Study on Physiological Roles of Stimulation of Prostaglandin E2 Receptor Subtype EP2 in Urethral Function in Rats

Objectives: We investigated the relaxant effect of stimulation of prostaglandin E-2 (PGE(2)) 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 PGE(2) and selective EP2 receptor agonist CP-533,536. Methods: Effects of PGE(2) 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 PGE(2) and CP-533,536 (0.01-10 mu mol/L) in rat urethral tissue pre-contracted with 10 mu mol/L phenylephrine were evaluated, and cAMP levels in isolated rat urethral tissue treated with these compounds were determined as well. The effects of PGE(2) and CP-533,536 (0.003-0.3 mg/kg intravenously) on urethral perfusion pressure (UPP) in anesthetized rats were also evaluated. Results: PGE(2) 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 mu mol/L. Both PGE(2) and CP-533,536 produced relaxation and increased cAMP levels in urethral tissues in a concentration-dependent manner. PGE(2) 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.