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.
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.
Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania.
J J
JJ
Lynch
A A
AA
Wallace
L H
LH
Van der Gaag
E P
EP
Baskin
C M
CM
Bear
J R
JR
Gehret
T
T
Kothstein
R F
RF
Stupienski
S D
SD
Appleby
M C
MC
Sanguinetti
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D016275:Atrial Function; D002478:Cells, Cultured; D004285:Dogs; D004594:Electrophysiology; D005289:Ferrets; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000503:physiopathology; D010881:Piperidones / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D010881:Piperidones; D013141:Spiro Compounds; C077569:L 691121