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.

Abstract

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 Jr, 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
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 265 Issue 2 Pg. 720-30 (May 1993) ISSN: 0022-3565 [Print] United States
• PMID: 8496818 (Publication Type: Journal Article)

Chemical References

• Anti-Arrhythmia Agents
• Piperidones
• Spiro Compounds
• L 691121

Topics

• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Atrial Function
• Cells, Cultured
• Dogs
• Electrophysiology
• Ferrets
• Guinea Pigs
• Heart Atria (drug effects)
• Heart Ventricles (drug effects)
• In Vitro Techniques
• Male
• Myocardial Infarction (physiopathology)
• Myocardial Ischemia (physiopathology)
• Piperidones (pharmacology)
• Spiro Compounds (pharmacology)
• Ventricular Function