Protective effects of trimetazidine on hypoxic cardiac myocytes from the rat

Abstract

The electrophysiological effects of the antianginal drug trimetazidine (TMZ) were investigated in cultured rat ventricular myocytes using a substrate-free hypoxia model of ischemia. The transmembrane potentials were recorded with glass microelectrodes and the contractions were simultaneously monitored with a video motion detector. The cardiomyocytes were treated with TMZ (1-5.10(-4) M final concentration) in the bath. The untreated and the drug-treated cells were submitted either to 150 min normoxia or to 150 min hypoxia followed by 90 min reoxygenation in the absence of oxidizable substrate. In normoxic conditions, TMZ did not affect the maximal diastolic potential (MDP) but significantly lowered the plateau potential level (OS) and decreased the upstroke velocity (Vmax) and the spontaneous action potential rate (APR). Conversely, TMZ significantly increased action potential duration at 80% repolarization (APD80). Under substrate-free hypoxia, the untreated cells displayed a progressive contractile failure and an important decrease in OS and APD. In parallel, early postdepolarizations triggering high rate spikes were observed. Prolonging oxygen depletion led to the cessation of the spontaneous electrical activity and thereafter to a gradual decrease in MDP. Near normal rhythmic action potentials and contractions resumed after reoxygenation. Comparatively, the treatment by 5.10(-4) M TMZ almost completely prevented the decrease in plateau amplitude, resting membrane potential, Vmax, APD80, and rate caused by substrate-free hypoxia. Moreover, the hypoxia-induced arrhythmias and the cessation of spontaneous electromechanical activities did not occur in the presence of TMZ (5.10(-4) M). After reoxygenation, the TMZ-treated cells exhibited a higher action potential amplitude than that of the untreated cells, although the TMZ-induced depressive effects on the spontaneous frequency and the Vmax persisted. In conclusion, this study shows that TMZ (5.10(-4) M) is efficient in protecting the isolated cardiac myocytes against the functional alterations induced by substrate-free hypoxia and led thus to a better recovery upon reoxygenation. The cytoprotective action may be linked, at least in part, to apparent ion channel blocking effects of the drug, which appeared in basal conditions at concentrations used in this study.