Vol. 290, Issue 3, 1417-1426, September 1999

Action Potentials, Contraction, and Membrane Currents in Guinea Pig Ventricular Preparations Treated with the Antispasmodic Agent Terodiline¹

Lesya M. Shuba, Yuji Kasamaki, Stephen E. Jones, Toshitsugu Ogura, John R. McCullough and Terence F. McDonald

Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada (L.M.S., S.E.J., T.O., T.F.M.); Nihon University School of Medicine, 2nd Department of Internal Medicine, Itabashi-ku, Tokyo, Japan (Y.K.); and Sepracor Inc., Marlborough, Massachusetts (J.R.M.)

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 IC₅₀ value 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.