Effects of combined treatment with fesoterodine and mirabegron in a pelvic congestion rat model: Results from in vitro and in vivo functional studies.

OBJECTIVES: To examine the effect of combining a nonselective muscarinic receptor antagonist, 5-hydroxymethyl tolterodine (an active metabolite of fesoterodine), with a ß3 adrenoceptor agonist, mirabegron, in a rat model of pelvic congestion. METHODS: The rat pelvic congestion model used female Sprague-Dawley rats with their bilateral common iliac and uterine veins ligated. Expressions of M2 and M3 receptor subtypes in the urothelium and detrusor were detected by real-time polymerase chain reaction assays. The effects of both drugs were investigated on isolated bladder strips contracted by electrical field stimulation. in vivo single cystometry was used to assess the effects of 5-hydroxymethyl tolterodine and mirabegron independently or in combination on bladder capacity, micturition pressure, and threshold pressure. RESULTS: Pelvic congestion rats showed decreased bladder capacity compared with controls, but micturition pressure and threshold pressure were unchanged. Pelvic congestion model rats also demonstrated an approximately two-fold increase in expression of both M2 and M3 receptor subtypes in the urothelium. Additive relaxant effects of 5-hydroxymethyl tolterodine and mirabegron were observed in vitro in the electrical field stimulation-induced contractions of bladder strips from pelvic congestion rats. In vivo, bladder capacity was increased significantly by a combination of 5-hydroxymethyl tolterodine and mirabegron, with the combined effect exceeding the sum of the effects of monotherapies. Micturition pressure and threshold pressure did not significantly differ between groups. CONCLUSIONS: The combination of 5-hydroxymethyl tolterodine with mirabegron suggests the potential of synergistic effects in a rat pelvic congestion model.