Expression of E-series prostaglandin (EP) receptors and urodynamic effects of an EP4 receptor antagonist on cyclophosphamide-induced overactive bladder in rats.

Abstract

To investigate the expression of four subtypes of E-series prostaglandin (EP(1) -EP(4) ) receptors and the urodynamic effects of an EP(4) receptor antagonist (AH23848) in cyclophosphamide (CYP)-induced overactive bladder (OAB) in rats, as intravesical prostaglandin E(2) (PGE(2) ) induces OAB via activation of EP receptors and sensitization of afferent nerves. Experimental and control rats were injected with CYP (200 mg/kg, intraperitoneally) or saline, respectively. Continuous cystometrograms (CMGs) were performed 48 h after CYP or saline injection under urethane anaesthesia. AH23848 was given intravenously at doses of 0.01 and 0.1 mg/kg. The bladder was then harvested for histology. Some bladders were harvested for analysis of EP receptors expression by Western blotting without a CMG study. CMG variables (baseline pressure; intercontraction interval [ICI], pressure threshold [PT], contraction amplitude) and histological changes were measured. CYP-induced up-regulation of EP(4) receptor (100% increase) accompanied by detrusor overactivity (ICI 70.5% decrease; PT, 67.7% increase). However, CYP down-regulated EP(1) receptor expression (51.9% decrease), but had no significant effects on the EP(2) and EP(3) receptors. AH23848 significantly extended the ICI in CYP-treated rats but it had no effects on other urodynamic variables or in control rats. Modulation of EP receptors plays a role in CYP-induced OAB. Antagonists to the EP(4) receptor may be a new target for treatment of patients with OAB.