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

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 (I-Ca) in guinea pig detrusor smooth muscle cells have been compared to those of terodiline by a whole-cell patch-clamp technique. Like terodiline (10 mu M), both NS-21 (10 mu M) and RCC-36 (10 mu M) induced a sizeable decrease in I-Ca elicited from a holding potential of -60 mV without changing the current-voltage relationship. The three drugs shifted the inactivation curves for I-Ca in the hyperpolarizing direction by 13 to 20 mV but had no effect on the activation curves for I-Ca, 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 I-Ca in a concentration- and holding-potential-dependent manner. The IC50 values at a holding potential of -60 mV were 7.9 mu M for NS-21, 6.4 mu M for RCC-36, and 5.9 mu M for terodiline, and at -40 mV they were 1.3, 1.2, and 3.5 mu M, 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 I-Ca 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.