CLASS-III ELECTROPHYSIOLOGIC ACTIONS OF IMIDAZOLE-SUBSTITUTED DIHETERABICYCLONONANES IN CANINE MYOCARDIUM

The electrophysiologic effects of the imidazole-substituted diheterabi cyclo[3.3.1]nonane compounds GLG-V-13 and KMC-IV-84 were evaluated in canine ventricular tissues using intracellular and extracellular recor dings. The drugs produced a concentration-dependent prolongation of ac tion 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 potent ial amplitude, overshoot potential, V-max, conduction velocity or Purk inje fiber automaticity. Prolongation of the effective refractory peri od 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, GL G-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+, 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 imi dazole-substituted diheterabicyclo[3.3.1]nonane compounds.