Document Detail


Cardiac electrophysiologic and antiarrhythmic actions of 3,4-dihydro-1'-[2-(benzofurazan-5-yl) ethyl]-6-methanesulfonamidospiro [(2H)-1-benzopyran-2,4'-piperidin]-4-one HCl (L-691,121), a novel class III agent.
MedLine Citation:
PMID:  8496818     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The cardiac electrophysiologic and antiarrhythmic actions of 3,4-dihydro-1'-[2-(benzofurazan-5-yl)ethyl]-6-methyl-sulfonamid ospiro [(2H)-1-benzopyran-2,4'-piperidin]-4-one HCl (L-691,121), a novel spirobenzopyran piperidine class III agent, were assessed in vitro and in vivo. In ferret isolated papillary muscles, L-691,121 significantly prolonged effective refractory period (EC25 = 13 nM) and elicited a modest positive inotropic effect. In guinea pig isolated ventricular myocytes, L-691,121 prolonged action potential duration by selectively blocking (IC50 = 4.4 nM) a rapidly activating and rectifying component of the delayed rectifier K+ current, Ikr. The class III activity of L-691,121 in isolated papillary muscles was reverse frequency-dependent, and reversed by hypoxic perfusion. L-691,121 modestly depressed spontaneous beating rate (-14%) in guinea pig isolated right atria at concentrations up to 3 microM. In anesthetized dogs, the i.v. administration of 10 to 100 micrograms/kg of L-691,121 significantly increased atrial and ventricular refractoriness and prolonged the electrocardiographic Q-T interval, but did not alter atrioventricular nodal, His-Purkinje, atrial or ventricular conduction. In conscious dogs with spontaneous premature ventricular complexes at 48 hr after myocardial infarction, 10 to 1000 micrograms/kg i.v. of L-691, 121 failed to reduce premature ventricular complex frequency. However, in anesthetized dogs studied chronically (7.9 +/- 0.3 days) after infarction, 10 and 100 micrograms/kg i.v. of L-691,121 suppressed the induction of ventricular tachyarrhythmia by programmed stimulation in 8/14 (57%) and 11/14 (79%) dogs tested, respectively, and reduced the incidence of lethal ventricular arrhythmias triggered by a secondary myocardial ischemic event from 14/15 (93%) in vehicle controls to 5/14 (36%; P < .01) in L-691,121-treated (100 micrograms/kg i.v.) animals. The latter findings suggest the potential for L-691,121 to prevent the development of malignant ventricular arrhythmias in the setting of previous myocardial infarction.
Authors:
J J Lynch; A A Wallace; L H Van der Gaag; E P Baskin; C M Bear; J R Gehret; T Kothstein; R F Stupienski; S D Appleby; M C Sanguinetti
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  265     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  1993 May 
Date Detail:
Created Date:  1993-06-22     Completed Date:  1993-06-22     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  720-30     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Arrhythmia Agents / pharmacology*
Atrial Function
Cells, Cultured
Dogs
Electrophysiology
Ferrets
Guinea Pigs
Heart Atria / drug effects
Heart Ventricles / drug effects
Male
Myocardial Infarction / physiopathology
Myocardial Ischemia / physiopathology
Piperidones / pharmacology*
Spiro Compounds / pharmacology*
Ventricular Function
Chemical
Reg. No./Substance:
0/Anti-Arrhythmia Agents; 0/Piperidones; 0/Spiro Compounds; 136075-61-1/L 691121

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