Dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium.

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Unger SA, Kennedy JA, McFadden-Lewis K, Minerds K, Murphy GA, Horowitz JD

Dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium.

J Cardiovasc Pharmacol. 2005 Dec;46(6):849-55.

PubMed ID

16306812 [ View in PubMed

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Abstract

The antianginal agent perhexiline inhibits rat cardiac carnitine palmitoyltransferase-1 (CPT-1) and CPT-2, key enzymes for mitochondrial transport of long-chain fatty acids. We tested the hypothesis that perhexiline, in therapeutic concentrations (2 microM), inhibits palmitate oxidation and enhances glucose oxidation in isolated rat cardiomyocytes and in the working rat heart, thereby increasing efficiency of oxygen utilization. In isolated cardiomyocytes, perhexiline (2 microM) exerted no acute effects on palmitate oxidation, but after 48 hours pre-exposure oxidation was inhibited by perhexiline (2 to 10 microM) by 15% to 35% (P < 0.0002). In non-ischemic working rat hearts (3%BSA, 0.4 mM palmitate, 11 mM glucose, 100 microU/mL insulin) perhexiline (2 microM) had no significant acute effect on cardiac efficiency, palmitate or glucose oxidation, but 24 hours pretreatment with transdermal perhexiline increased cardiac work (by 29%, P < 0.05) and cardiac efficiency (by 30%, P < 0.02) without significant effects on palmitate oxidation. The selective CPT-1 inhibitor oxfenicine (2 mM) inhibited palmitate oxidation and enhanced glucose oxidation, but failed to enhance cardiac efficiency. In conclusion, in the non-ischemic working rat heart, perhexiline increases myocardial efficiency by a mechanism(s) that is largely or entirely independent of its effects on CPT. Effects on cardiac efficiency during ischemia, and with changes in fatty acid oxidation after longer perhexiline pretreatment remain to be determined.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Perhexiline	Carnitine O-palmitoyltransferase 1, liver isoform	Protein	Humans	Yes	Inhibitor	Details
Perhexiline	Carnitine O-palmitoyltransferase 2, mitochondrial	Protein	Humans	Yes	Inhibitor	Details