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

Authors


Yao-Chi Chuang, 123 Ta Pei Road, Niao Song Hsiang, Kaohsiung Hsien 833, Taiwan. e-mail: chuang82@ms26.hinet.net

Abstract

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 PGE2-induced bladder overactivity.
  • • Systemic or intravesical MF191 administration for the treatment of overactive bladder merits clinical study.

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