Abstract
Terodiline was widely prescribed for urinary incontinence before reports of adverse cardiac effects that included bradycardia, QT lengthening, and ventricular tachyarrhythmia. The present study on guinea pig papillary muscles and ventricular myocytes was undertaken to gain insight into the cardioactive properties of the drug. Clinically relevant concentrations (<10 μM) of terodiline lengthened the action potential duration by up to 12%; higher concentrations shortened the duration in a concentration-dependent manner. The drug depressed maximal upstroke velocity in a use-dependent manner; the IC50 value was near 150 μM in muscles driven at 1 Hz, 60 μM at 3 Hz, 38 μM at 5 Hz, and 3 μM at 1 Hz in muscles depolarized with 14 mM K+. Submicromolar terodiline frequently had a small positive inotropic effect, whereas micromolar concentrations depressed force in a frequency-dependent manner. Voltage-clamp results on myocytes indicate that terodiline inhibits three membrane currents that govern repolarization: 1) E4031-sensitive, rapidly activating K+ current with an IC50value near 0.7 μM as previously reported; 2) slowly activating, delayed-rectifier K+ current with an IC50 value of 26 μM; and 3) L-type Ca2+ current with an IC50 value of 12 μM. These findings are correlated with the changes in action potential configuration and developed tension and discussed in relation to the cardiotoxic effects of the drug.
Footnotes
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Send reprint requests to: Dr. T. F. McDonald, Department of Physiology and Biophysics, Dalhousie University, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7. E-mail:terence.mcdonald{at}dal.ca
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↵1 This work was supported by the Medical Research Council of Canada, the Heart and Stroke Foundation of New Brunswick, and Sepracor Inc. L.M.S. was supported by an award from the Dalhousie Medical Research Foundation.
- Abbreviations:
- V˙
- upstroke velocity
- APA
- action potential amplitude
- APD
- action potential duration
- APD20
- action potential duration at 20% repolarization level
- APD90
- action potential duration at 90% repolarization level
- DMSO
- dimethyl sulfoxide
- ICa, L
- L-type Ca2+ current
- IK
- delayed-rectifier K+ current
- IK1
- inward-rectifying K+ current
- IKr
- rapidly activating component of IK
- IKs
- slowly activating component of IK
- V˙max
- maximal upstroke velocity
- Received February 24, 1998.
- Accepted April 21, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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