title: Dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium.
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.
authors.affiliation: Cardiology Unit, The Queen Elizabeth Hospital, Adelaide University, Woodville South, South Australia, 5011.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Unger
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kennedy
authors.forename: Kate
authors.initials: K
authors.lastname: McFadden-Lewis
authors.forename: Kirsty
authors.initials: K
authors.lastname: Minerds
authors.forename: Geraldine A
authors.initials: GA
authors.lastname: Murphy
authors.forename: John D
authors.initials: JD
authors.lastname: Horowitz
mesh_terms: D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D010480:Perhexiline / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D019308:Palmitic Acid; C023010:4-hydroxyphenylglycine; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose; D010480:Perhexiline; D005998:Glycine