Urodynamic effects of a novel EP(1) receptor antagonist in normal rats and rats with bladder outlet obstruction.
OBJECTIVE
Prostaglandin E(2) and its EP(1) receptor were suggested as endogenous modulators of bladder function in the normal physiological state and under pathophysiological conditions. We investigated if the new EP(1) receptor antagonist PF-2907617-02 would influence the regulation of normal micturition in rats, and if it affects bladder function in animals with partial bladder outlet obstruction.


METHODS
The study was performed in normal female Sprague-Dawley rats and in rats with moderate, experimentally induced bladder outlet obstruction 2 weeks in duration. All animals underwent continuous cystometry in the awake state. PF-2907617-02 was given intravenously at doses of 0.1 and 1.0 mg/kg(-1) in normal rats, and at 1.0 mg/kg(-1) in bladder outlet obstructed animals. In a group of normal rats detrusor overactivity was produced by intravesical instillation of prostaglandin E(2).


RESULTS
In normal rats PF-2907617-02 (1 mg/kg(-1)) significantly increased bladder capacity, micturition volume and the micturition interval but it had no effect on other urodynamic parameters. The lower dose of PF-2907617 (0.1 mg/kg(-1)) showed no effect. Intravesical prostaglandin E(2) (50 muM) induced detrusor overactivity. The antagonist significantly decreased the stimulatory effects of prostaglandin E(2) at 0.1 and 1.0 mg/kg(-1). In obstructed animals PF-2907617-02 significantly increased the micturition interval but not bladder capacity and residual volume. The drug also decreased the frequency and amplitude of nonvoiding contractions.


CONCLUSIONS
EP(1) receptor is involved in initiation of the micturition reflex in normal rats and in animals with bladder outlet obstruction. It may also contribute to the generation of detrusor overactivity after bladder outlet obstruction. Thus, EP(1) receptor antagonists may have potential as treatment for detrusor overactivity in humans.
Lee
Tack
T
Department of Clinical and Experimental Pharmacology, Lund University Hospital, Lund, Sweden.
Hedlund
Petter
P
Newgreen
Donald
D
Andersson
Karl-Erik
KE
D000818:Animals; D005260:Female; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D001748:Urinary Bladder Neck Obstruction / Q000503:physiopathology*; D014563:Urodynamics / Q000187:drug effects*
C545635:PTGER1 protein, human; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype