CARDIOPROTECTIVE PROFILE OF MET-88, AN INHIBITOR OF CARNITINE SYNTHESIS, AND INSULIN DURING HYPOXIA IN ISOLATED-PERFUSED RAT HEARTS

3-(2,2,2-trimethylhydrazinium) propionate (MET-88) is an inhibitor of carnitine synthesis. This study was carried out to investigate whether or not reduction of carnitine content could attenuate hypoxic damage in isolated perfused rat hearts. Rats were divided into four groups: 1 ) vehicle control; 2) pretreatment with MET-88 (MET-88); 3) applicatio n of insulin (500 mu U/mL) in the perfusate (insulin); and 4) pretreat ment with MET-88 and application of insulin (MET-88 + insulin). MET-88 (100 mg/kg) was orally administered once a day for 10 days until the day before the experiments. Hearts were initially perfused for a 10 mi n period under normoxia, followed by a 30 min period under hypoxia. He arts were frozen at the end of hypoxia for the measurement of high-ene rgy phosphates, carnitine derivatives, and glycolysis intermediates. I n a separate series of untreated and MET-88 treated hearts, exogenous glucose and palmitate oxidation was measured. MET-88 decreased the ext ent of the depression of cardiac contractility (+dP/dt), and aortic fl ow during the hypoxic state. Insulin also improved cardiac function, a nd co-treatment of MET-88 and insulin additionally improved cardiac fu nction during hypoxia. MET-88 prevented the decrease of high-energy ph osphate and the increase of long-chain acylcarnitine after 30 min of h ypoxic perfusion. In addition, MET-88 increased the steady state of gl ucose oxidation in hypoxic perfused rat hearts. These results indicate that MET-88 has cardioprotective effects on contractile function and energy metabolism of isolated perfused rat hearts in a hypoxic conditi on. Preventing the accumulation of long-chain acylcarnitine may serve to protect hypoxic hearts. (C) 1998 Elsevier, Paris.