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Enhanced bladder capacity and reduced prostaglandin E₂-mediated bladder hyperactivity in EP3 receptor knockout mice

Urogenital Biology, Cardiovascular and Urogenital Center for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania

Submitted 30 January 2008 ; accepted in final form 23 May 2008

Nonsteroidal anti-inflammatory cyclooxygenase inhibitors that function to reduce prostaglandin E₂ (PGE₂) production have been widely reported as effective agents in models of urinary bladder overactivity. We therefore investigated a potential role for the PGE₂ receptor, EP3, in urinary bladder function by performing conscious, freely moving cystometry on EP3 receptor knockout (KO) mice. EP3 KO mice demonstrated an enhanced bladder capacity compared with wild-type (WT) mice (185% of WT) under control conditions, based on larger voided and infused bladder volumes. Infusion of the EP3 receptor agonist GR63799X into the bladder of WT mice reduced the bladder capacity. This was ineffective in EP3 KO mice that demonstrated a time-dependent increase in bladder capacity with GR63799X, an effect similar to that observed with vehicle in both genotypes. In addition, infusion of PGE₂ into WT mice induced bladder overactivity, an effect that was significantly blunted in the EP3 KO mice. The data reported here provide the first evidence supporting a functional role for EP3 receptors in normal urinary bladder function and implicate EP3 as a contributor to bladder overactivity during pathological conditions of enhanced PGE₂ production, as reported previously in overactive bladder patients.

GR63799X; conscious cystometry