Abstract

We studied the electrophysiological effects of LU111995 (1–15 mg/kg p.o.) in 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%) with the maximal effect at 4 h after a 10 mg/kg dose. At 10 and 15 mg/kg, it increased the ERP/Q–T ratio. In vitro, the effects of LU111995 (1 × 10⁻⁷ to 1 × 10⁻⁵m) on action potentials of Purkinje fibers (PFs) and M cells were studied at cycle lengths (CL) of 300 to 2000 ms. It had no effects on maximum diastolic potential and action potential amplitude in either tissue. High concentrations induced a moderate, rate-independent decrease ofV˙_max in M cells. In PFs and M cells, it produced reverse use-dependent lengthening of action potential duration (APD). In PFs at long CL, the drug exhibited a biphasic concentration-dependent effect on APD: maximum prolongation (by 26% at a CL of 2000 ms) was attained at 1 × 10⁻⁶m, and a decrease of APD occurred at higher concentrations. In M cells, the maximum effect on APD occurred at 3 × 10⁻⁶m. Early afterdepolarizations were seen in 50% of M cell preparations but only at CL of 2000 ms. Triggered activity did not occur. In summary, LU111995 prolongs the Q–T interval to a limited degree and is not arrhythmogenic over the physiological range of CLs.