title: Comparison of direct negative chronotropic and positive inotropic effects of sematilide to those of E-4031 and MS-551 and the reverse frequency-dependent prolongation of cardiac refractoriness of sematilide.
abstract: Direct cardiac effects of sematilide, a new class III antiarrhythmic drug, were compared with those of E-4031 and MS-551 in canine isolated blood-perfused heart preparations. Doses of sematilide, E-4031, and MS-551 causing a 10% decrease in the spontaneous sinoatrial beating rate were 58 +/- 15, 9 +/- 5, and 84 +/- 10 micrograms (n = 5); those causing a 10% increase in developed tension of the papillary muscle were 485 +/- 49, 17 +/- 2, and 267 +/- 50 micrograms (n = 6); and those causing a 10% prolongation of effective refractory period (ERP) of the atrioventricular node were 68 +/- 10, 11 +/- 2, and 53 +/- 15 micrograms (n = 5), respectively. There were few effects on atrio-His or His-ventricular intervals. Also, in in situ open-chest dog hearts, the percent increases in ERP of the atrioventricular conduction system caused by 1 mg/kg of sematilide were 21 +/- 3, 16 +/- 2 and 9 +/- 1% at cycle lengths of 800, 600, and 400 ms, respectively (p < 0.01; n = 8). These results indicate that (a) sematilide, as well as E-4031 and MS-551, has direct negative chronotropic and positive inotropic effects and prolongs cardiac refractoriness without affecting conduction velocities; (b) quantitatively, the cardiac effects of sematilide were almost identical to those of MS-551 and five to ten times less potent than those of E-4031; (c) and prolongation of ERP of the atrioventricular conduction system by sematilide occurred in a reverse frequency-dependent manner.
authors.affiliation: Department of Pharmacology, Yamanashi Medical University, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yamada
authors.forename: S
authors.initials: S
authors.lastname: Motomura
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001283:Atrioventricular Node / Q000187:drug effects; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011342:Procainamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D012849:Sinoatrial Node / Q000187:drug effects
chemical_list: D000889:Anti-Arrhythmia Agents; D010880:Piperidines; D011725:Pyridines; D011744:Pyrimidinones; C062818:sematilide; C063968:E 4031; C076259:nifekalant; D011342:Procainamide