Differences in the effects of urinary incontinence agents S-oxybutynin andterodiline on cardiac K+ currents and action potentials

1 The cardiac electrophysiological effects of S-oxybutynin, a single-enanti omer drug under evaluation for the management of urinary incontinence, have been investigated and compared with those of terodiline, an incontinence a gent withdrawn following reports of QT lengthening and ventricular tachyarr hythmia. Membrane currents were recorded from whole-cell configured guineap ig and rabbit ventricular myocytes, and action potentials were recorded fro m guinea-pig and rabbit papillary muscles. 2 L-type Ca2+ current (I-Ca,I-L), rapidly-activating K+ current (I-Kr) and slowly-activating K+ current (I-Ks) were unaffected by submicromolar S-oxyb utynin and inhibited by higher concentrations; IC50 values were 17.8 mu M f or I-Ca,L, 12 mu M for I-Kr, and 41 mu M for I-Ks. Terodiline IC50 values w ere somewhat lower for I-Ca,I-L (15.2 mu M) and I-Ks (30 mu M), but 24 fold lower in the case of I-Kr (0.5 mu M). 3 The durations of action potentials in guinea-pig and rabbit papillary mus cles driven at 1 Hz were unaffected or moderately shortened by 0.1-100 mu M S-oxybutynin, but lengthened by terodiline. Terodiline (less than or equal to 10 mu M) 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 sho rtening was significantly smaller in the presence of drugs (30 mu M S-oxybu tynin, 3 and 30 mu M terodiline), suggesting that they suppress the transie nt outward current (I-to) involved in rate-dependent shortening. In experim ents on rabbit ventricular myocytes, 3 and 30 mu M S-oxybutynin inhibited I -to by 9+/-2% and 35+3%, respectively, whereas 3 and 30 mu M terodiline inh ibited the current by 31+/-3% and 87+/-3%, respectively. 5 The results indicate that S-oxybutynin has relatively weak non-specific e ffects on cardiac ion channels, and that clinically relevant submicromolar concentrations are unlikely to have terodiline-like proarrhythmic actions o n the myocardium.