title: Class III electrophysiologic actions of imidazole-substituted diheterabicyclononanes in canine myocardium.
abstract: The electrophysiologic effects of the imidazole-substituted diheterabicyclo[3.3.1]nonane compounds GLG-V-13 and KMC-IV-84 were evaluated in canine ventricular tissues using intracellular and extracellular recordings. The drugs produced a concentration-dependent prolongation of action potential duration at 90% of repolarization in Purkinje (338 +/- 26 to 611 +/- 43 msec, 10 mg/l GLG-V-13; 328 +/- 17 to 468 +/- 18 msec, 10 mg/l KMC-IV-84), in right ventricular subendocardium (260 +/- 18 to 335 +/- 18 msec, 10 mg/l GLG-V-13; 221 +/- 9 to 264 +/- 13 msec, 10 mg/l KMC-IV-84) and in left ventricular epicardium (195 +/- 13 to 256 +/- 18 msec, 10 mg/l GLG-V-13; 203 +/- 11 to 273 +/- 26 msec, 10 mg/l KMC-IV-84) without altering resting membrane potential, action potential amplitude, overshoot potential, Vmax, conduction velocity or Purkinje fiber automaticity. Prolongation of the effective refractory period was proportional to the change in action potential duration at 90% of repolarization. Prolongation of action potential duration at 90% of repolarization was maximal at paced cycle lengths exceeding 1000 msec and was minimal at a paced cycle length of 250 msec (Purkinje: 266 +/- 20 vs. 6 +/- 8 msec, GLG-V-13; 178 +/- 12 vs. 10 +/- 10 msec, KMC-IV-84. Right ventricular subendocardium: 70 +/- 12 vs. 10 +/- 2 msec, GLG-V-13; 60 +/- 8 vs. 19 +/- 6 msec. Left ventricular epicardium: 67 +/- 13 vs. 10 +/- 5 msec, GLG-V-13; 68 +/- 12 vs. 16 +/- 8 msec, KMC-IV-84). An increase in K+(o) to 12 mM reduced action potential prolongation by GLG-V-13 and KMC-IV-84 in left ventricular epicardium. The results demonstrate selective class III electrophysiologic properties for imidazole-substituted diheterabicyclo[3.3.1]nonane compounds.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.
authors.forename: E
authors.initials: E
authors.lastname: Patterson
authors.forename: B J
authors.initials: BJ
authors.lastname: Scherlag
authors.forename: S
authors.initials: S
authors.lastname: Sangiah
authors.forename: G L
authors.initials: GL
authors.lastname: Garrison
authors.forename: K M
authors.initials: KM
authors.lastname: Couch
authors.forename: K D
authors.initials: KD
authors.lastname: Berlin
authors.forename: R
authors.initials: R
authors.lastname: Lazzara
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology
chemical_list: D000889:Anti-Arrhythmia Agents; D007093:Imidazoles