Inhibition of cardiac inward-rectifier K+ current by terodiline.
The antispasmodic agent terodiline has cardiotoxic effects that include QT lengthening. To determine whether inhibition of inwardly-rectifying K+ current (I(K1)) might be a factor in the cardiotoxicity, we measured I(K1) in guinea pig ventricular myocytes. Terodiline reduced outward I(K1) with an IC50 of 7 microM; maximal reduction was 60% with 100-300 microM concentration. Inhibition was independent of current direction, and persisted after removal of the drug. Terodiline (3-5 microM) lengthened action potentials in guinea pig papillary muscles by ca. 10%, primarily by slowing phase 3 repolarization; higher concentrations abbreviated the plateau and markedly slowed late repolarization. Terodiline washout provoked an extra lengthening, consistent with persistent inhibition of I(K1) and rapid recovery of net inward plateau current. The results suggest that inhibition of I(K1) is a likely factor in the cardiotoxicity of the drug.
Jones
S E
SE
Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
Kasamaki
Y
Y
Ogura
T
T
Shuba
L M
LM
McCullough
J R
JR
McDonald
T F
TF
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002082:Butylamines / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010210:Papillary Muscles / Q000187:drug effects; D011188:Potassium / Q000378:metabolism*
D002082:Butylamines; D002121:Calcium Channel Blockers; C010637:terodiline; D011188:Potassium; D002118:Calcium