title: Cardiac electrophysiologic and inotropic actions of new and potent methanesulfonanilide class III antiarrhythmic agents in anesthetized dogs.
abstract: The effects of cumulative intravenous (i.v.) administration of potent and selective methanesulfonanilide class III antiarrhythmic agents on cardiac electrophysiologic and hemodynamic parameters were compared with those of D-sotalol in chloralose-anesthetized dogs. The new class III agents tested were E-4031 [1-(2-(6-methyl-2-pyridyl)ethyl)-(4-methanesulfonamidobenzoyl)pipe ridine]; UK-66,914 [N-(4-(1-hydroxy-2-(4-(4-pyridinyl)-1-piperazinyl)ethyl)phenyl) methanesulfonamide], and UK-68,798 [1-(4-methanesulfonamidophenoxy)-2-(N- (4-methanesulfonamidophenethyl)-N-methylamino)ethane]. The class III agents produced significant and dose-dependent increases in ventricular refractoriness, with effective doses required to increase ventricular relative refractory period 20 ms above baseline (ED20, micrograms/kg i.v., with 95% confidence limits) of 5.2 (4.2-6.6) for UK-68,798, 17 (13-23) for E-4031, 75 (58-99) for UK-66,914, and 3,700 (2,600-5,800) for D-sotalol. Significant increases in the electrocardiographic QT and QTc intervals paralleled the increases in ventricular refractoriness for the four class III agents. Significant increases in left ventricular (LV) + dP/dt also paralleled increases in ventricular refractoriness and QT intervals for E-4031 (10-1,000 micrograms/kg i.v.), UK-66,914 (100-1,000 micrograms/kg i.v.), and UK-68,798 (30-1,000 micrograms/kg i.v.), but not for D-sotalol. No concomitant alterations in LV-dP/dt were observed for the new and potent methanesulfonanilide class III agents, resulting in significant increases in the ratio of LV + dP/dt/-dP/dt for E-4031, UK-66,914, and UK-68,798. Potent and selective methanesulfonanilide class III agents therefore may augment cardiac contractility in addition to prolonging ventricular refractoriness.
authors.affiliation: Department of Pharmacology, Merck, Sharp and Dohme Research Laboratories, West Point, PA 19486.
authors.forename: A A
authors.initials: AA
authors.lastname: Wallace
authors.forename: R F
authors.initials: RF
authors.lastname: Stupienski
authors.forename: L M
authors.initials: LM
authors.lastname: Brookes
authors.forename: H G
authors.initials: HG
authors.lastname: Selnick
authors.forename: D A
authors.initials: DA
authors.lastname: Claremon
authors.forename: J J
authors.initials: JJ
authors.lastname: Lynch
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D005260:Female; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010627:Phenethylamines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D010880:Piperidines; D011719:Pyrazines; D011725:Pyridines; D013449:Sulfonamides; C069454:UK 66914; C063968:E 4031; D013015:Sotalol; C063533:dofetilide