title: The in-vivo cardiovascular effects of a putative class III anti-arrhythmic drug, AM 92016.
abstract: AM 92016 (1-(4-methanesulphonamidophenoxy)- 3-(N-methyl-3-4-dichlorophenethylamino)-2-propanol benzoic acid salt), an oxypropanolamine analogue of sotalol, has been shown to possess Class III anti-arrhythmic properties in-vitro at concentrations showing 1000 times more potency than sotalol. The aim of this study was to characterize the effects of AM 92016 in-vivo. When administered to anaesthetized guinea-pigs, AM 92016 (10 micrograms kg-1 -5 mg kg-1) significantly increased heart rate, systolic arterial blood pressure, left ventricular systolic pressure and the contractile index dp dtmax. AM 92016 also significantly decreased the QT interval of the electrocardiogram from 135 +/- 10 to 105 +/- 4 ms (5 mg kg-1). The time to onset of the first arrhythmia and ventricular fibrillation, induced by intravenous infusion of ouabain, was shortened in the presence of AM 92016. Ouabain-induced ventricular fibrillation occurred at 18 +/- 5 and 12 +/- 3 min (P < 0.05) in control and AM 92016-(1 mg kg-1) treated guinea-pigs, respectively. An infusion of AM 92016 (2.5 micrograms kg-1 min-1) to anaesthetized pigs significantly increased the total number of arrhythmias occurring following coronary artery occlusion from 266 +/- 26 in control pigs to 535 +/- 148 (P < 0.05) in those receiving AM 92016. The time to onset of ventricular fibrillation was also significantly reduced in anaesthetized pigs from 24 +/- 1 to 18 +/- 3 min in the presence of AM 92016. The drug did not change haemodynamics in the anaesthetized pig. We conclude that AM 92016 exhibited proarrhythmic rather than antiarrhythmic activity when administered in-vivo to either guinea-pigs or pigs.
authors.affiliation: Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, Scotland, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Hagerty
authors.forename: C L
authors.initials: CL
authors.lastname: Wainwright
authors.forename: K A
authors.initials: KA
authors.lastname: Kane
mesh_terms: D000769:Anesthesia, Inhalation; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000517:prevention & control; D001794:Blood Pressure / Q000187:drug effects; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000503:physiopathology; D010042:Ouabain; D013015:Sotalol / Q000031:analogs & derivatives* / Q000494:pharmacology; D013552:Swine; D014693:Ventricular Fibrillation / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents; C102243:AM 92016; D010042:Ouabain; D013015:Sotalol