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

Abstract

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.

Block and modified gating of cardiac calcium channel currents by terodiline

“…Terodiline induced a concentration‐dependent reduction in the amplitude of I Ca,L in guinea‐pig ventricular myocytes pulsed to 0 mV at 0.1–0.2 Hz. Data from myocytes bathed and dialysed with K + solutions were best described by a Hill equation with IC 50 of 15.2 μ M , whereas data on Cd 2+ ‐sensitive peak I Ca,L from myocytes investigated under K + ‐free conditions were best described with an IC 50 of 12.2 μ M. The estimate determined under K + conditions is considerably lower than the K 0.5 of 33.5 μ M reported by Hayashi et al . (1997) in a study on guinea‐pig ventricular myocytes under similar (K + , temperature, pulsing rate) experimental conditions.…”

“…For example, Larsson‐Backström et al . (1985) found that terodiline inhibited rat papillary muscle contraction with an IC 50 of 18 μ M , and Hayashi et al . (1997) reported that the drug inhibited guinea‐pig ventricular I Ca,L with an IC 50 of 34 μ M .…”

Inhibition of the rapid component of the delayed‐rectifier K+ current by therapeutic concentrations of the antispasmodic agent terodiline

“…The effects of 0.03 to 10 μM terodiline on guinea‐pig ventricular I K have been evaluated, and the results indicate that the drug preferentially inhibits the I Kr component of the current. Identification of this mechanism sheds light on the cardiotoxicity of the compound, and helps clarify recent findings of Hayashi et al (1997) on guinea‐pig ventricular myocytes. These investigators measured tail I K at −40 mV after 500 ms depolarizations to positive potentials, and found that 10 μM terodiline reduced the amplitude by ca.…”

“…Adverse effects of terodiline on the heart include bradycardia, atrioventricular disturbances, QT prolongation, and malignant ventricular tachycardia (torsades de pointes) (Connolly et al , 1991; McLeod et al , 1991; Stewart et al , 1992; Pressler et al , 1995). Since terodiline inhibits cardiac I Ca,L (Hayashi et al , 1997, Ogura et al submitted; Pressler et al , 1995), it is possible that this is the sole mechanism by which the drug causes bradycardia and atrioventricular block. However, inhibition of I Kr by terodiline may contribute in both a direct and an indirect manner if, as in rabbit nodal tissues (Shibasaki, 1987; Verheijck et al , 1995; Ono & Ito, 1995; Lei & Brown, 1995), partial inhibition of I Kr in human nodal tissues lengthens the action potential, slows the pacemaker rate, and lowers the maximum diastolic potential.…”

Functional human cell-based vascularised cardiac tissue model for biomedical research and testing

“…Terodiline has two optical isomers, R- and S-terodiline, which were both present in the racemic terodiline used in our experiments. R-terodiline shows high anticholinergic properties, responsible for the prolongation of FPD 46 , whereas S-terodiline shows calcium antagonist properties 47 . It is likely that the FPD shortening effect of calcium antagonist S-terodiline concealed the FPD prolongation effect of R-terodiline.…”