 2 days of OA administration, there were no significant changes in myocardial uracil or cytosine nucleotides or total RNA. Infarction significantly reduced functional recovery after global ischemia (sham = 62%; infarct = 26% of preischemic level; P < 0.05). OA improved the recovery of preischemic function by 133% (P < 0.05) in infarcted, but not sham-operated, hearts. Preischemic ATP and total adenine nucleotides (TAN) were decreased in the surviving myocardium of infarcted hearts (ATP reduced from 21.7 +/- 0.8 to 14.7 +/- 0.7 mumol/g dry wt, P < 0.001; TAN decreased from 30.3 +/- 0.8 to 22.4 +/- 1.1 mumol/g dry wt, P < 0.001). OA treatment prevented these reductions. Study 3 showed that uridine improved myocardial ATP and TAN levels, and decreased purine loss in hypoxic hearts. The increased AN levels were accompanied by evidence of enhancement of anerobic glycolysis. We conclude: (1) That OA acts on the heart via the liver by increasing the availability of plasma uridine and cytidine. (2) Uridine is capable of increasing myocardial ATP production by stimulating anerobic glycolysis. (3) OA treatment improves tolerance to global ischemia in infarcted but not normal hearts by preventing depletion of AN in the surviving myocardium.
authors.affiliation: Cardiac Surgical Research Unit, Baker Medical Research Institute, Melbourne, Australia.
authors.forename: F L
authors.initials: FL
authors.lastname: Rosenfeldt
authors.forename: S M
authors.initials: SM
authors.lastname: Richards
authors.forename: Z
authors.initials: Z
authors.lastname: Lin
authors.forename: S
authors.initials: S
authors.lastname: Pepe
authors.forename: R A
authors.initials: RA
authors.lastname: Conyers
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D006321:Heart / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D009963:Orotic Acid / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D011687:Purines / Q000378:metabolism; D011743:Pyrimidines / Q000097:blood / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014529:Uridine / Q000378:metabolism
chemical_list: D000227:Adenine Nucleotides; D011687:Purines; D011743:Pyrimidines; D009963:Orotic Acid; D014529:Uridine