Electropharmacological effects of amantadine on cardiovascular system assessed with J-T_peak and T_peak-T_end analysis in the halothane-anesthetized beagle dogs

抄録

Since amantadine-induced long QT syndrome has been clinically reported, we investigated its electropharmacological effects to estimate the extent of proarrhythmic risk by using the halothane-anesthetized beagle dogs (n = 4). Amantadine in doses of 0.1, 1 and 10 mg/kg was infused over 10 min with a pause of 20 min under the monitoring of multiple cardiovascular variables. J-T_peak and T_peak-T_end were separately measured on the lead II electrocardiogram to precisely analyze the net balance between inward and outward current modifications by amantadine. The low dose increased the ventricular contractile force, but suppressed the intraventricular conduction. The middle dose prolonged the QT interval besides enhancing the changes induced by the low dose. The high dose increased the mean blood pressure, left ventricular end-diastolic pressure and total peripheral resistance, and accelerated the atrioventricular nodal conduction, but decreased the cardiac output besides enhancing the changes induced by the middle dose. A reverse use-dependence was confirmed in the repolarization delay. Amantadine hardly affected the J-T_peak, but prolonged the T_peak-T_end. Amantadine can be considered to stimulate Ca²⁺ channel but inhibit Na⁺ and K⁺ channels in the in situ heart. J-T_peak and T_peak-T_end analysis suggests that amantadine may possess modest risk for arrhythmia.