Effects of mexiletine on the canine cardiovascular system complicating cisapride overdose: potential utility of mexiletine for the treatment of drug-induced long QT syndrome.
The purpose of this study was to test the potential utility of mexiletine for the treatment of drug-induced long QT syndrome in vivo. Beagle dogs were anesthetized with halothane inhalation (n =7). Monophasic action potential (MAP) of the right ventricle, ECG, systemic and left ventricular pressure, cardiac output and effective refractory period (ERP) of the right ventricle were measured. The electrically vulnerable period was estimated by the difference between MAP duration and ERP. An intentionally high dose of 1 mg/kg, i.v. of cisapride decreased the heart rate, mean blood pressure, left ventricular contraction and cardiac output and prolonged the ventricular repolarization phase and ERP, in which the increment was greater in the former than in the latter, indicating the increase of electrical vulnerability. The left ventricular end-diastolic pressure and atrioventricular as well as intraventricular conduction were hardly affected. Additional administration of an antiarrhythmic dose of 3 mg/kg, i.v. of mexiletine increased the heart rate, decreased the left ventricular contraction and cardiac output, suppressed the atrioventricular as well as intraventricular conduction, and prolonged the ERP, but shortened the ventricular repolarization phase. There was no change in the afterload and preload of the left ventricle. Thus, mexiletine decreased the electrical vulnerability of the heart during cisapride overdose, suggesting that it may become a potential pharmacological strategy for drug-induced long QT syndrome.
Satoh
Y
Y
Second Department of Internal Medicine, Yamanashi Medical University, Japan.
Sugiyama
A
A
Tamura
K
K
Hashimoto
K
K
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002302:Cardiac Output / Q000187:drug effects / Q000502:physiology; D002319:Cardiovascular System / Q000187:drug effects; D020117:Cisapride / Q000009:adverse effects; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D008133:Long QT Syndrome / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D008801:Mexiletine / Q000494:pharmacology* / Q000627:therapeutic use; D017366:Serotonin Receptor Agonists / Q000009:adverse effects; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D000889:Anti-Arrhythmia Agents; D017366:Serotonin Receptor Agonists; D008801:Mexiletine; D020117:Cisapride