Vol. 281, Issue 1, 155-162, 1997

Class III Electrophysiologic Actions of Imidazole-Substituted Diheterabicyclononanes in Canine Myocardium

Eugene Patterson , Benjamin J. Scherlag , Subiah Sangiah, Gregory L. Garrison, Kevin M. Couch, K. Darrell Berlin and Ralph Lazzara

Departments of Pharmacology (E.P.) and Medicine (E.P., B.J.S., R.L.), College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, Research Service (E.P., B.J.S.), Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma and Departments of Pharmacology (S.S.) and Chemistry (G.L.G., K.M.C., K.D.B.), Oklahoma State University, Stillwater, Oklahoma

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, V_max, 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.