Characterization of Murine Vasopressor and Vasodepressor Prostaglandin E 2 Receptors

Abstract

Abstract —Four E-prostanoid (EP) receptors, designated EP 1 , EP 2 , EP 3 , and EP 4 , mediate the cellular effects of prostaglandin E 2 (PGE 2 ). The present studies pharmacologically characterize the vasopressor and vasodepressor EP receptors in wild-type mice (EP 2 +/+ mice) and mice with targeted disruption of the EP 2 receptor (EP 2 −/− mice). Mean arterial pressure (MAP) was measured via a carotid artery catheter in anesthetized male mice. Intravenous infusion of PGE 2 decreased MAP in EP 2 +/+ mice but increased MAP in EP 2 −/− mice. Infusion of EP 3 -selective agonists, including MB28767, SC46275, and sulprostone, increased MAP in both EP 2 +/+ and EP 2 −/− mice. Pretreatment with SC46275 desensitized mice to the subsequent pressor effect of sulprostone, but the vasodepressor effect of PGE 2 in EP 2 +/+ mice remained intact. Although PGE 2 alone increased MAP in EP 2 −/− mice, prior desensitization of the pressor effect with SC46275 allowed a residual vasodepressor effect of PGE 2 to be seen in the EP 2 −/− mice. An EP 4 -selective agonist (prostaglandin E 1 -OH) functioned also as a vasodepressor in both EP 2 −/− and EP 2 +/+ mice. High levels of EP 3 receptor mRNA were detected in mouse aortas and rabbit preglomerular arterioles by nuclease protection, with lower expressions of EP 1 , EP 2 , and EP 4 mRNA. The findings suggest that combined vasodepressor effects of EP 2 and EP 4 receptors normally dominate, accounting for the depressor effects of PGE 2 . In contrast, in EP 2 −/− mice, EP 4 receptor activity alone is insufficient to overcome the EP 3 vasopressor effect. These findings suggest that a balance between pressor and depressor PGE 2 receptors determines its net effect on arterial pressure and that these receptors may be important therapeutic targets.