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

  1. Lesya M. Shuba1,
  2. Yuji Kasamaki2,
  3. Stephen E. Jones1,
  4. Toshitsugu Ogura1,
  5. John R. McCullough3 and
  6. Terence F. McDonald1
  1. 1Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada (L.M.S., S.E.J., T.O., T.F.M.); 2Nihon University School of Medicine, 2nd Department of Internal Medicine, Itabashi-ku, Tokyo, Japan (Y.K.); and 3Sepracor Inc., Marlborough, Massachusetts (J.R.M.)

    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

    • 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

    • ↵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.
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    1. JPET September 1, 1999 vol. 290 no. 3 1417-1426
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