Biphasic actions of prostaglandin E2 on the renal afferent arteriole -: Role of EP3 and EP4 receptors

Prostaglandin (PG) E-2 is an important modulator of the actions of angoiotensin (Ang) II, In the present study, we investigated the renal microvascular actions of PGE(2) and the EP receptor subtypes involved. Ibuprofen potentiated Ang II-induced vasoconstriction in in vitro perfused normal rat kidneys and augmented afferent arteriolar, but not efferent arteriolar, responses in the hydronephrotic rat kidney model. This preglomerular effect of endogenous prostanoids was mimicked by exogenous PGE(2), which reversed Ang II-induced afferent arteriolar vasoconstriction at concentrations of 0.1 to 10 nmol/L without affecting the efferent arteriole. The PGE(2)-induced vasodilation was potentiated by the phosphodiesterase inhibitor Ro 20-1724 and was mimicked by 11-deoxy-PGE(1) (0.01 to 1 nmol/L), Butaprost, which acts preferentially at EP2 receptors, was relatively ineffective. Whereas 0.1 to 10 nmol/L PGE(2) elicited vasodilation, higher concentrations (1 to 10 mu mol/L) restored Ang II-induced afferent arteriolar vasoconstriction. This response was blocked by pertussis toxin (200 mu g/mL) and was mimicked by the EP1/EP3 agonist sulprostone (1 to 300 nmol/L). Reverse transcription-polymerase chain reaction of individually isolated afferent arterioles revealed the presence of message for EP4 and all 3 EP3 splice variants (alpha, beta, and gamma) but not EP1 or EP2. Our findings thus indicate that PGE(2) elicits both vasodilatory and vasoconstrictor actions on the afferent arteriole, The vasodilation is mediated by EP4 receptors coupled to cAMP, presumably via G(alpha s). The vasoconstriction is mediated by an EP3 receptor coupled to G(alpha 1) and appears to reflect a functional antagonism of the EP4-induced vasodilatio.