Study on Physiological Roles of Stimulation of Prostaglandin E2 Receptor Subtype EP2 in Urethral Function in Rats.
OBJECTIVE
We investigated the relaxant effect of stimulation of prostaglandin E2 (PGE2 ) receptor subtype EP2 as well as the involvement of a cyclic AMP (cAMP)-dependent pathway related to stimulation of EP2 receptors in urethral function in rats by evaluating effects of PGE2 and selective EP2 receptor agonist CP-533,536.


METHODS
Effects of PGE2 and CP-533,536 on cAMP accumulation were assessed in Chinese hamster ovary (CHO)-K1 cells expressing rat EP2 or EP4 receptors. Relaxant responses to PGE2 and CP-533,536 (0.01-10 µmol/L) in rat urethral tissue pre-contracted with 10 µmol/L phenylephrine were evaluated, and cAMP levels in isolated rat urethral tissue treated with these compounds were determined as well. The effects of PGE2 and CP-533,536 (0.003-0.3 mg/kg intravenously) on urethral perfusion pressure (UPP) in anesthetized rats were also evaluated.


RESULTS
PGE2 concentration-dependently increased the accumulation of cAMP in cells expressing rat EP2 (EC50 value = 1.3 nmol/L) and EP4 receptors (EC50 value = 17 nmol/L). While CP-533,536 similarly increased the accumulation of cAMP in cells expressing rat EP2 receptors (EC50 value = 3.0 nmol/L), no such effects were noted in cells expressing rat EP4 receptors up to 10 µmol/L. Both PGE2 and CP-533,536 produced relaxation and increased cAMP levels in urethral tissues in a concentration-dependent manner. PGE2 and CP-533,536 both dose-dependently decreased UPP in anesthetized rats.


CONCLUSIONS
Taken together, these results suggest that stimulation of EP2 receptors induces relaxation likely via activation of cAMP-dependent mechanisms in rat urethral tissue, leading to a reduction of UPP.
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.
Kenichiro
K
Ishizu
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.
Taiji
T
Yoshino
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
Noriyuki
N
Masuda
D000704:Analysis of Variance; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists* / Q000502:physiology; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D014521:Urethra / Q000187:drug effects / Q000502:physiology*
C475539:CP533536; D011725:Pyridines; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000242:Cyclic AMP
EP2; cAMP; relaxation; urethra