Critical Role of Angiotensin II in Excess Salt-Induced Brain Oxidative Stress of Stroke-Prone Spontaneously Hypertensive Rats

Kim‐Mitsuyama, Shokei; Yamamoto, Eiichiro; Tanaka, Tomoko; Zhan, Yumei; Izumi, Yasukatsu; Izumiya, Yasuhiro; Ioroi, Takeshi; Wanibuchi, Hideki; Itoh, Hiroshi

doi:10.1161/01.str.0000163084.16505.e3

Cited by 87 publications

(58 citation statements)

References 37 publications

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“…Moreover, salt loading had upregulated the inhibitory response of RSNA, AP, and HR to ICV DPI, an NADPH oxidase inhibitor, in the hypothalamus of DSs. In findings similar to the present data, brain oxidative stress production via NADPH oxidase had been reported in the salt-loaded stroke-prone SHR 18 and a central Ang II-induced hypertensive rat. 11,12 Primary cultures from the hypothalamus indicated that extracellular application of tempol and gp91ds-tat, a selective NADPH oxidase inhibitor, attenuated the Ang II-induced increase in the neuronal firing rate.…”

Section: Discussionsupporting

confidence: 93%

“…16 Furthermore, salt loading increased superoxide production and NADPH oxidase activity in the brain of stroke-prone SHRs. 18 However, it has not yet been determined whether saltinduced ROS in the brain contributes to central sympathetic activation and AP elevation in salt-sensitive hypertension. The aim of the present study was, therefore, to elucidate whether the central sympathoexcitatory effect of oxidative stress mediates AP elevation in salt-sensitive hypertension.…”

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confidence: 99%

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Sympathoexcitation by Oxidative Stress in the Brain Mediates Arterial Pressure Elevation in Salt-Sensitive Hypertension

et al. 2007

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Abstract-Central sympathoexcitation is involved in the pathogenesis of salt-sensitive hypertension. We have suggested that oxidative stress in the brain modulates the sympathetic regulation of arterial pressure. Thus, we investigated whether oxidative stress could mediate central sympathoexcitation in salt-sensitive hypertension. Five-to 6-week-old male Dahl salt-sensitive rats and salt-resistant rats were fed with a normal (0.3%) or high-(8%) salt diet for 4 weeks. In urethane-anesthetized and artificially ventilated rats, arterial pressure, renal sympathetic nerve activity, and heart rate decreased in a dose-dependent fashion, when 20 or 40 mol of tempol, a membrane-permeable superoxide dismutase mimetic, was infused into the lateral cerebral ventricle. The same degree of reduction was noted in salt-sensitive and salt-resistant rats without salt loading. Salt loading significantly increased central tempol-induced reductions in arterial pressure (Ϫ29.1Ϯ4.8% versus Ϫ10.6Ϯ3.3% at 40 mol; PϽ0.01), sympathetic nerve activity (Ϫ18.7Ϯ2.0% versus Ϫ7.1Ϯ1.8%; PϽ0.01), and heart rate (Ϫ10.7Ϯ2.8% versus Ϫ2.0Ϯ0.7%; PϽ0.05) in salt-sensitive rats but not in salt-resistant rats. Intracerebroventricular diphenyleneiodonium, a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, also elicited significantly greater reduction in each parameter in salt-loaded salt-sensitive rats. Moreover, salt loading increased reduced nicotinamide-adenine dinucleotide phosphate-dependent superoxide production in the hypothalamus in salt-sensitive rats but not in salt-resistant rats. In addition, reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits p22 phox , p47 phox , and gp91 phox mRNA expression significantly increased in the hypothalamus of salt-loaded salt-sensitive rats. In conclusion, in salt-sensitive hypertension, increased oxidative stress in the brain, possibly via activation of reduced nicotinamide-adenine dinucleotide phosphate oxidase, may elevate arterial pressure through central sympathoexcitation. Key Words: salt-sensitive hypertension Ⅲ oxidative stress Ⅲ brain Ⅲ hypertension Ⅲ salt Ⅲ sympathetic nervous system Ⅲ Dahl rat S ubstantial findings indicate that abnormal modulation of the sympathetic nervous system may be involved in salt-induced development of hypertension in humans 1 and animals. [2][3][4][5][6] In our previous study, 2 salt loading impaired the arterial baroreceptor reflex associated with abnormal central properties in spontaneously hypertensive rats (SHRs); the sympathetic nerve activity (SNA) was less inhibited by stimulation of the aortic depressor nerve in salt-loaded SHRs. However, salt loading did not affect the SNA in Wistar-Kyoto rats. Similarly, the SNA was augmented with salt loading in Dahl salt-sensitive rats (DSs), but not in Dahl salt-resistant rats (DRs). 3 Intracerebroventricular (ICV) infusion of sodium caused sympathoexcitatory and pressor responses to a greater degree in DSs than in DRs. 4 Thus, central sympathetic activation may be involved in salt-sensitive ...

