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MP62-09 DETRUSOR RELAXATION MEDIATED BY ACTIVATION OF THE SUCCINATE RECEPTOR GPR91.

INTRODUCTION AND OBJECTIVES: The bladder urothelium and detrusor layer express the succinate receptor, GPR91. The acute and immediate effects of its activation on bladder function have yet been described. The aim of this study is to demonstrate the acute effect of succinate activation of its receptor GPR91 on bladder contraction/relaxation using a mouse model with specific deletion of the GPR91 receptor. METHODS: Conscious cystometry was carried out on C57Bl6 and GPR91(-/-) mice with and without succinate intravesical instillation. Contractile properties of bladder strips from the 2 strains were analyzed by organ bath. Characteristics of bladder were analyzed by Masson's trichrome and immunoblotting. Primary urothelial cell culture from both groups were investigated for nitric oxide secretion (colorimetric assay), ATP and cGMP levels (commercial kits). RESULTS: The body weight was similar between GPR91(-/-) and C57Bl6 mice, while the bladder mass was higher in GPR91(-/-) mice. Masson's trichrome revealed a thicker urothelium and lamina propria in GPR91(-/-) mice. Conscious cystometry showed that GPR91(-/-) mice had a lower bladder capacity, lower micturition volume and lower intercontraction interval. Intravesical instillation of succinate (10 mM) increased the bladder capacity in C57Bl6 mice only. In organ bath, bladder strips from C57Bl6 and GPR91(-/-) mice had similar contractions elicited by potassium chloride ,carbachol and electrical field stimulation. Succinate administration relaxed carbachol-stimulated strips in C57Bl6 mice only. In vitro, short-term secretion of nitric oxide by urothelial cells from C57Bl6 and KO mice were similar at all concentrations (from 200 µM to 10 mM), confirming that nitric oxide is not involved in relaxation elicited by succinate. Succinate did not affect cGMP levels either in cell culture but decreased ATP released into the culture medium. CONCLUSIONS: These results suggest that succinate modulates the relaxation-contraction of the detrusor through its action on its receptor GPR91, possibly by decreasing ATP synthesis in the urothelium. Source of Funding: This research was funded by the FRQS.