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      Angiotensin II Infusion Alters Vascular Function in Mouse Resistance Vessels: Roles of O –·2 and Endothelium


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          We hypothesized that prolonged angiotensin II (AngII) infusion would alter vascular reactivity by enhancing superoxide anion (O<sup>–·2</sup>) generation. Male C57BL/6 mice were infused with AngII at 400 ng/kg/min (n = 16, AngII mice) or vehicle (n = 16, sham mice) for 2 weeks via subcutaneous osmotic minipumps. Contraction and relaxation of mesenteric resistance vessels (MRVs) were assessed using a Mulvany-Halpern myograph. AngII infusion increased systolic blood pressure, MRV NADPH oxidase activity and expression of p22<sup>phox</sup> mRNA. Contraction to norepinephrine was unchanged, but AngII infusion increased contractile responses to AngII (41 ± 5 vs. 10 ± 4%, p < 0.001) and endothelin-1 (ET-1; 95 ± 10 vs. 70 ± 9%, p < 0.05), which was normalized by tempol (10<sup>–4</sup> M, a stable membrane-permeable superoxide dismutase mimetic) and ebselen [10<sup>–5</sup> M, a peroxynitrite (ONOO<sup>–</sup>) scavenger]. Endothelium removal enhanced MRV contraction to AngII and ET-1 in sham mice but blunted these contractile responses in AngII mice. Relaxation to ACh was impaired in AngII mice (60.1 ± 8.8 vs. 83.2 ± 3.5%, p < 0.01), which normalized by tempol, whereas relaxation to sodium nitroprusside was similar in both groups. N-nitro- L-arginine (NNLA, a nitric oxide synthase inhibitor), partially inhibited acetylcholine relaxation of vessels from sham mice but not from AngII mice. The residual endothelium-dependent hyperpolarizing-factor-like relaxation was not different between groups. In conclusion,the AngII slow pressor response in mouse MRVs consisted of specific contractile hyperresponsiveness and impairment in the NO-mediated component of endothelium-dependent relaxation, which was mediated by O<sup>–·2</sup> and ONOO<sup>–</sup> in the vascular smooth muscle cell.

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          Most cited references 24

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          Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor.

          Endothelium-derived vascular relaxing factor (EDRF) is a humoral agent that is released by vascular endothelium and mediates vasodilator responses induced by various substances including acetylcholine and bradykinin. EDRF is very unstable, with a half-life of between 6 and 50 s, and is clearly distinguishable from prostacyclin. The chemical structure of EDRF is unknown but it has been suggested that it is either a hydroperoxy- or free radical-derivative of arachidonic acid or an unstable aldehyde, ketone or lactone. We have examined the role of superoxide anion (O-2) in the inactivation of EDRF released from vascular endothelial cells cultured on microcarrier beads and bioassayed using a cascade of superfused aortic smooth muscle strips. With this system, we have now demonstrated that EDRF is protected from breakdown by superoxide dismutase (SOD) and Cu2+, but not by catalase, and is inactivated by Fe2+. These findings indicate that O-2 contributes significantly to the instability of EDRF.
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            Role of p47 phox in Vascular Oxidative Stress and Hypertension Caused by Angiotensin II

            Hypertension caused by angiotensin II is dependent on vascular superoxide (O 2 ·−) production. The nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase is a major source of vascular O 2 ·− and is activated by angiotensin II in vitro. However, its role in angiotensin II-induced hypertension in vivo is less clear. In the present studies, we used mice deficient in p47 phox , a cytosolic subunit of the NADPH oxidase, to study the role of this enzyme system in vivo. In vivo, angiotensin II infusion (0.7 mg/kg per day for 7 days) increased systolic blood pressure from 105±2 to 151±6 mm Hg and increased vascular O 2 ·− formation 2- to 3-fold in wild-type (WT) mice. In contrast, in p47 phox-/- mice the hypertensive response to angiotensin II infusion (122±4 mm Hg; P <0.05) was markedly blunted, and there was no increase of vascular O 2 ·− production. In situ staining for O 2 ·− using dihydroethidium revealed a marked increase of O 2 ·−production in both endothelial and vascular smooth muscle cells of angiotensin II-treated WT mice, but not in those of p47 phox-/- mice. To directly examine the role of the NAD(P)H oxidase in endothelial production of O 2 ·−, endothelial cells from WT and p47 phox-/- mice were cultured. Western blotting confirmed the absence of p47 phox in p47 phox-/- mice. Angiotensin II increased O 2 ·− production in endothelial cells from WT mice, but not in those from p47 phox-/- mice, as determined by electron spin resonance spectroscopy. These results suggest a pivotal role of the NAD(P)H oxidase and its subunit p47 phox in the vascular oxidant stress and the blood pressure response to angiotensin II in vivo.
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              Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice.

              The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several endothelium-derived relaxing factors, such as prostacyclin, nitric oxide (NO), and the previously unidentified endothelium-derived hyperpolarizing factor (EDHF). In this study, we examined our hypothesis that hydrogen peroxide (H(2)O(2)) derived from endothelial NO synthase (eNOS) is an EDHF. EDHF-mediated relaxation and hyperpolarization in response to acetylcholine (ACh) were markedly attenuated in small mesenteric arteries from eNOS knockout (eNOS-KO) mice. In the eNOS-KO mice, vasodilating and hyperpolarizing responses of vascular smooth muscle per se were fairly well preserved, as was the increase in intracellular calcium in endothelial cells in response to ACh. Antihypertensive treatment with hydralazine failed to improve the EDHF-mediated relaxation. Catalase, which dismutates H(2)O(2) to form water and oxygen, inhibited EDHF-mediated relaxation and hyperpolarization, but it did not affect endothelium-independent relaxation following treatment with the K(+) channel opener levcromakalim. Exogenous H(2)O(2) elicited similar relaxation and hyperpolarization in endothelium-stripped arteries. Finally, laser confocal microscopic examination with peroxide-sensitive fluorescence dye demonstrated that the endothelium produced H(2)O(2) upon stimulation by ACh and that the H(2)O(2) production was markedly reduced in eNOS-KO mice. These results indicate that H(2)O(2) is an EDHF in mouse small mesenteric arteries and that eNOS is a major source of the reactive oxygen species.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                December 2005
                21 December 2005
                : 43
                : 1
                : 109-119
                Division of Nephrology and Hypertension, Department of Medicine, Georgetown University, Washington, D.C., USA
                89969 J Vasc Res 2006;43:109–119
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 56, Pages: 11
                Research Paper


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