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This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/F984    most recent 90373.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Su, X. Articles by Laping, N. J. PubMed PubMed Citation Articles by Su, X. Articles by Laping, N. J.

Modulation of bladder function by prostaglandin EP₃ receptors in the central nervous system

¹Department of Urology, ²Biological Reagents and Assay Development, and ³Department of Medicinal Chemistry, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania

Submitted 17 June 2008 ; accepted in final form 15 July 2008

Prostaglandin EP₃ receptors in the central nervous system (CNS) may exert an excitatory effect on urinary bladder function via modulation of bladder afferent pathways. We have studied this action, using two EP₃ antagonists, (2E)-3-{1-[(2,4-dichlorophenyl)methyl]-5-fluoro-3-methyl-1H-indol-7-yl}-N-[(4,5-dichloro-2-thienyl)sulfonyl]-2-propenamide (DG041) and (2E)-N-{[5-bromo-2-(methyloxy)phenyl] sulfonyl}-3-[2-(2-naphthalenylmethyl)phenyl]-2-propenamide (CM9). DG041 and CM9 were proven to be selective EP₃ antagonists with radioligand binding and functional fluorescent imaging plate reader (FLIPR) assays. Their effects on volume-induced rhythmic bladder contraction and the visceromotor reflex (VMR) response to urinary bladder distension (UBD) were evaluated in female rats after intrathecal or intracerebroventricular administration. Both DG041 and CM9 showed a high affinity for EP₃ receptors at subnanomolar concentrations without significant selectivity for any splice variants. At the human EP_3C receptor, both inhibited calcium influx produced by the nonselective agonist PGE₂. After intrathecal or intracerebroventricular administration both CM9 and DG041 dose-dependently reduced the frequency, but not the amplitude, of the bladder rhythmic contraction. With intrathecal administration DG041 and CM9 produced a long-lasting and robust inhibition on the VMR response to UBD, whereas with intracerebroventricular injection both compounds elicited only a transient reduction of the VMR response to bladder distension. These data support the concept that EP₃ receptors are involved in bladder micturition at supraspinal and spinal centers and in bladder nociception at the spinal cord. A centrally acting EP₃ receptor antagonist may be useful in the control of detrusor overactivity and/or pain associated with bladder disorders.

rhythmic contraction; nociception; bladder distension