title: 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.
authors.affiliation: Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hayashi
authors.forename: T
authors.initials: T
authors.lastname: Natsukawa
authors.forename: C
authors.initials: C
authors.lastname: Suma
authors.forename: Y
authors.initials: Y
authors.lastname: Ukai
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshikuni
authors.forename: K
authors.initials: K
authors.lastname: Kimura
mesh_terms: D000818:Animals; D002082:Butylamines / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D018680:Cholinergic Antagonists / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D010276:Parasympatholytics / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010648:Phenylacetates / Q000378:metabolism / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism
chemical_list: D002082:Butylamines; D002121:Calcium Channel Blockers; D018680:Cholinergic Antagonists; D010276:Parasympatholytics; D010648:Phenylacetates; C107100:RCC 36; C010637:terodiline; C105354:temiverine; D011188:Potassium; D002118:Calcium