Electrophysiological Effects of LU111995 on Canine Hearts: In Vivo and In Vitro Studies1
- Eugene A. Sosunov1,
- Ravil Z. Gainullin1,
- Peter Danilo, Jr.1,
- Evgeny P. Anyukhovsky1,
- Michael Kirchengast2 and
- Michael R. Rosen1,2
- Departments of 1Pharmacology (E.A.S., R.Z.G., P.D., E.P.A., M.R.R.) and 2Pediatrics (M.R.R.), College of Physicians and Surgeons of Columbia University, New York, New York
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.
Footnotes
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Send reprint requests to: Michael R. Rosen, M.D., Gustavus A. Pfeiffer Professor of Pharmacology, Professor of Pediatrics, College of Physicians and Surgeons of Columbia University, Department of Pharmacology, 630 West 168 St., PH7 West-321, New York, NY 10032. E-mail: emf3{at}Columbia.edu
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↵1 This study was supported in part by U.S. Public Health Service National Heart, Lung, and Blood Institute Grant HL53956 and by Knoll AG.
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↵2 Present address: Knoll AG, Ludwigshaten, Germany.
- Abbreviations:
- MDP
- maximum diastolic potential
- APD
- action potential duration
- EAD
- early afterdepolarization
- Vmax
- maximum rate of rise of phase 0
- ERP
- effective refractory period
- PF
- Purkinje fiber
- CL
- cycle length
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- Received January 7, 1999.
- Accepted March 8, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
