Mechanisms and urodynamic effects of a potent and selective EP4 receptor antagonist, MF191, on cyclophosphamide and prostaglandin E₂-induced bladder overactivity in rats

Study Type - Aetiology (case control) Level of Evidence 3b What's known on the subject? and What does the study add? Recent evidence has suggested that up-regulation of the prostaglandin E₂ (PGE₂) receptor subtype 4 (EP4) receptor in the bladder is involved in bladder overactivity. The present study found that MF191, a selective EP4 receptor antagonist, may have effects on the bladder urothelium and inflammatory cells and suppress CYP- or PGE₂-induced bladder overactivity. Systemic or intravesical MF191 administration for the treatment of overactive bladder may merit clinical study. OBJECTIVE To investigate the mechanisms and urodynamic effects of a potent and selective prostaglandin E₂ (PGE₂) receptor subtype 4 (EP4) antagonist, MF191, on cyclophosphamide (CYP) or PGE₂-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 PGE₂ (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). PGE₂-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.