Inhibition of long-chain acylcarnitine accumulation during coronary artery occlusion does not alter infarct size in dogs.
We tested whether inhibition of carnitine acyl-transferase-1 (CAT-1) during coronary artery occlusion can limit infarct size (IS) by suppressing accumulation of long-chain acylcarnitines (LCAs), potentially cytotoxic intermediates of fatty acid metabolism. The CAT-1 inhibitor 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (POCA) was administered to dogs before 90-min occlusion and 4-h reperfusion of the left anterior 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. Biopsies 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 occlusion. 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) and did not increase significantly during LCX occlusion; 22 +/- 8 to 27 +/- 5 pmol/mg wet weight (p < 0.005 vs. vehicle). LCX occlusion resulted in larger areas at risk and larger infarcts (as a percentage of left ventricle) than did LAD occlusion. IS as a percentage of the region at risk did not differ significantly among the experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Vogel
W M
WM
Hoffmann La-Roche, Nutley, New Jersey 07110-1199.
Bush
L R
LR
Cavallo
G C
GC
Heathers
G P
GP
Hirkaler
G M
GM
Kozak
M Z
MZ
Higgins
A J
AJ
D000108:Acetylcarnitine / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002333:Carnitine Acyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004285:Dogs; D004852:Epoxy Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015425:Myocardial Reperfusion
D004852:Epoxy Compounds; D000108:Acetylcarnitine; C033891:ethyl 2-(5-(4-chlorophenyl)pentyl)oxiran-2-carboxylate; D002333:Carnitine Acyltransferases