Electrophysiological effects of LU111995 on canine hearts: In vivo and in vitro studies

We studied the electrophysiological effects of LU111995 (1-15 mg/kg p.o.) i n conscious dogs with chronic atrioventricular block and ventricular pacing at 50 to 130 beats/min. LU111995 had no effects on idioventricular rhythm, QRS duration, and ventricular conduction time. It significantly prolonged Q-T interval (by 5-8%) and effective refractory period (ERP) (by 5-12%) wit h the maximal effect at 4 h after a 10 mg/kg dose. At 10 and 15 mg/kg, it i ncreased the ERP/Q-T ratio. In vitro, the effects of LU111995 (1 x 10(-7) t o 1 x 10(-5) M) on action potentials of Purkinje fibers (PFs) and M cells w ere studied at cycle lengths (CL) of 300 to 2000 ms. It had no effects on m aximum diastolic potential and action potential amplitude in either tissue. High concentrations induced a moderate, rate-independent decrease of V-max in M cells. In PFs and M cells, it produced reverse use-dependent lengthen ing of action potential duration (APD). In PFs at long CL, the drug exhibit ed a biphasic concentration-dependent effect on APD: maximum prolongation ( by 26% at a CL of 2000 ms) was attained at 1 x 10(-6) M, and a decrease of APD occurred at higher concentrations. In M cells, the maximum effect on AP D occurred at 3 x 10(-6) M. Early afterdepolarizations were seen in 50% of M cell preparations but only at CL of 2000 ms. Triggered activity did not o ccur. In summary, LU111995 prolongs the Q-T interval to a limited degree an d is not arrhythmogenic over the physiological range of CLs.