Dual modulation of urinary bladder activity and urine flow by prostanoid EP3 receptors in the conscious rat.
OBJECTIVE
Cyclooxygenase inhibitors function to reduce levels of prostaglandin E(2) (PGE(2)) and are broadly efficacious in models of bladder overactivity. We therefore investigated a regulation of urinary bladder function in conscious rats by modulation of the EP(3) receptor for PGE(2).


METHODS
The activity of the EP(3) receptor agonist GR63799X, and EP(3) receptor antagonists, CM9 and DG041, at recombinant EP(3) receptors was evaluated in vitro. In vivo, intraduodenal dosing during conscious, continuous-filling cystometry of spontaneously hypertensive rats was utilized to determine the urodynamic effect of EP(3) receptor modulation.


RESULTS
GR63799X dose-dependently (0.001-1 mg x kg(-1)) reduced bladder capacity, as indicated by a reduction in both the micturition interval and volume of urine per void. In contrast, CM9 (10 and 30 mg x kg(-1)) and DG041 (30 mg x kg(-1)) enhanced bladder capacity, as indicated by significantly longer micturition intervals and larger void volumes. CM9 and DG041 inhibited the responses to GR63799X supporting the in vivo activity of these pharmacological agents at the EP(3) receptor. In addition to its effect on bladder capacity, GR63799X increased endogenous urine production. Intra-arterial infusion of saline mimicked the enhancement of urine flow observed with GR63799X, and the response was inhibited by CM9.


CONCLUSIONS
These data support the EP(3) receptor as a modulator of urinary bladder activity in the conscious rat, and in addition, indicate a role for EP(3) receptor activity in regulating urine flow.
Jugus
M J
MJ
Urogenital Biology, Cardiovascular and Urogenital Center for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA 19406, USA.
Jaworski
J P
JP
Patra
P B
PB
Jin
J
J
Morrow
D M
DM
Laping
N J
NJ
Edwards
R M
RM
Thorneloe
K S
KS
D000818:Animals; D002460:Cell Line; D003243:Consciousness / Q000502:physiology; D005260:Female; D006801:Humans; D011459:Prostaglandins E, Synthetic / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000502:physiology*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology*; D014554:Urination / Q000187:drug effects / Q000502:physiology*
C545647:PTGER3 protein, human; D011459:Prostaglandins E, Synthetic; C545649:Ptger3 protein, rat; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; C067522:GR 63799X