title: Prevention of class III-induced proarrhythmias by flecainide in an animal model of the acquired long QT syndrome.
abstract: The influence of the class Ic agent, flecainide, on the incidence of class III-induced torsades de pointes was examined in an animal model of the acquired long QT syndrome. Twenty-four chloralose-anaesthetized rabbits were pretreated at random with flecainide or vehicle and subsequently given a concomitant infusion of methoxamine and the class III antiarrhythmic agent almokalant. In seven out of eight vehicle-treated rabbits, almokalant induced torsades de pointes which was preceded by a significant lengthening of the JTU interval (used as an indirect measure of ventricular repolarization time) by 55 +/- 9.2 msec. Flecainide dose-dependently reduced the incidence of almokalant-induced torsades de pointes. Hence, in a group of rabbits given a low dose (0.14 mumol/kg + 1.4 mumol/kg/hr) of flecainide, four out of eight animals experienced torsades de pointes (P = 0.1538 versus vehicle) whereas no case (n = 8) was observed after a higher dose (4.8 mumol/kg + 4.8 mumol/kg/hr, P = 0.0007). In the former group almokalant induced a maximal increase in the JTU interval not differing from that seen in the vehicle-treated group (58 + 12.1 msec, P > 0.05). Pretreatment with the high dose of flecainide, however, caused a significant attenuation of the almokalant-induced lengthening of the JTU interval (18 +/- 6.5 msec. P < 0.05). It is concluded that flecainide reduces the risk of proarrhythmia in the setting of delayed repolarization partially by attenuating the primary electrophysiological effect of class III agents.
authors.affiliation: Astra Hässle AB, Mölndal, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Hallman
authors.forename: L
authors.initials: L
authors.lastname: Carlsson
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D005424:Flecainide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008729:Methoxamine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011412:Propanolamines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D016171:Torsades de Pointes / Q000517:prevention & control*
chemical_list: D000317:Adrenergic alpha-Antagonists; D000889:Anti-Arrhythmia Agents; D011412:Propanolamines; D008729:Methoxamine; C074334:almokalant; D005424:Flecainide