Action potentials, contraction, and membrane currents in guinea pig ventricular preparations treated with the antispasmodic agent terodiline

Terodiline was widely prescribed for urinary incontinence before reports of adverse cardiac effects that included bradycardia, QT lengthening, and ven tricular tachyarrhythmia. The present study on guinea pig papillary muscles and ventricular myocytes was undertaken to gain insight into the cardioact ive properties of the drug. Clinically relevant concentrations (<10 mu M) o f 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 mu M in muscles driven at I Hz, 60 mu M at 3 Hz, 3 8 mu M at 5 Hz, and 3 mu M at 1 Hz in muscles depolarized with 14 mM K+. Su bmicromolar terodiline frequently had a small positive inotropic effect, wh ereas micromolar concentrations depressed force in a frequency-dependent ma nner. Voltage-clamp results on myocytes indicate that terodiline inhibits t hree membrane currents that govern repolarization: 1) E4031-sensitive, rapi dly activating K+ current with an IC50 value near 0.7 mu M as previously re ported; 2) slowly activating, delayed-rectifier K+ current with an IC50 val ue of 26 mu M; and 3) L-type Ca2+-current with an IC50 value of 12 mu M. Th ese findings are correlated with the changes in action potential configurat ion and developed tension and discussed in relation to the cardiotoxic effe cts of the drug.