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Sources of Funding: none

Introduction

GsMTx4, an inhibitor of stretch-activated-channels (SACs), showed dose-dependent effect. At EAU2014, we reported that the intraperitoneal administration (i.p) of GsMTx4 1.35mg/kg could reduce voiding frequency (VF) and increase urine volume/voiding (Uvol/v) in mice. Furthermore, we reported at ICS2016 that Clock mutant mouse showed a phenotype of nocturia (NOC) because of the loss of circadian sensation of bladder fullness, which regulated by clock genes. In order to assess the effect of GsMTx4 on NOC, and the differences of these effects according to circadian rhythm of urine sensation, we measured voiding behavior pre and post i.p of GsMTx4 in different time between wild type mice and Clock mutant mice. _x000D_

Methods

Male C57BL/6 mice (WT) and C57BL/6 Clock mutant mice (mutant) were bred under 12 h light/dark cycles for 2 week. The light period (sleep phase in mice) started from 6 a.m. [zeitgeber time (ZT) 0]. GsMTx4 0.75 mg/kg diluted with normal saline (NS) 100 ul was administrated by i.p at the peak and nadir of gene expression time of SACs, which consistent with the beginning of active phase (ZT12) and the beginning of sleep phase (ZT0), respectively. In control of each genotype, NS 100 ul was administrated. The changes of following parameters were measured using metabolic cage: VF, urine volume (UV) and Uvol/v. In ZT12 i.p group, during 12hrs voiding behavior in active phase of pre and post i.p, In ZT0 i.p group, during 12hrs voiding behavior in sleep phase of pre and post i.p, were compared between WT and mutant mice. Data were analysed using Wilcoxon signed-rank test and Mann-Whitney u-test.

Results

UV didn't show differences between WT and mutant mice. In WT, VF after ZT0 i.p (during sleep phase) was significantly decreased. In contrast, mutant showed significant decreasing in VF both ZT0 and ZT12 i.p (Fig. 1). Uvol/v was not increased both ZT0 and ZT12 i.p in WT mice. In contrast, Uvol/v was significantly increased both ZT0 and ZT12 i.p in mutant mice.

Conclusions

In WT, the lower VF and higher Uvol/v after GsMTx4 1.35 mg/kg i.p was not observed in 0.75mg/kg i.p. These effects seemed to be change with time-dependently, namely to be enhanced during sleep phase in WT when the SACs expression level were lower. In contrast, mutant showed significant effect on the voiding suppression both ZT0 and ZT12 i.p. These results suggested that GsMTx4 may show the improving effect on NOC with the lower dose if appreciate administration time were selected, and be useful for the treatment of NOC caused by the disruption of circadian rhythm in sensation of bladder fullness.

Funding

none