Cardiac electrophysiological actions of NS-21 and its active metabolite, RCC-36, compared with terodiline

Terodiline, an anticholinergic drug with a Ca2+ blocking action, is thought to be associated with torsade de pointes, a serious ventricular tachycardia. NS-21 is a newly developed drug for the treatment of urinary frequency and urinary incontinence and it has pharmacological properties similar to those of terodiline. It remains unknown, however, whether NS-21 and its active metabolite, RCC-36, have any proarrhythmic activity. The electrophysiological properties of NS-21 and RCC-36 were examined in guinea pig ventricular myocytes and were compared with those of terodiline using the whole-cell patch-clamp technique. NS-21, RCC-36 and terodiline inhibited L-type Ca2+ currents in a concentration-dependent manner with IC50 values of 27.0, 27.0 and 33.5 microM, respectively. At a concentration of 10 microM, terodiline inhibited both the time-dependent current and the tail current of the delayed rectifier K+ current, with the latter being significantly inhibited at voltages more positive than +10 mV. In contrast, NS-21 and RCC-36 had almost no effect on either of these currents. Terodiline also inhibited the inward rectifier K+ current significantly at voltages more negative than -100 mV, whereas NS-21 and RCC-36 had little effect. If the proarrhythmic activity of terodiline resulted primarily from the combined inhibition of K+ and Ca2+ currents, one might expect that NS-21 and RCC-36, which inhibit L-type Ca2+ currents without affecting either the delayed rectifier K+ current or the inward rectifier K+ current, would not share the proarrhythmic activities of terodiline.