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Mechanisms and urodynamic effects of a potent and selective EP4 receptor antagonist, MF191, on cyclophosphamide and prostaglandin E 2 ‐induced bladder overactivity in rats
Author(s) -
Chuang YaoChi,
Tyagi Pradeep,
Huang ChaoCheng,
Chancellor Michael B.,
Yoshimura Naoki
Publication year - 2012
Publication title -
bju international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.773
H-Index - 148
eISSN - 1464-410X
pISSN - 1464-4096
DOI - 10.1111/j.1464-410x.2012.11096.x
Subject(s) - antagonist , overactive bladder , urothelium , urinary bladder , downregulation and upregulation , prostaglandin e2 , receptor antagonist , prostaglandin , saline , medicine , chemistry , endocrinology , prostaglandin e , receptor , pharmacology , inflammation , pathology , biochemistry , alternative medicine , gene
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 E 2 (PGE 2 ) 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 PGE 2 ‐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 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.