Lysophospholipids, long chain acylcarnitines and membrane dysfunction in the ischaemic heart.

Several findings suggest that the accumulation of ions and metabolites contribute to the electrophysiological alterations and associated malignant arrhythmias in the ischaemic heart. Our studies have focused on two amphipathic metabolites, lysophosphoglycerides (LPGs) and long-chain acylcarnitines (LCA). In an attempt to implicate any metabolite as contributing to the early electrophysiological alterations or subsequent development of irreversible cell injury in the ischaemic heart, several methodological and interpretative issues must be addressed, including the time course of accumulation and subcellular distribution. Current findings include: (1) both LPGs and LCA increase in ischaemic myocardium within 3 min, although the precise subcellular distributions have yet to be clarified, (2) electrophysiological alterations, analogous to those seen during ischaemia, are induced in vitro by both LPGs and LCA when as little as 1 mol% is incorporated into the sarcolemma (SL) based on EM autoradiography, (3) electrophysiological effects of LPGs are dependent on extracellular delivery, based on studies using intracellular pressure microinjection, (4) LPGs increase in both cardiac lymph and venular effluents in vivo within minutes to concentrations sufficient to induce electrophysiological alterations, (5) LCA increases in rat myocytes in vitro during hypoxia with a 5-fold increase in the SL determined by quantitative EM autoradiography. Inhibition of carnitine acyltransferase I (CAT-I) during hypoxia prevents not only the SL accumulation of LCA but also the associated electrophysiological alterations. Since the two major catabolic enzymes for LPGs are inhibited by LCA, studies are currently underway to assess the effects of inhibition of CAT-I during ischaemia in vivo, on both LCA and LPG accumulation and the influence on regional electrophysiological alterations and arrhythmogenesis.