Glucose oxidation is stimulated in reperfused ischemic hearts with the carnitine palmitoyltransferase 1 inhibitor, Etomoxir.
The effect of the carnitine palmitoyltransferase 1 (CPT 1) inhibitor, Etomoxir, on glucose oxidation rates was determined in ischemic hearts reperfused in the presence of fatty acids. Isolated working rat hearts were perfused with 11 mM (14C)-glucose and 1.2 mM palmitate at a 15 cm H2O preload, 80 mm Hg afterload. Hearts were subjected to either 60 min aerobic perfusion, or 15 min work followed by 25 min global ischemia then 60 min of aerobic reperfusion. Steady state glucose oxidation rates in reperfused ischemic hearts were not significantly different from non-ischemic hearts. If 10(-9) M Etomoxir was added immediately prior to reperfusion no significant change in glucose oxidation occurred. Addition of 10(-8) M and 10(-6) M Etomoxir, however, significantly increased glucose oxidation. Etomoxir also significantly improved recovery of mechanical function at a concentration of 10(-8) M or greater. As we previously reported, no significant improvement of function was seen when 10(-9) M Etomoxir was added to the perfusate (Lopaschuk GD et al., Circ Res 63: 1036-1043, 1988). Long chain acylcarnitine levels were significantly reduced in the presence of both 10(-9) M and 10(-8) M Etomoxir. These data demonstrate that the beneficial effect of Etomoxir on reperfusion recovery of ischemic hearts is not due to a lowering of long chain acylcarnitine levels. Etomoxir may improve recovery of function by overcoming fatty acid inhibition of glucose oxidation.
Lopaschuk
G D
GD
Department of Pediatrics, Faculty of Medicine, University of Alberta, Edmonton, Canada.
McNeil
G F
GF
McVeigh
J J
JJ
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D004852:Epoxy Compounds / Q000494:pharmacology*; D004988:Ethers, Cyclic / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D010168:Palmitates; D000217:Acyltransferases; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose; C054207:etomoxir; D002331:Carnitine