title: Electropharmacological effects of amantadine on cardiovascular system assessed with J-Tpeak and Tpeak-Tend analysis in the halothane-anesthetized beagle dogs.
abstract: 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-Tpeak and Tpeak-Tend 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-Tpeak, but prolonged the Tpeak-Tend. Amantadine can be considered to stimulate Ca(2+) channel but inhibit Na(+) and K(+) channels in the in situ heart. J-Tpeak and Tpeak-Tend analysis suggests that amantadine may possess modest risk for arrhythmia.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University.
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Wada
authors.forename: Hiroko
authors.initials: H
authors.lastname: Izumi-Nakaseko
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ando
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugiyama
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000547:Amantadine / Q000633:toxicity*; D018685:Anesthetics, Inhalation; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D062186:Arterial Pressure / Q000187:drug effects; D002120:Calcium Channel Agonists / Q000633:toxicity*; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006221:Halothane; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D023421:Models, Animal; D026902:Potassium Channel Blockers / Q000633:toxicity*; D018570:Risk Assessment; D026941:Sodium Channel Blockers / Q000633:toxicity*; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D018685:Anesthetics, Inhalation; D002120:Calcium Channel Agonists; D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers; D000547:Amantadine; D006221:Halothane