Enhanced bladder capacity and reduced prostaglandin E2-mediated bladder hyperactivity in EP3 receptor knockout mice.
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 ( approximately 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.
Urogenital Biology, Cardiovascular and Urogenital Center for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Gerald P
GP
McCafferty
Blake A
BA
Misajet
Nicholas J
NJ
Laping
Richard M
RM
Edwards
Kevin S
KS
Thorneloe
D019342:Acetic Acid; D000818:Animals; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D001743:Urinary Bladder / Q000473:pathology* / Q000503:physiopathology*; D053201:Urinary Bladder, Overactive / Q000139:chemically induced / Q000378:metabolism*
D011459:Prostaglandins E, Synthetic; D020033:Protein Isoforms; C545648:Ptger3 protein, mouse; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; C067522:GR 63799X; D015232:Dinoprostone; D019342:Acetic Acid