A novel partial fatty acid oxidation inhibitor decreases myocardial oxygen consumption and improves cardiac efficiency in demand-induced ischemic heart.
The benefits of inhibition of fatty acid oxidation (FOX) and stimulation of glucose oxidation (GOX) in ischemia are controversial. The objective of this study was to evaluate the effect of the FOX inhibitor CVT-4325 on the rates of FOX, GOX, myocardial oxygen consumption (MVO2), and cardiac efficiency in the absence and presence of palmitate during demand-induced ischemia of the rodent isolated hearts. Palmitate concentration-dependently increased FOX, decreased GOX, and increased MVO2. CVT-4325 inhibited FOX and increased GOX in the presence (but not the absence) of 1.2 mM palmitate, with EC50 values of 0.9 and 5.8 microM, respectively. The potency for CVT-4325 to inhibit FOX was 10-fold greater (0.9 versus 9.7 microM) in the presence of 1.2 mM compared with 0.4 mM palmitate. The increase in MVO2 caused by 1.2 mM palmitate was significantly reduced by 3 to 10 microM CVT-4325 in guinea pig hearts. In the presence of 1.2 mM palmitate, an increase in pacing rate of the guinea pig heart from 3.5 to 6.5 Hz caused a significant 50% increase in MVO2, a decrease in cardiac efficiency, and an increase in lactate concentration in the cardiac effluent from 0.04 +/- 0.01 to 0.10 +/- 0.02 mM (P < 0.01). CVT-4325 (3 microM) attenuated the increase (P < 0.05) in MVO2 while maintaining cardiac contractility, and decreased the lactate production to 0.05 +/- 0.01 mM (P < 0.01). Thus, the FOX inhibitor CVT-4325 decreased MVO2 and increased myocardial efficiency during demand-(pacing)-induced ischemia in the presence of palmitate in the rodent isolated hearts.
Wu
Lin
L
Department of Pharmacological Sciences, CV Therapeutics, Inc., Palo Alto, CA 94304, USA. lin.wu@cvt.com
Belardinelli
Luiz
L
Fraser
Heather
H
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects*; D010168:Palmitates / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000187:drug effects
D002316:Cardiotonic Agents; D005227:Fatty Acids; D010069:Oxadiazoles; D010168:Palmitates; C499690:para-trifluoro-methyl-5-phenyl-1,2,4-oxadiazole; D005947:Glucose