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

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 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.

• Authors: E A Sosunov, R Z Gainullin, P Danilo Jr, E P Anyukhovsky, M Kirchengast, M R Rosen
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 290 Issue 1 Pg. 146-52 (Jul 1999) ISSN: 0022-3565 [Print] United States
• PMID: 10381770 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antipsychotic Agents
• Fumarates
• LU 111995
• Quinazolines

Topics

• Action Potentials (drug effects)
• Animals
• Antipsychotic Agents (pharmacology)
• Chronic Disease
• Dogs
• Electrocardiography (drug effects)
• Electrophysiology
• Female
• Fumarates (pharmacology)
• Heart (drug effects)
• Heart Block (physiopathology)
• Heart Rate (drug effects)
• In Vitro Techniques
• Male
• Myocardial Contraction (drug effects)
• Myocardium (cytology)
• Purkinje Fibers (drug effects, physiology)
• Quinazolines (pharmacology)
• Refractory Period, Electrophysiological (drug effects)