Inhibition of the rapid component of the delayed-rectifier K+ current by therapeutic concentrations of the antispasmodic agent terodiline.
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.
Jones
S E
SE
Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
Ogura
T
T
Shuba
L M
LM
McDonald
T F
TF
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
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