EFFECTS OF THE ANTIHYPOXIC AND NEUROPROTECTIVE DRUG, LUBELUZOLE, ON REPOLARIZATION PHASE OF CANINE HEART ASSESSED BY MONOPHASIC ACTION-POTENTIAL RECORDING

The cardiovascular effects of the antihypoxic and neuroprotective drug , lubeluzole, were investigated using beagle dogs anesthetized with ha lothane. Endocardial-contact electrode catheter was used for continuou s monitoring of monophasic action potential (MAP), which could provide a precise information of repolarization phase. Intravenous administra tion of an efficacious dose of lubeluzole (0.63 mg/kg, n = 6) slightly decreased both the heart rate and the blood pressure. It did not chan ge PQ interval and QRS width, while it significantly prolonged QT inte rval, corrected QT (QTc) and the duration of the MAP during the observ ation period. over 60 min. The effects of drug on repolarization phase were late-onset and long-lasting compared with the time course of pla sma drug concentrations, which changed as predicted by the two-compart ment theory of pharmacokinetics. Additional injection of lubeluzole (2 .5 mg/kg, n = 6) showed qualitatively similar changes to those of lowe r dose, and did not induce the cardiovascular collapse in any dog. Nei ther afterdepolarization nor ventricular escaped beat was detected dur ing the observation period. The drug concentration in cardiac tissue w as correlated linearly with the plasma drug concentration at 60 min af ter the second drug administration. These results indicate that lubelu zole exerts only minor cardiovascular effects except the prolongation of the repolarization period. The monitoring of plasma drug concentrat ion may be helpful to estimate the steady-state distribution of drug t o the heart, but less helpful to predict the QT prolongation. In futur e clinical trials, care must be taken with patients, especially those at risk to have prolonged repolarization. (C) 1996 Academic Press, Inc .