Modulation of bladder function by prostaglandin EP3 receptors in the central nervous system.
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 EP3C 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.
Su
Xin
X
GlaxoSmithKline Pharmaceuticals, Department of Urology, 709 Swedeland Rd., King of Prussia, PA 19406-0939, USA.
Leon
Lisa A
LA
Wu
Charlene W
CW
Morrow
Dwight M
DM
Jaworski
Jon-Paul
JP
Hieble
J Paul
JP
Lashinger
Erin S R
ES
Jin
Jian
J
Edwards
Richard M
RM
Laping
Nicholas J
NJ
D000178:Acrylamides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000187:drug effects / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D006801:Humans; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D007668:Kidney / Q000166:cytology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000502:physiology; D012516:Osteosarcoma; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D012018:Reflex / Q000187:drug effects / Q000502:physiology*; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology; D014162:Transfection; D014316:Tritium; D001743:Urinary Bladder / Q000294:innervation* / Q000502:physiology*; D014554:Urination / Q000502:physiology
C531572:3-(1-((2,4-dichlorophenyl)methyl)-5-fluoro-3-methyl-1H-indol-7-yl)-N-((4,5-dichloro-2-thienyl)sulfonyl)-2-propenamide; D000178:Acrylamides; C545647:PTGER3 protein, human; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013450:Sulfones; D014316:Tritium; D015232:Dinoprostone