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444: RQ-00434739, a novel TRPM8 antagonist, inhibits prostaglandin-E2-induced hyperactivity of the primary bladder afferent nerves in rats

Speaker
N. Aizawa, Tokyo (JP)
Authors
Aizawa N. 1 , Ohshiro H. 2 , Watanabe S. 2 , Homma Y. 3 , Igawa Y. 1
Institutions
1The University of Tokyo Graduate School of Medicine, Dept. of Continence Medicine, Tokyo, Japan, 2RaQualia Pharma Inc., Discovery Research, Nagoya, Japan, 3Japanese Red Cross Medical Center, Director, Tokyo, Japan, 4
Event
33rd Annual EAU Congress Copenhagen
Date – time - Location
18 March 2018, 12:15 - 13:45, Green Area, Room 1 (Level 0)
Session
Poster Session 33 - Better understanding LUTS: A look behind the curtain
Topic
Functional LUTS, incontinence and neuro-urology: Basic science

Introduction & Objectives

Transient Receptor Potential Melastatin 8 (TRPM8), a non-selective cation channel activated by low temperatures, menthol, and icilin, may be a possible target for the treatments of bladder hypersensitive disorders. We examined the effect of RQ-00434739 (RQ), a novel selective TRPM8 antagonist, on bladder functions, especially on primary bladder single-unit afferent activities (SAAs) induced by intravesical prostaglandin E2 (PGE2)-instillation in rats.

Materials & Methods

Thirty-six female Sprague-Dawley rats were used. Cystometry (CMG) was performed under a conscious and free-moving condition 4 days after bladder catheterization. In separate rats, SAAs measured from left L6 dorsal root under a urethane-anesthetized condition, and the fibers were grouped as Aδ- or C-fiber based on their conduction velocity at a cut-off value of 2.5 m/s. In both measurements, after baseline recording with saline-instillation at a rate of 6 mL/h, further recording was performed with intravesical PGE2 (60 µM)-instillation after intravenous (i.v.) pretreatment with RQ (1 mg/kg) or its vehicle.

Results

In the CMG measurements, PGE2-instillation decreased mean voided volume after pretreatment with vehicle, whereas such effect was not observed after RQ-pretreatment (Figure 1). In the SAAs measurements, 32 single afferent fibers (n = 16 in each fiber) were isolated from 24 rats. In the presence of vehicle, PGE2-instillations increased the SAAs of C-fibers, but not of Aδ-fibers. Pretreatment with RQ significantly inhibited the PGE2-induced activation of C-fiber SAAs (Figure 2).
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Conclusions

The present results suggest that TRPM8 channels play a role in pathological activation of bladder mechanosensitive C-fibers induced by intravesical PGE2-instillation in rats. TRPM8 antagonists may be a promising drug for bladder hypersensitive disorders via an inhibitory action at mechanosensitive C-fibers.