(Hypertension. 2000;35:1129.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Characterization of Murine Vasopressor and Vasodepressor Prostaglandin E2 Receptors
From the Division of Nephrology (Y.Z., Y.G., A.S., S.B., R.M.B., M.D.B.), the Departments of Molecular Physiology and Biophysics and Veterans Administration Medical Center (M.D.B.), and the Department of Pharmacology (R.M.B.), Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Dr Matthew D. Breyer, Division of Nephrology, S-3223 MCN, Vanderbilt University Medical Center, Nashville, TN 37232. E-mail matthew.breyer{at}mcmail.vanderbilt.edu
Abstract—Four E-prostanoid (EP) receptors, designated EP1, EP2, EP3, and EP4, mediate the cellular effects of prostaglandin E2 (PGE2). The present studies pharmacologically characterize the vasopressor and vasodepressor EP receptors in wild-type mice (EP2+/+ mice) and mice with targeted disruption of the EP2 receptor (EP2-/- mice). Mean arterial pressure (MAP) was measured via a carotid artery catheter in anesthetized male mice. Intravenous infusion of PGE2 decreased MAP in EP2+/+ mice but increased MAP in EP2-/- mice. Infusion of EP3-selective agonists, including MB28767, SC46275, and sulprostone, increased MAP in both EP2+/+ and EP2-/- mice. Pretreatment with SC46275 desensitized mice to the subsequent pressor effect of sulprostone, but the vasodepressor effect of PGE2 in EP2+/+ mice remained intact. Although PGE2 alone increased MAP in EP2-/- mice, prior desensitization of the pressor effect with SC46275 allowed a residual vasodepressor effect of PGE2 to be seen in the EP2-/- mice. An EP4-selective agonist (prostaglandin E1-OH) functioned also as a vasodepressor in both EP2-/- and EP2+/+ mice. High levels of EP3 receptor mRNA were detected in mouse aortas and rabbit preglomerular arterioles by nuclease protection, with lower expressions of EP1, EP2, and EP4 mRNA. The findings suggest that combined vasodepressor effects of EP2 and EP4 receptors normally dominate, accounting for the depressor effects of PGE2. In contrast, in EP2-/- mice, EP4 receptor activity alone is insufficient to overcome the EP3 vasopressor effect. These findings suggest that a balance between pressor and depressor PGE2 receptors determines its net effect on arterial pressure and that these receptors may be important therapeutic targets.
Key Words: hypertension, sodium-dependent • blood pressure • prostaglandins
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