INHIBITION OF LONG-CHAIN ACYLCARNITINE ACCUMULATION DURING CORONARY-ARTERY OCCLUSION DOES NOT ALTER INFARCT SIZE IN DOGS

We tested whether inhibition of carnitine acyltransferase-1 (CAT-1) du ring coronary artery occlusion can limit infarct size (IS) by suppress ing accumulation of long-chain acylcarnitines (LCAs), potentially cyto toxic intermediates of fatty acid metabolism. The CAT-1 inhibitor -[5- (4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (POCA) was administered to dogs before 90-min occlusion and 4-h reperfusion of the left anter ior descending or left circumflex coronary artery (LAD, LCX). Dogs in the LAD occlusion series received 7.5 (n = 5) or 15 (n = 2) mg/kg POCA intravenously (i.v.); dogs in the LCX occlusion series received 15 mg /kg i.v. (n = 7); an equal number were treated with drug vehicle. Biop sies were obtained for determination of myocardial LCAs. The region at risk and IS were delineated by dye injection and tetrazolium staining . In vehicle-treated dogs, myocardial LCAs (in picomoles per milligram of wet weight +/- SEM) increased from 11 +/- 3 to a peak of 75 +/- 24 during LAD occlusion and from 32 +/- 10 to 192 +/- 55 during LCX occl usion. In POCA-treated dogs LCAs increased from 12 +/- 2 to only 33 +/ - 13 pmol/mg wet weight during LAD occlusion (p < 0.05 vs. vehicle) an d did not increase significantly during LCX occlusion; 22 +/- 8 to 27 +/- 5 pmol/ mg wet weight (p < 0.005 vs. vehicle). LCX occlusion resul ted in larger areas at risk and larger infarcts (as a percentage of le ft ventricle) than did LAD occlusion. IS as a percentage of the region at risk did not differ significantly among the experimental groups. A fter LAD occlusion, IS was 25 +/- 4% of risk region for vehicle treatm ent and 26 +/- 4% of risk region for POCA treatment. After LCX occlusi on, the values were 32 +/- 3% for vehicle and 35 +/- 4% for POCA. Vent ricular fibrillation (VF) occurred in 2 of the 26 dogs during occlusio n and in 12 dogs during reperfusion, with no effect of drug treatment or occlusion site. We conclude that accumulation of LCAs during ischem ia is not a primary determinant of irreversible injury in this coronar y occlusion-reperfusion model.