Masashi Honda1,2, Katsuya Hikita1, Bunya Kawamoto1, Kuniyasu Muraoka1, Shogo Shimizu3, Motoaki Saito3, Takehiro Sejima1, Michael B Chancellor4, Naoki Yoshimura5, Atsushi Takenaka1. 1. Department of Urology, Tottori University Faculty of Medicine, 36-1 Nishi, Yonago, 683-8504, Japan. 2. Department of Urology, University of Pittsburgh School of Medicine, Suite 700 Kaufmann Medical Building, 3471 Fifth Avenue, Pittsburgh, PA, 15213, USA. 3. Department of Pharmacology, Kochi University School of Medicine, Okocho Kohasu, Nankoku, 7838505, Japan. 4. Department of Urology, William Beaumont Hospital, 3535 W 13 Mile Rd #404, Royal Oak, MI, 48073, USA. 5. Department of Urology, University of Pittsburgh School of Medicine, Suite 700 Kaufmann Medical Building, 3471 Fifth Avenue, Pittsburgh, PA, 15213, USA. nyos@pitt.edu.
Abstract
PURPOSE: Glycine is an inhibitory neurotransmitter in the central nervous system. So far, two types of glycine transporters (GlyTs), GlyT-1 and GlyT-2, have been cloned. The aim of this study is to investigate the effects of a selective GlyT-1 inhibitor that can increase endogenous glycine concentration on the micturition reflex in urethane-anesthetized rats. METHODS: Continuous cystometrograms (0.04 ml/min) were performed in female Sprague-Dawley rats (232-265 g) under urethane anesthesia. After stable micturition cycles were established, ALX5407, a selective GlyT-1 inhibitor, was administered intrathecally or intracerebroventricularly to evaluate changes in bladder activity. Cystometric parameters were recorded and compared before and after drug administration. RESULTS: Intrathecal administration of ALX5407 (1, 3, 10 and 30 μg) increased intercontraction intervals at doses of 3 μg or higher in a dose-dependent fashion. Intrathecal administration of ALX5407 (1, 3, 10 and 30 μg) also increased pressure threshold at doses of 3 μg or higher in a dose-dependent fashion. However, when ALX5407 (1, 3, 10 and 30 μg) was administered intracerebroventricularly, there were no significant changes in intercontraction intervals, pressure threshold, maximum voiding pressure or baseline pressure or post-void residual urine volume at any doses tested. CONCLUSION: The results of our study indicate that GlyT-1 plays an important role in the modulation of micturition. Furthermore, these findings indicate that in urethane-anesthetized rats suppression of GlyT-1 can inhibit the micturition reflex at the spinal cord level. Thus, GlyT-1 could be a potential target for the treatment of bladder dysfunction such as overactive bladder.
PURPOSE:Glycine is an inhibitory neurotransmitter in the central nervous system. So far, two types of glycine transporters (GlyTs), GlyT-1 and GlyT-2, have been cloned. The aim of this study is to investigate the effects of a selective GlyT-1 inhibitor that can increase endogenous glycine concentration on the micturition reflex in urethane-anesthetized rats. METHODS: Continuous cystometrograms (0.04 ml/min) were performed in female Sprague-Dawley rats (232-265 g) under urethane anesthesia. After stable micturition cycles were established, ALX5407, a selective GlyT-1 inhibitor, was administered intrathecally or intracerebroventricularly to evaluate changes in bladder activity. Cystometric parameters were recorded and compared before and after drug administration. RESULTS: Intrathecal administration of ALX5407 (1, 3, 10 and 30 μg) increased intercontraction intervals at doses of 3 μg or higher in a dose-dependent fashion. Intrathecal administration of ALX5407 (1, 3, 10 and 30 μg) also increased pressure threshold at doses of 3 μg or higher in a dose-dependent fashion. However, when ALX5407 (1, 3, 10 and 30 μg) was administered intracerebroventricularly, there were no significant changes in intercontraction intervals, pressure threshold, maximum voiding pressure or baseline pressure or post-void residual urine volume at any doses tested. CONCLUSION: The results of our study indicate that GlyT-1 plays an important role in the modulation of micturition. Furthermore, these findings indicate that in urethane-anesthetized rats suppression of GlyT-1 can inhibit the micturition reflex at the spinal cord level. Thus, GlyT-1 could be a potential target for the treatment of bladder dysfunction such as overactive bladder.