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Thromboxane‐prostaglandin H 2 receptors mediate blunted nitric oxide production in Angiotensin II‐preconditioned endothelial cells
Author(s) -
Kawada Noritaka,
Wang Dan,
Connors Stephanie,
Kawada Julie,
Luo Zaiming,
Welch William J,
Wilcox Christopher S
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a291-b
Subject(s) - medicine , endocrinology , angiotensin ii , nadph oxidase , thromboxane , chemistry , prostacyclin , vasoconstriction , nitric oxide , vasodilation , enos , receptor , prostaglandin , thromboxane a2 , oxidative stress , nitric oxide synthase , platelet
We tested the hypothesis that thromboxane‐prostaglandin H 2 receptors (TP) mediate a blunted NO production in vascular endothelial cells (ENDO) after prolonged exposure to AngII. AngII (10 −7 M) induces vasoconstriction in isolated mesenteric arteries (MAs) from mice under spontaneous tone, but induces vasodilatation in MAs preconstricted with norepinephrine (+21.5±2.1%; p<0.05). This relaxation response was blunted by endothelium removal (+13.2±2.2%; p<0.05) or by L‐NAME (+12.7±2.3%; p<0.05). In mouse endothelioma cells (EOMA), acute AngII (10 −7 M for 4 hrs) increased NO metabolites (NOx: +3.4±0.5 vs vehicle +2.0±0.2uM; p<0.05, n=6) and NADPH oxidase activity (+24±5%; p<0.05, n=6). This implies that NO release from ENDO during acute AngII may offset the vasoconstriction and oxidative stress. In contrast, EOMA preconditioned with AngII (10 −7 M) chronically for 6 days (preAngIIEOMA), have a negligible increase in NOx (+0.2±0.4uM; p<0.05, n=4) and an exaggerated increase in NADPH oxidase activity (+36±3%; p<0.05, n=4). PreAngIIEOMA had an unchanged expression of mRNA for eNOS (+7±3%, n=4) but an increase in iNOS (+16±3%; p<0.05, n=4). Supplementation of L‐arginine reduced ROS, measured by lucigenin, in untreated EOMA (n=6, p<0.05), but increased ROS in preAngIIEOMA (n=6, p<0.05). PreAngIIEOMA treated with TP antagonist, Ifetroban restored NOx production (+2.2±0.3uM; p<0.05, n=4) and prevented induction of iNOS mRNA (−16±3% vs. preAngII; p<0.05, n=4). In conclusion; acute AngII stimulates eNOS‐delived NO that offsets vasoconstriction. However, prolonged AngII upregulates NADPH oxidase and iNOS via activation of TP that prevent bioactive NO and reinforce the vasoconstrictor action of chronic AngII.