title: Stereospecific in vitro and in vivo effects of the new sinus node inhibitor (+)-S 16257.
abstract: The effects of the two isomers, (+)-S 16257 and (-)-S 16260, of a new bradycardic agent, (+/-)-S 15544 (7,8-dimethoxy 3-[3-[[(4.5-dimethoxybenzocyclobutan-1-yl)methyl] methylamino]propyl]1,3,4,5-tetrahydro-2H-3-benzazepin-2-one), were compared in vitro and in vivo on cardiac spontaneous rate and repolarization time. In the isolated rabbit sino-atrial node, the three compounds (3 microM) were equi-effective to reduce the action potential firing rate. In anesthetized pigs, both isomers (0.03, 0.1, 0.3 and 1 mg kg(-1) i.v.) were equipotent to reduce heart rate. For all compounds, the negative chronotropic effect resulted from a reduction in the slope of diastolic depolarization of pacemaker cells. In sino-atrial node cells, (-)-S 16260 (3 microM) increased action potential duration while (+)-S 16257 had a smaller effect. In driven guinea-pig papillary muscles exposed to increasing concentrations of compounds (0.1 to 10 microM) a small prolongation of action potential duration was observed. This prolongation was more marked in rabbit Purkinje fibers stimulated at a low rate. In all cardiac preparations the highest prolongation was observed with (-)-S 16260. In vivo, (-)-S 16260 prolonged QTc at the two highest doses tested while (+)-S 16257 had no effect. In conclusion, resolution of (+/-)-S 15544 into its two enantiomers yielded compounds with the same bradycardic effects. Of the isomers, (+)-S 16257 has an increased specificity with minimal direct effect on action potential repolarization.
authors.affiliation: Division pathologies cardiaques et vasculaires, Institut de Recherches Servier, Suresnes, France.
authors.forename: C
authors.initials: C
authors.lastname: Thollon
authors.forename: J P
authors.initials: JP
authors.lastname: Bidouard
authors.forename: C
authors.initials: C
authors.lastname: Cambarrat
authors.forename: L
authors.initials: L
authors.lastname: Lesage
authors.forename: H
authors.initials: H
authors.lastname: Reure
authors.forename: I
authors.initials: I
authors.lastname: Delescluse
authors.forename: J
authors.initials: J
authors.lastname: Vian
authors.forename: J L
authors.initials: JL
authors.lastname: Peglion
authors.forename: J P
authors.initials: JP
authors.lastname: Vilaine
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001683:Biological Clocks; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D000077550:Ivabradine; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects; D011690:Purkinje Fibers / Q000187:drug effects; D011817:Rabbits; D012849:Sinoatrial Node / Q000187:drug effects*; D013237:Stereoisomerism; D013552:Swine
chemical_list: D001552:Benzazepines; D002316:Cardiotonic Agents; D000077550:Ivabradine