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 ϩ/ϩ mice) and mice with targeted disruption of the EP 2 receptor (EP 2 Ϫ/Ϫ 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 ϩ/ϩ mice but increased MAP in EP 2 Ϫ/Ϫ mice. Infusion of EP 3 -selective agonists, including MB28767, SC46275, and sulprostone, increased MAP in both EP 2 ϩ/ϩ and EP 2 Ϫ/Ϫ mice. Pretreatment with SC46275 desensitized mice to the subsequent pressor effect of sulprostone, but the vasodepressor effect of PGE 2 in EP 2 ϩ/ϩ mice remained intact. Although PGE 2 alone increased MAP in EP 2 Ϫ/Ϫ mice, prior desensitization of the pressor effect with SC46275 allowed a residual vasodepressor effect of PGE 2 to be seen in the EP 2 Ϫ/Ϫ mice. An EP 4 -selective agonist (prostaglandin E 1 -OH) functioned also as a vasodepressor in both EP 2 Ϫ/Ϫ and EP 2 ϩ/ϩ 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 Ϫ/Ϫ 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. Key Words: hypertension, sodium-dependent Ⅲ blood pressure Ⅲ prostaglandins P rostaglandins are critical regulators of vascular tone and arterial pressure. 1-5 Inhibition of endogenous prostaglandin synthesis by NSAIDs may result in systemic hypertension or compromise the control of blood pressure in subjects with preexisting salt-sensitive hypertension. 3,5 Prostaglandin E 2 (PGE 2 ) is a potent vasodilator in several vascular beds and directly relaxes preconstricted vascular rings. 6 Conversely, PGE 2 directly constricts smooth muscle in other tissues, including ileum and vas deferens. 7,8 These opposing effects of PGE 2 are thought to be mediated by distinct G-protein-coupled E-prostanoid (EP) receptors, designated EP 1 , EP 2 , EP 3 , and EP 4 . 7 These receptors may be distinguished by their functional effects and by their affinity for structural analogues of PGE 2 . At least 2 constrictor EP receptors, designated EP 1 and EP 3 , exist. 7-11 The EP 1 receptor signals through increased cell calcium and is highly active in vas deferens and ileal smooth muscle. 7,8,12,13 The EP 3 receptor signals through an inhibitory G protein (G i ) to decrease cAMP and is selectively activated by MB28767 and SC46275. 11,14,15 There are also 2 distinct EP recep...