Direct evidence that perhexiline modifies myocardial substrate utilization from fatty acids to lactate.
Perhexiline maleate, originally classified as a calcium antagonist, is in use as an antianginal agent. The mechanism of its protective effect is unknown, but there is speculation that it involves a modification of myocardial substrate utilization, in which glycolytic sources are used rather than fatty acids. This hypothesis was tested by employing [13C]NMR isotopomer analysis to measure substrate selection in the working rat heart. Substrate utilization was measured from a mixture of substrates present at their physiological concentration, as follows: acetoacetate, glucose, lactate and long-chain fatty acids. Control perfusions were compared with those perfused with perhexiline. It was found that perhexiline increased lactate utilization, which reduced the extent of fatty acid and endogenous substrate oxidation. There was also a significant increase in cardiac output for a small and insignificant increase in oxygen consumption, which suggested an improvement in myocardial efficiency. Thus, it was confirmed by direct measurement that this drug does modify substrate oxidation, which suggests that further investigations of the role that this agent can play in the management of ischemic heart disease would be beneficial.
Jeffrey
F M
FM
Department of Radiology, UT Southwestern Medical Center, Mary Nell and Ralph B. Rogers Magnetic Resonance Center, Dallas, TX 75235-9085, USA.
Alvarez
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L
Diczku
V
V
Sherry
A D
AD
Malloy
C R
CR
D000090:Acetoacetates / Q000378:metabolism; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007773:Lactates / Q000378:metabolism*; D019344:Lactic Acid; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D010480:Perhexiline / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000090:Acetoacetates; D005227:Fatty Acids; D007773:Lactates; D019344:Lactic Acid; D018698:Glutamic Acid; D005947:Glucose; D010480:Perhexiline