Effect of Selective Prostaglandin E2 EP2 Receptor Agonist CP-533,536 on Voiding Efficiency in Rats with Midodrine-Induced Functional Urethral Obstruction.
OBJECTIVE
We investigated the effect of the selective prostaglandin E2 EP2 receptor agonist CP-533,536 on voiding efficiency in rats with midodrine-induced functional urethral obstruction.


METHODS
The effect of CP-533,536 (0.03-0.3 mg/kg, intravenous [i.v.]) on urethral perfusion pressure (UPP) was investigated in anesthetized rats pre-treated with midodrine (1 mg/kg, i.v.), which forms an active metabolite that acts as an α1 -adrenoceptor agonist. The effect of CP-533,536 (0.03-0.3 mg/kg, i.v.) on cystometric parameters was also investigated in anesthetized rats. In addition, the effect of CP-533,536 (0.03-0.3 mg/kg, i.v.) on residual urine volume (RV) and voiding efficiency (VE) was investigated in conscious rats treated with midodrine (1 mg/kg, i.v.).


RESULTS
CP-533,536 dose-dependently decreased UPP elevated by midodrine in anesthetized rats. In contrast, CP-533,536 did not affect maximum voiding pressure, intercontraction interval, or intravesical threshold pressure. In conscious rats, midodrine (1 mg/kg, i.v.) markedly increased RV and reduced VE. CP-533,536 dose-dependently ameliorated increases in RV and decreases in VE induced by midodrine.


CONCLUSIONS
These results suggest that a selective EP2 receptor agonist could ameliorate the elevation of RV and improve the reduction of VE in rats with functional urethral obstruction caused by stimulation of α1 -adrenoceptors. The mechanism of action might be not potentiation of bladder contraction but rather preferential relief of urethral constriction.
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
Ryoko
R
Kurihara
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
Katsunori
K
Imazumi
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
Hajime
H
Takamatsu
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
Kenichiro
K
Ishizu
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
Taiji
T
Yoshino
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
Noriyuki
N
Masuda
D058646:Adrenergic alpha-1 Receptor Agonists / Q000633:toxicity; D000818:Animals; D005260:Female; D008297:Male; D008879:Midodrine / Q000633:toxicity; D011725:Pyridines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists*; D012018:Reflex / Q000187:drug effects; D014524:Urethral Obstruction / Q000188:drug therapy* / Q000503:physiopathology; D014554:Urination / Q000187:drug effects*
D058646:Adrenergic alpha-1 Receptor Agonists; C475539:CP533536; D011725:Pyridines; D058307:Receptors, Prostaglandin E, EP2 Subtype; D008879:Midodrine
EP2; rat; urethra; voiding efficiency