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Inactivation of the E-prostanoid 3 receptor attenuates the angiotensin II pressor response via decreasing arterial contractility.

Chen L, Miao Y, Zhang Y, Dou D, Liu L, Tian X, Yang G, Pu D, Zhang X, Kang J, Gao Y, Wang S, Breyer MD, Wang N, Zhu Y, Huang Y, Breyer RM, Guan Y
Arterioscler Thromb Vasc Biol. 2012 32 (12): 3024-32

PMID: 23065824 · PMCID: PMC3565847 · DOI:10.1161/ATVBAHA.112.254052

OBJECTIVE - The present studies aimed at elucidating the role of prostaglandin E(2) receptor subtype 3 (E-prostanoid [EP] 3) in regulating blood pressure.

METHODS AND RESULTS - Mice bearing a genetic disruption of the EP3 gene (EP(3)(-/-)) exhibited reduced baseline mean arterial pressure monitored by both tail-cuff and carotid arterial catheterization. The pressor responses induced by EP3 agonists M&B28767 and sulprostone were markedly attenuated in EP3(-/-) mice, whereas the reduction of blood pressure induced by prostaglandin E(2) was comparable in both genotypes. Vasopressor effect of acute or chronic infusion of angiotensin II (Ang II) was attenuated in EP3(-/-) mice. Ang II-induced vasoconstriction in mesenteric arteries decreased in EP3(-/-) group. In mesenteric arteries from wild-type mice, Ang II-induced vasoconstriction was inhibited by EP3 selective antagonist DG-041 or L798106. The expression of Arhgef-1 is attenuated in EP3 deficient mesenteric arteries. EP3 antagonist DG-041 diminished Ang II-induced phosphorylation of myosin light chain 20 and myosin phosphatase target subunit 1 in isolated mesenteric arteries. Furthermore, in vascular smooth muscle cells, Ang II-induced intracellular Ca(2+) increase was potentiated by EP3 agonist sulprostone but inhibited by DG-041.

CONCLUSIONS - Activation of the EP3 receptor raises baseline blood pressure and contributes to Ang II-dependent hypertension at least partially via enhancing Ca(2+) sensitivity and intracellular calcium concentration in vascular smooth muscle cells. Selective targeting of the EP3 receptor may represent a potential therapeutic target for the treatment of hypertension.

MeSH Terms (17)

Angiotensin II Animals Blood Pressure Calcium Cells, Cultured Gene Deletion Guanine Nucleotide Exchange Factors Male Mesenteric Arteries Mice Mice, Inbred C57BL Mice, Knockout Models, Animal Muscle, Smooth, Vascular Receptors, Prostaglandin E, EP3 Subtype Rho Guanine Nucleotide Exchange Factors Vasoconstriction

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