title: Inhibitory effects of NS-21, a novel drug for urinary incontinence, and its active metabolite, RCC-36, on L-type calcium currents in isolated guinea pig detrusor smooth muscle cells.
abstract: The inhibitory effects of NS-21, a newly developed drug for the treatment of urinary frequency and urinary incontinence, and its active metabolite, RCC-36, on L-type Ca2+ currents (ICa) in guinea pig detrusor smooth muscle cells have been compared to those of terodiline by a whole-cell patch-clamp technique. Like terodiline (10 microM), both NS-21 (10 microM) and RCC-36 (10 microM) induced a sizeable decrease in ICa elicited from a holding potential of -60 mV without changing the current-voltage relationship. The three drugs shifted the inactivation curves for ICa in the hyperpolarizing direction by 13 to 20 mV but had no effect on the activation curves for ICa resulting in a decrease in the calcium window current. The inhibitory effects of NS-21 and RCC-36 were greater than those of terodiline. The three drugs inhibited ICa in a concentration- and holding-potential-dependent manner. The IC50 values at a holding potential of -60 mV were 7.9 microM for NS-21, 6.4 microM for RCC-36, and 5.9 microM for terodiline, and at -40 mV they were 1.3, 1.2, and 3.5 microM, respectively. The ratio calculated by dividing the IC50 value at -60 mV by the value at -40 mV was 6.1, 5.3 and 1.7, respectively, indicating that the inhibitory effects of NS-21 and RCC-36 on ICa were more sensitive to voltage than those of terodiline. These results suggest that NS-21 and RCC-36 could be more effective in the treatment of urinary bladder ailments, such as urinary frequency and urinary incontinence.
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: 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 / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects*; D010276:Parasympatholytics / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018408:Patch-Clamp Techniques; D010648:Phenylacetates / Q000008:administration & dosage / Q000494:pharmacology*; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism; D014549:Urinary Incontinence / Q000188:drug therapy
chemical_list: D002082:Butylamines; D002121:Calcium Channel Blockers; D010276:Parasympatholytics; D010648:Phenylacetates; C107100:RCC 36; C010637:terodiline; C105354:temiverine; D002118:Calcium