OBJECTIVE: To test the hypothesis that the enhanced vascular responsiveness to norepinephrine that occurs during deoxycorticosterone acetate (DOCA)-salt induced hypertension is causally related to increased expression of cyclo-oxygenase (COX)-2 and oxidative stress, which diminishes the vasomodulatory influence of endothelium-derived nitric oxide. METHODS: Four groups of age-matched, male Sprague-Dawley rats were studied: Sham (normotensive); DOCA-salt (hypertensive); DOCA-salt treated with manganese(III) tetra(4-benzoic acid) porphyrin chloride [MnTBAP, an antioxidant; 15 mg/kg intraperitoneally (i.p.) for 21 days]; DOCA-salt treated with {N-[2-(cyclohexyloxy)-4-nitrophenyl]-methane sulfonamide} (NS-398, a COX-2 selective blocker; 5 mg/kg i.p. for 7 days). Contraction and relaxation were measured with FT03 force transducers coupled to a Grass polygraph in aortic rings bathed with physiologic salt solution (37 degrees C) and bubbled with a 5%CO2/95%O2 gas mixture. Aortic sensitivities (pD2 values) to norepinephrine and serum isoprostanes (8-iso-prostaglandin F2alpha, a marker of oxidative stress) were measured for each experimental paradigm. RESULTS: NS-398 significantly reduced maximal contractions in response to norepinephrine in aortic rings from Sham (44 +/- 3%) and DOCA-salt (96 +/- 2%) group rats. Expression of COX-2 protein increased significantly in vessels from DOCA-salt rats compared with those from Sham group rats. Treatment of DOCA-salt rats with either MnTBAP or NS-398 alleviated hypertension, normalized aortic pD2 values for norepinephrine and restored serum 8-isoprostane concentrations towards those observed in Sham group rats. CONCLUSIONS: COX-2 expression increases during DOCA-salt hypertension, and mediates production of factors that enhance rat aortic contractility in response to norepinephrine. Our data also suggest a role for increased oxidative stress, which is at least in part dependent on enhanced COX-2 expression, in the mechanism(s) of enhanced aortic contractility in response to norepinephrine during DOCA-salt hypertension.
OBJECTIVE: To test the hypothesis that the enhanced vascular responsiveness to norepinephrine that occurs during deoxycorticosterone acetate (DOCA)-salt induced hypertension is causally related to increased expression of cyclo-oxygenase (COX)-2 and oxidative stress, which diminishes the vasomodulatory influence of endothelium-derived nitric oxide. METHODS: Four groups of age-matched, male Sprague-Dawley rats were studied: Sham (normotensive); DOCA-salt (hypertensive); DOCA-salt treated with manganese(III) tetra(4-benzoic acid) porphyrin chloride [MnTBAP, an antioxidant; 15 mg/kg intraperitoneally (i.p.) for 21 days]; DOCA-salt treated with {N-[2-(cyclohexyloxy)-4-nitrophenyl]-methane sulfonamide} (NS-398, a COX-2 selective blocker; 5 mg/kg i.p. for 7 days). Contraction and relaxation were measured with FT03 force transducers coupled to a Grass polygraph in aortic rings bathed with physiologic salt solution (37 degrees C) and bubbled with a 5%CO2/95%O2 gas mixture. Aortic sensitivities (pD2 values) to norepinephrine and serum isoprostanes (8-iso-prostaglandin F2alpha, a marker of oxidative stress) were measured for each experimental paradigm. RESULTS:NS-398 significantly reduced maximal contractions in response to norepinephrine in aortic rings from Sham (44 +/- 3%) and DOCA-salt (96 +/- 2%) group rats. Expression of COX-2 protein increased significantly in vessels from DOCA-saltrats compared with those from Sham group rats. Treatment of DOCA-saltrats with either MnTBAP or NS-398 alleviated hypertension, normalized aortic pD2 values for norepinephrine and restored serum 8-isoprostane concentrations towards those observed in Sham group rats. CONCLUSIONS:COX-2 expression increases during DOCA-salthypertension, and mediates production of factors that enhance rat aortic contractility in response to norepinephrine. Our data also suggest a role for increased oxidative stress, which is at least in part dependent on enhanced COX-2 expression, in the mechanism(s) of enhanced aortic contractility in response to norepinephrine during DOCA-salthypertension.
Authors: Xiao Yu Tian; Wing Tak Wong; Fung Ping Leung; Yang Zhang; Yi-Xiang Wang; Hung Kay Lee; Chi Fai Ng; Zhen Yu Chen; Xiaoqiang Yao; Chak Leung Au; Chi Wai Lau; Paul M Vanhoutte; John P Cooke; Yu Huang Journal: Antioxid Redox Signal Date: 2011-12-02 Impact factor: 8.401
Authors: Dale A Schuschke; Ayotunde S O Adeagbo; Phani K Patibandla; Uchechi Egbuhuzo; Rafael Fernandez-Botran; W Thomas Johnson Journal: Inflammation Date: 2009-10 Impact factor: 4.092