期刊
HYPERTENSION
卷 50, 期 3, 页码 525-530出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.107.088948
关键词
cyclooxygenase; cGMP; hypertension; phosphorylation; thromboxane
The present experiments were designed to test the hypothesis that prostaglandin (PG) E-2 causes vasodilatation through activation of endothelial NO synthase ( eNOS). Aortic rings from mice with targeted deletion of eNOS and E-prostanoid (EP) receptors were used for contraction studies. Blood pressure changes in response to PGE(2) were measured in conscious mice. Single doses of PGE2 caused concentration-dependent relaxations during contractions to phenylephrine (EC50=5* 10(-8) mol/L). Relaxation after PGE(2) was absent in rings without endothelium and in rings from eNOS(-/-) mice and was abolished by N-G-nitro-L-arginine methyl ester and the soluble guanylate cyclase inhibitor 1H(1,2,4)-oxadiazolo-[4,3-a] quinoxalin-1-one. In PGE(2)-relaxed aortic rings, the cGMP content increased significantly. PGE(2)-induced relaxations were abolished by the EP4 receptor antagonist AE3-208 (10(-8) mol/L) and mimicked by an EP4 agonist (AE1-329, 10(-7) mol/L) in the presence of endothelium and eNOS only. Relaxations were attenuated significantly in rings from EP4(-/-) mice but normal in EP2(-/-). Inhibitors of the cAMP-protein kinase A pathway attenuated, whereas the inhibitor of protein phosphatase 1C, calyculin (10(-8) mol/L), abolished the PGE2-mediated relaxation. In aortic rings, PGE2 dephosphorylated eNOS at Thr(495). Chronically catheterized eNOS(-/-) mice were hypertensive (137 +/- 3.6 mm Hg, n=13, versus 101 +/- 3.9 mm Hg, n=9) and exhibited a lower sensitivity of blood pressure reduction in response to PGE(2) compared with wild-type mice. There was no difference in the blood pressure response to nifedipine. These findings show that PGE(2) elicits EP4 receptor-mediated, endothelium-dependent stimulation of eNOS activity by dephosphorylation at Thr(495) resulting in guanylyl cyclase-dependent vasorelaxation and accumulation of cGMP in aortic rings.
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