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      Aging Increases Neuronal Nitric Oxide Release and Superoxide Anion Generation in Mesenteric Arteries from Spontaneously Hypertensive Rats


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          We hypothesized that neuronal NO release as well as its bioavailability and vasomotor response could be affected when aging and hypertension are present simultaneously. The neuronal nitric oxide (NO) release, its metabolism and vasomotor response induced by electrical field stimulation was analyzed in isolated segments of endothelium-denuded mesenteric arteries from young and old spontaneously hypertensive rats (SHR). The nitric oxide synthase (NOS) inhibitor N<sup>G</sup>-nitro-arginine-methyl ester ( L-NAME) and NOS inhibitor 7-nitroindazole both strengthened electrical field stimulation-elicited contractions more in arteries from young than aged SHR rats. Superoxide dismutase (SOD) potentiated the L-NAME effect in segments from old rats, whereas catalase decreased the contractions induced by electrical field stimulation and noradrenaline but did not modify the L-NAME effect. In noradrenaline-precontracted segments, sodium nitroprusside induced a similar relaxation in arteries from both experimental groups. This relaxation was increased by SOD in old SHR. 8Br cGMP induced greater relaxation in segments from old than from young SHR. Electrical field stimulation induced a tritium release in arteries preincubated with [<sup>3</sup>H]-noradrenaline, that was similar in both young and old SHR rats. Electrical field stimulation induced NO<sub>2</sub><sup>–</sup> formation, which was greater in segments from old than young SHR rats. Basal cGMP levels and those stimulated with sodium nitroprusside were similar in segments from both groups. Superoxide anion production was greater from old than young SHR rats. Peroxynitrite production induced by electrical field stimulation was only detected in segments from old SHR. The results obtained in mesenteric arteries from old SHR showed increased neuronal NO release and superoxide anion production with respect to those observed in arteries from young SHR rats. This induced decreased NO bioavailability through peroxynitrite formation. The final effect is to decrease the involvement of neuronal NO in electrical field stimulation-induced vasomotor response in arteries from old SHR rats.

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          Most cited references 22

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          Oxidative stress and vascular damage in hypertension.

          Oxidative stress, a state of excessive reactive oxidative species activity, is associated with vascular disease states such as hypertension. In this review, we discuss the recent advances in the field of reactive oxidative species-mediated vascular damage in hypertension. These include the identification of redox-sensitive tyrosine kinases, the characterization of enzymatic sources of superoxide production in human blood vessels, and their relationship with vascular damage in atherosclerosis and hypertension. Finally, recent developments in the search for strategies to attenuate vascular oxidative stress are reviewed.
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            Vasodilator dysfunction in aged spontaneously hypertensive rats: changes in NO synthase III and soluble guanylyl cyclase expression, and in superoxide anion production.

            Genetic hypertension is associated with an apparent endothelial dysfunction and impaired endothelium-dependent vasodilatation in response to increased flow and receptor-dependent agonists. However, the link between impaired vasodilatation and nitric oxide (NO) synthase expression is still unclear. In the present study, dilator responses were determined in the aorta and coronary circulation of 16 month old spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY). Changes in vascular reactivity were compared with alterations in superoxide anion production as well as endothelial NO synthase (NOS III) and soluble guanylyl cyclase expression. In the isolated perfused heart both the bradykinin- and sodium nitroprusside-induced vasodilator responses were attenuated in SHR compared to WKY. Western blot analysis revealed a parallel reduction in NOS III expression in coronary microvascular endothelial cells from SHR. Superoxide anion production in aortae from SHR was markedly elevated over that of aortae from WKY, and was almost completely abolished by pretreatment with superoxide dismutase. Superoxide dismutase induced similar relaxations in phenylephrine-preconstricted aortic rings from both SHR and WKY, but failed to restore the attenuated acetylcholine- and sodium nitroprusside-induced relaxations in SHR. No difference in NOS III expression was detected in the aortae from either strain whereas soluble guanylyl cyclase expression was markedly decreased in SHR. These results demonstrate that NOS III expression in different tissues is differentially affected by hypertension. Moreover, although an elevated superoxide anion production is apparent in the aorta, a reduced soluble guanylyl cyclase expression appears to account for the observed vasodilator dysfunction in SHR.
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              NAD(P)H oxidase-derived reactive oxygen species as mediators of angiotensin II signaling.

              Angiotensin II has been shown to participate in both physiological processes, such as sodium and water homeostasis and vascular contraction, and pathophysiological processes, including atherosclerosis and hypertension. The effects of this molecule on vascular tissue are mediated at least in part by the modification of the redox milieu of its target cells. Angiotensin II has been shown to activate the vascular NAD(P)H oxidase(s) resulting in the production of reactive oxygen species, namely superoxide and hydrogen peroxide. In this article, we review what is known about the molecular steps that link angiotensin II and its receptor to production of reactive oxygen species and subsequent redox-mediated events, focusing on the structural and functional properties of the vascular NAD(P)H oxidases and their downstream mediators. As such, we provide a framework linking angiotensin II to crucial vascular pathologies, such as hypertension, atherosclerosis, and restenosis after angioplasty, by means of the NAD(P)H-dependent oxidases and their effector molecules.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                December 2003
                29 January 2004
                : 40
                : 6
                : 509-519
                Departamentos de aFisiología and bFarmacología y Terapeútica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
                75183 J Vasc Res 2003;40:509–519
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 8, Tables: 1, References: 63, Pages: 11
                Research Paper


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