Differences in the effects of urinary incontinence agents S-oxybutynin and terodiline on cardiac K(+) currents and action potentials.
1. The cardiac electrophysiological effects of S-oxybutynin, a single-enantiomer drug under evaluation for the management of urinary incontinence, have been investigated and compared with those of terodiline, an incontinence agent withdrawn following reports of QT lengthening and ventricular tachyarrhythmia. Membrane currents were recorded from whole-cell configured guinea-pig and rabbit ventricular myocytes, and action potentials were recorded from guinea-pig and rabbit papillary muscles. 2. L-type Ca(2+) current (I:(Ca,L)), rapidly-activating K(+) current (I:(Kr)) and slowly-activating K(+) current (I:(Ks)) were unaffected by submicromolar S-oxybutynin and inhibited by higher concentrations; IC(50) values were 17.8 microM for I:(Ca,L), 12 microM for I:(Kr), and 41 microM for I:(Ks). Terodiline IC(50) values were somewhat lower for I:(Ca,L) (15.2 microM) and I:(Ks) (30 microM), but 24 fold lower in the case of I:(Kr) (0.5 microM). 3. The durations of action potentials in guinea-pig and rabbit papillary muscles driven at 1 Hz were unaffected or moderately shortened by 0.1 - 100 microM S-oxybutynin, but lengthened by terodiline. Terodiline (< or =10 microM) also depressed maximal upstroke velocity. 4. The action potential plateau shortened by an average of 23% when control rabbit papillary muscles were driven at 0.4 Hz instead of 1 Hz. Plateau shortening was significantly smaller in the presence of drugs (30 microM S-oxybutynin, 3 and 30 microM terodiline), suggesting that they suppress the transient outward current (I:(to)) involved in rate-dependent shortening. In experiments on rabbit ventricular myocytes, 3 and 30 microM S-oxybutynin inhibited I:(to) by 9+/-2% and 35+/-3%, respectively, whereas 3 and 30 microM terodiline inhibited the current by 31+/-3% and 87+/-3%, respectively. 5. The results indicate that S-oxybutynin has relatively weak non-specific effects on cardiac ion channels, and that clinically relevant submicromolar concentrations are unlikely to have terodiline-like proarrhythmic actions on the myocardium.
Jones
S E
SE
Department of Physiology and Biophysics, Dalhousie University Halifax, Nova Scotia, B3H 4H7 Canada.
Shuba
L M
LM
Zhabyeyev
P
P
McCullough
J R
JR
McDonald
T F
TF
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002082:Butylamines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008333:Mandelic Acids / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010276:Parasympatholytics / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D011817:Rabbits; D014549:Urinary Incontinence / Q000503:physiopathology; D016276:Ventricular Function
D002082:Butylamines; D008333:Mandelic Acids; D010276:Parasympatholytics; D015221:Potassium Channels; C010637:terodiline; C005419:oxybutynin