ON THE ROLES OF LONG-CHAIN ACYL CARNITINE ACCUMULATION AND IMPAIRED GLUCOSE-UTILIZATION IN ISCHEMIC 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 a nd cardiac damage, and that this may be due to long-chain acyl carniti ne accumulation and/or impairment of glucose utilization. In isolated guinea-pig papillary muscles, palmitoyl (DL) carnitine was found to ha ve a positive inotropic effect, with a slow onset of action suggestive of an intracellular site of action, and with a maximal effect of abou t two-fold at a concentration of 5-10 mu M; higher concentrations led to decreased contraction, probably due to increasing detergent-like ef fects. In isolated fura-2-loaded chick cardiomyocytes, palmitoyl carni tine increased intracellular [Ca2+]; it is proposed that this is the m eans 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 palmit ate (1.5 mM) during low-now ischaemia (92% reduction in flow) for up t o 60 min. With 11.7 mM glucose, the presence of palmitate caused contr acture development and increased enzyme release during ischaemia. Cont racture 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 s tudies show that long-chain acyl carnitine accumulation has the potent ial to induce contracture during ischaemia, although a reduction in gl ucose availability may also contribute. (C) 1996 Academic Press Limite d