title: Inhibition of the rapid component of the delayed-rectifier K+ current by therapeutic concentrations of the antispasmodic agent terodiline.
abstract: Prolongation of the QT interval and malignant ventricular arrhythmia have been observed in patients administered terodiline for urinary incontinence. Since this adverse reaction might be caused by inhibition of delayed-rectifier K+ current (IK), we investigated whether clinically relevant (< or = 10 microM) concentrations of the drug modify IK in guinea-pig ventricular myocytes. Myocytes superfused with normal Tyrode's solution were pulsed from -40 mV to more positive test potentials (V) for 0.2 - 1 s to elicit tail IK on repolarization and measure tail IK-V relationships. IKr was distinguished from IKs by its sensitivity to the selective blocker E4031. Inhibition of IKr by 5 microM E4031 was completely occluded by pretreatment with 3 microM terodiline. In addition, action potential lengthening by E4031 in guinea-pig papillary muscles (29+/-3%) was abolished (3+/-2%) (P<0.001) by terodiline pretreatment. Inhibition of IKr by terodiline appeared to be voltage-independent, and the parameters of the Hill equation describing the inhibition were IC50 = 0.7 microM and nH = 1.6. High concentrations of the drug also affect IKs; in experiments with K+-free Tyrode's, 10 microM terodiline inhibited tail IKs by 27+/-3% (n=5) (P< 0.001). These data suggest that QT lengthening at therapeutic concentrations of the drug (approximately equal to 1.5 microM) is primarily due to inhibition of IKr. Inhibition of other K+ currents such as IKs is likely to be important at higher concentrations.
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: S E
authors.initials: SE
authors.lastname: Jones
authors.forename: T
authors.initials: T
authors.lastname: Ogura
authors.forename: L M
authors.initials: LM
authors.lastname: Shuba
authors.forename: T F
authors.initials: TF
authors.lastname: McDonald
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002082:Butylamines / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010276:Parasympatholytics / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011188:Potassium / Q000502:physiology*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D016276:Ventricular Function
chemical_list: D000889:Anti-Arrhythmia Agents; D002082:Butylamines; D002121:Calcium Channel Blockers; D010276:Parasympatholytics; D010880:Piperidines; D015221:Potassium Channels; D011725:Pyridines; C063968:E 4031; C010637:terodiline; D011188:Potassium