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Section: Discussionsupporting

confidence: 93%

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confidence: 99%

Sympathoexcitation by Oxidative Stress in the Brain Mediates Arterial Pressure Elevation in Salt-Sensitive Hypertension

et al. 2007

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“…This botanical compound is derived from the root of Picrorhiza kurroa (Dodd-O and Pearse, 2000) and has been used as a Chinese medicinal herb for treatment of a number of infectious and inflammatory diseases (Hougee et al, 2006;Kim-Mitsuyama et al, 2005;Lafeber et al, 1999). Studies from our laboratory showed the ability for apocynin to protect against delayed neuronal death induced by global cerebral ischemia in the gerbil .…”

Section: Discussionmentioning

confidence: 98%

Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and ERK1/2-dependent NADPH oxidase

Miller

Sun

2007

Brain Research

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Excess production of reactive oxygen species (ROS) is an important mechanism underlying the pathogenesis of a number of neurodegenerative diseases including Parkinson's disease (PD) which is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. Exposure to paraquat, an herbicide with structure similar to the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium (MPP + ), has been shown to produce PD-like symptoms. Despite previous focus on the dopaminergic neurons and signaling pathways involved in their cell death, recent studies have implicated microglial cells as a major producer of ROS for damaging neighboring neurons. In this study, we examined the source of ROS and the underlying signaling pathway for paraquat-induced cytotoxicity to BV-2 microglial cells. Paraquat-induced ROS production (including superoxide anions) in BV-2 cells was accompanied by translocation of the p67phox cytosolic subunit of NADPH oxidase to the membrane. Paraquat-induced ROS production was inhibited by NADPH oxidase inhibitors, apocynin and diphenylene iodonium (DPI), but not the xanthine/xanthine oxidase inhibitor, allopurinol. Apocynin and DPI also rescued cells from paraquat-induced toxicity. The inhibitors for protein kinase C delta (PKCδ) or extracellular signal-regulated kinases (ERK1/2) could partially attenuate paraquat-induced ROS production and cell death. Rottlerin, a selective PKCδ inhibitor, also inhibited paraquat-induced translocation of p67phox. Taken together, this study demonstrates the involvement of ROS from NADPH oxidase in mediating paraquat cytotoxicity in BV-2 microglial cells and this process is mediated through PKCδ-and ERK-dependent pathways.

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“…One of the more potent modulators of cardiovascular processes mediated by the NTS is Angiotensin II (AngII), a peptide that acts locally via the angiotensin AT-1A receptor to inhibit the baroreflex (12). These actions may be mediated by production of reactive oxygen species (ROS), molecules that are emerging as an important molecular substrate of central autonomic regulation, in addition to their better known role in mediating hypertension-induced cellular plasticity in the systemic vasculature (7,10,22,29,53).…”

Section: Introductionmentioning

confidence: 99%

Changes in the subcellular distribution of NADPH oxidase subunit p47phox in dendrites of rat dorsomedial nucleus tractus solitarius neurons in response to chronic administration of hypertensive agents

Glass

Chan

Frys

et al. 2007

Experimental Neurology

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NADPH oxidase-generated superoxide can modulate crucial intracellular signaling cascades in neurons of the nucleus tractus solitarius (NTS), a brain region that plays an important role in cardiovascular processes. Modulation of NTS signaling by superoxide may be linked to the subcellular location of the mobile NADPH oxidase p47 phox subunit, which is known to be present in dendrites of NTS neurons. It is not known, however, if hypertension can produce changes in the trafficking of p47 phox in defined NTS subregions, particularly the preferentially barosensitive dorsomedial NTS (dmNTS), or preferentially gastrointestinal medial NTS (mNTS). We used immunogold electron microscopy to determine if p47 phox localization was differentially affected in dendritic profiles of neurons from these NTS subregions of the rat in response to distinct models of hypertension, namely chronic seven-day subcutaneous administration of angiotensin II (AngII), or phenylephrine. In small (<1 μm) dendritic processes, both AngII and phenylephrine produced a decrease in intracellular p47 phox labeling selectively in dmNTS neurons. In intermediate-size (1-2 μm) dendritic profiles in the dmNTS region only, there was an increase in p47 phox labeling in response to each hypertensive agent, although these changes occurred in different subcellular compartments. There was an increase in non-vesicular labeling in response to AngII, but an increase in surface labeling with phenylephrine. Moreover, each of the changes in p47 phox targeting mentioned above occurred in dendritic profiles with, or without immunoperoxidase labeling for the AngII AT-1A receptor subtype (AT-1A). These results indicate that chronic administration of agents that induce hypertension can also produce changes in the subcellular localization in p47 phox in dmNTS neurons. Thus, systemic hypertension may produce alterations in the trafficking of proteins associated with superoxide production in central autonomic neurons, thus revealing a potentially important neurogenic component of free radical production and systemic blood pressure elevation.

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Critical Role of Angiotensin II in Excess Salt-Induced Brain Oxidative Stress of Stroke-Prone Spontaneously Hypertensive Rats

Cited by 87 publications

References 37 publications

Sympathoexcitation by Oxidative Stress in the Brain Mediates Arterial Pressure Elevation in Salt-Sensitive Hypertension

Sympathoexcitation by Oxidative Stress in the Brain Mediates Arterial Pressure Elevation in Salt-Sensitive Hypertension

Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and ERK1/2-dependent NADPH oxidase

Changes in the subcellular distribution of NADPH oxidase subunit p47phox in dendrites of rat dorsomedial nucleus tractus solitarius neurons in response to chronic administration of hypertensive agents

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