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.) 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 x 10(-7) to 1 x 10(-5) M) 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 of Vmax 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 x 10(-6) M, and a decrease of APD occurred at higher concentrations. In M cells, the maximum effect on APD 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 occur. In summary, LU111995 prolongs the Q-T interval to a limited degree and is not arrhythmogenic over the physiological range of CLs.
Sosunov
E A
EA
Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
Gainullin
R Z
RZ
Danilo
P
P
Anyukhovsky
E P
EP
Kirchengast
M
M
Rosen
M R
MR
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002908:Chronic Disease; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D005260:Female; D005650:Fumarates / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006327:Heart Block / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D011799:Quinazolines / Q000494:pharmacology*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects
D014150:Antipsychotic Agents; D005650:Fumarates; C120146:LU 111995; D011799:Quinazolines