OBJECTIVE: To investigate the mechanisms and urodynamic effects of a potent and selective prostaglandin E(2) (PGE(2)) receptor subtype 4 (EP4) antagonist, MF191, on cyclophosphamide (CYP) or PGE(2)-induced bladder overactivity in rats. MATERIALS AND METHODS: Experimental and control rats were injected with CYP (200 mg/kg i.p.) or saline on day 1. Continuous cystometrogram (CMGs) were performed on day 3. In group 1, MF191 (vehicle 0.1 and 1 mg/kg) was given i.v. The bladder was then harvested for histology and immunohistochemistry. Some bladders were harvested for analysis of EP4 expression by Western blotting without a CMG study. In group 2, MF191 (vehicle 10 nM, and 100 nM) was continuously infused into the bladder. In group 3, bladder overactivity was induced by intravesical instillation of PGE(2) (200 uM) and vehicle or MF191 (1 mg/kg) was given i.v. RESULTS: CYP induced bladder inflammation, overactivity and EP4 upregulation. The CYP effects were suppressed by MF191 (1 mg/kg i.v.; intercontraction interval [ICI]: 39.4% increase, and reduced inflammatory cells infiltration, and EP4 expression). Intravesical instillation of MF191 (100 nM) suppressed CYP-induced bladder overactivity (ICI: 71.8% increase). PGE(2)-induced bladder overactivity was suppressed by MF191 (ICI: 43.2% increase). MF191 had no significant effects on other CMG variables or on control rats. CONCLUSIONS: MF191 might affect the bladder urothelium and inflammatory cells and suppresses CYP- or PGE(2)-induced bladder overactivity. Systemic or intravesical MF191 administration for the treatment of overactive bladder merits clinical study.
OBJECTIVE: To investigate the mechanisms and urodynamic effects of a potent and selective prostaglandin E(2) (PGE(2)) receptor subtype 4 (EP4) antagonist, MF191, on cyclophosphamide (CYP) or PGE(2)-induced bladder overactivity in rats. MATERIALS AND METHODS: Experimental and control rats were injected with CYP (200 mg/kg i.p.) or saline on day 1. Continuous cystometrogram (CMGs) were performed on day 3. In group 1, MF191 (vehicle 0.1 and 1 mg/kg) was given i.v. The bladder was then harvested for histology and immunohistochemistry. Some bladders were harvested for analysis of EP4 expression by Western blotting without a CMG study. In group 2, MF191 (vehicle 10 nM, and 100 nM) was continuously infused into the bladder. In group 3, bladder overactivity was induced by intravesical instillation of PGE(2) (200 uM) and vehicle or MF191 (1 mg/kg) was given i.v. RESULTS: CYP induced bladder inflammation, overactivity and EP4 upregulation. The CYP effects were suppressed by MF191 (1 mg/kg i.v.; intercontraction interval [ICI]: 39.4% increase, and reduced inflammatory cells infiltration, and EP4 expression). Intravesical instillation of MF191 (100 nM) suppressed CYP-induced bladder overactivity (ICI: 71.8% increase). PGE(2)-induced bladder overactivity was suppressed by MF191 (ICI: 43.2% increase). MF191 had no significant effects on other CMG variables or on control rats. CONCLUSIONS: MF191 might affect the bladder urothelium and inflammatory cells and suppresses CYP- or PGE(2)-induced bladder overactivity. Systemic or intravesical MF191 administration for the treatment of overactive bladder merits clinical study.
Authors: Christopher L Langdale; James A Hokanson; Philip H Milliken; Arun Sridhar; Warren M Grill Journal: Am J Physiol Renal Physiol Date: 2020-04-20