On the roles of long-chain acyl carnitine accumulation and impaired glucose utilization in ischaemic contracture development and tissue damage in the guinea-pig heart.
It has been proposed that the presence of increasing concentrations of fatty acids may accelerate the development of ischaemic contracture and cardiac damage, and that this may be due to long-chain acyl carnitine accumulation and/or impairment of glucose utilization. In isolated guinea-pig papillary muscles, palmitoyl (DL) carnitine was found to have a positive inotropic effect, with a slow onset of action suggestive of an intracellular site of action, and with a maximal effect of about two-fold at a concentration of 5-10 microM; higher concentrations led to decreased contraction, probably due to increasing detergent-like effects. In isolated fura-2-loaded chick cardiomyocytes, palmitoyl carnitine increased intracellular [Ca2+]; it is proposed that this is the means by which it increases contraction. The main hypothesis above was studied using isolated guinea-pig hearts perfused with either 11.7 mM or 5 mM glucose, and either albumin alone (3%) or albumin bound palmitate (1.5 mM) during low-flow ischaemia (92% reduction in flow) for up to 60 min. With 11.7 mM glucose, the presence of palmitate caused contracture development and increased enzyme release during ischaemia. Contracture also developed when the glucose concentration was reduced to 5 mM in the absence of fatty acid, however, in its presence contracture developed to a greater extent and with increased enzyme release. Long-chain acyl carnitine accumulation was similar in both groups. These studies show that long-chain acyl carnitine accumulation has the potential to induce contracture during ischaemia, although a reduction in glucose availability may also contribute.
Clarke
B
B
Department of Pharmacology, Syntex Research Centre, Edinburgh, UK.
Wyatt
K M
KM
May
G R
GR
McCormack
J G
JG
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002331:Carnitine / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D005260:Female; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology / Q000503:physiopathology*; D066298:In Vitro Techniques; D007700:Kinetics; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000494:pharmacology; D010172:Palmitoylcarnitine / Q000378:metabolism / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D010477:Perfusion; D012709:Serum Albumin / Q000494:pharmacology; D013997:Time Factors
D010169:Palmitic Acids; D012709:Serum Albumin; D010172:Palmitoylcarnitine; D019308:Palmitic Acid; D005947:Glucose; D002331:Carnitine; D002118:Calcium