title: Hypocarnitinaemia induced by sodium pivalate in the rat is associated with left ventricular dysfunction and impaired energy metabolism.
abstract: Carnitine is a naturally occurring compound that is essential in energy metabolism of the mammalian heart. In addition to its essential role in facilitating beta-oxidation, carnitine eliminates excess toxic acyl residues and regulates the mitochondrial acetyl coenzyme A (CoA)/CoA ratio. Thus, it is not surprising that patients with carnitine deficiency syndromes exhibit defects in energy metabolism and in some cases demonstrate left ventricular dysfunction. Pivalic acid is commonly used to create prodrugs, such as pivampicillin and pivmecillinam, to facilitate enteral absorption and increase oral bioavailability. Pivalic acid released from the drug following absorption readily forms an ester with carnitine, which is then excreted as pivaloylcarnitine. Sustained loss of carnitine in the form of this ester induces a state of carnitine deficiency, exemplified by low plasma and tissue carnitine content. This review examines the effects in the rat of short- and long-term sodium pivalate treatment on: (1) cardiac carnitine content; (2) in vitro mechanical function; (3) markers of glycolytic and fatty acid metabolism; and (4) energy substrate metabolism. Treatment with sodium pivalate induces a gradual loss of cardiac carnitine content for up to 12 weeks. Doubling the duration of treatment is not associated with any further decrease in cardiac carnitine content. While heart function following short-term treatment (2 weeks) is normal under aerobic conditions, impaired recovery of function following ischaemia is seen. In contrast, long-term treatment (11-28 weeks) is associated with impaired heart function, which is dependent on workload and substrate availability. Impaired heart function is also associated with reductions in activity of 3-hydroxyacyl CoA dehydrogenase and rates of fatty acid oxidation. However, to maintain adenosine triphosphate production, glucose metabolism, expressed as hexokinase activity and glucose oxidation, is increased in carnitine-deficient hearts. Hearts from sodium pivalate-treated animals demonstrate a cardiomyopathy that is dependent on duration of treatment, workload and substrate supply. This model of hypocarnitinaemia may thus be useful to study the metabolic and cardiac consequences of carnitine-deficiency syndromes.
authors.affiliation: Department of Physiology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, Arizona 85308, USA. tbrode@midwestern.edu
authors.forename: Tom L
authors.initials: TL
authors.lastname: Broderick
mesh_terms: D000818:Animals; D002331:Carnitine / Q000097:blood / Q000172:deficiency / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism; D010421:Pentanoic Acids / Q000494:pharmacology*; D051381:Rats; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*
chemical_list: D010421:Pentanoic Acids; C005566:pivalic acid; D002331:Carnitine