Apocynin but Not Allopurinol Prevents and Reverses Adrenocorticotropic Hormone-Induced Hypertension in the Rat

Zhang, Yi; Chan, Matthew Ming Ki; Andrews, Miles C.; Mori, Trevor A.; Croft, Kevin D.; McKenzie, Katja U.S.; Schyvens, Christopher G.; Whitworth, Judith A.

doi:10.1016/j.amjhyper.2005.02.017

Cited by 81 publications

(67 citation statements)

References 31 publications

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“…Both have welldocumented potencies and selectivities for attenuating oxidative stress (56,67,68). In addition, the primary manner by which apocynin exerts its anti-ROS effect is via inhibition of NADPH oxidase-one of the two major ROS-producing pathways in cerebral vessels (the other being mitochondria) (32,69).…”

Section: Discussionmentioning

confidence: 99%

Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

Han

Zhou

Johnson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

112

103

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Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid β peptide (Aβ) within walls of cerebral arteries and is an important cause of intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in elderly patients with and without Alzheimer's Disease (AD). NADPH oxidase-derived oxidative stress plays a key role in soluble Aβ-induced vessel dysfunction, but the mechanisms by which insoluble Aβ in the form of CAA causes cerebrovascular (CV) dysfunction are not clear. Here, we demonstrate evidence that reactive oxygen species (ROS) and, in particular, NADPH oxidase-derived ROS are a key mediator of CAA-induced CV deficits. First, the NADPH oxidase inhibitor, apocynin, and the nonspecific ROS scavenger, tempol, are shown to reduce oxidative stress and improve CV reactivity in aged Tg2576 mice. Second, the observed improvement in CV function is attributed both to a reduction in CAA formation and a decrease in CAA-induced vasomotor impairment. Third, anti-ROS therapy attenuates CAA-related microhemorrhage. A potential mechanism by which ROS contribute to CAA pathogenesis is also identified because apocynin substantially reduces expression levels of ApoE-a factor known to promote CAA formation. In total, these data indicate that ROS are a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage. Thus, ROS and, in particular, NADPH oxidase-derived ROS are a promising therapeutic target for patients with CAA and AD.Alzheimer's disease | cerebral amyloid angiopathy | reactive oxygen species | NADPH oxidase | vasomotor dysfunction

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Section: Discussionmentioning

confidence: 99%

Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

Han

Zhou

Johnson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

112

103

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“…The effects of systemic NADPH oxidase inhibition have been demonstrated previously in SD rats. The increase in O 2 ⅐Ϫ production and elevation in blood pressure normally associated with aldosterone, 40 deoxycorticosterone acetate-salt, 41 and corticotropin-induced hypertension 42 were reduced by administration of apocynin in the drinking water. Similarly, mice deficient in p47 phox and infused with Ang II 14 or deoxycorticosterone acetate salt 17 showed no increase in vascular O 2 ⅐Ϫ production and exhibited markedly blunted hypertension.…”

Section: Taylor Et Al Renal Medullary Nadph Oxidase and Hypertensionmentioning

confidence: 99%

NADPH Oxidase in the Renal Medulla Causes Oxidative Stress and Contributes to Salt-Sensitive Hypertension in Dahl S Rats

et al. 2006

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Abstract-Dahl salt-sensitive (SS) rats exhibit increased renal medullary oxidative stress and blood pressure salt-sensitivity compared with consomic, salt-resistant SS-13 BN rats, despite highly similar genetic backgrounds. The present study examined potential sources of renal medullary superoxide in prehypertensive SS rats fed a 0.4% NaCl diet by assessing activity and protein levels of superoxide producing and scavenging enzymes. Superoxide production was nearly doubled in SS rats compared with SS-13 BN rats as determined by urinary 8-isoprostane excretion and renal medullary oxy-ethidium microdialysate levels. Medullary superoxide production in tissue homogenates was greater in SS rats, and the NADPH oxidase inhibitor diphenylene iodonium preferentially reduced SS levels to those found in SS-13 BN rats. Dinitrophenol, a mitochondrial uncoupler, eliminated the remaining superoxide production in both strains, whereas inhibition of xanthine oxidase, NO synthase, and cycloxygenase had no effect. L-arginine, NO synthase, superoxide dismutase, catalase, and glutathione peroxidase activities between SS and SS-13 BN rats did not differ. Chronic blood pressure responses to a 4% NaCl diet were then determined in the presence or absence of the NADPH oxidase inhibitor apocynin (3.5 g/kg per minute), chronically delivered directly into the renal medulla. Apocynin infusion reduced renal medullary interstitial superoxide from 1059Ϯ130 to 422Ϯ80 (oxyethidium fluorescence units) and mean arterial pressure from 175Ϯ4 to 157Ϯ6 mm Hg in SS rats, whereas no effects on either were observed in the SS-13 BN . We conclude that excess renal medullary superoxide production in SS rats contributes to salt-induced hypertension, and NADPH oxidase is the major source of the excess superoxide.

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“…1 For example, treatment of rat and mouse models of hypertension with antioxidants such as SOD and vitamins C and E, or NADPH oxidase inhibitors effectively reduced blood pressure. [25][26][27][28][29] Although xanthine oxidase, uncoupled endothelial NO synthase, and mitochondria are additional sources, the nonphagocytic, membrane-bound NADPH oxidases are known as a major source of superoxide production in the vascular mice infused with vehicle, BMP4, noggin, or BMP4ϩnoggin for 4 weeks (0.9 mg/kg) as described in Figure 1 were used to determine NADPH oxidase activity. Some mice were treated with apocynin (1.5 mmol/L in drinking water concurrently with BMP4 or vehicle (in vivo).…”

Section: Discussionmentioning

confidence: 99%

Bone Morphogenic Protein-4 Induces Hypertension in Mice

et al. 2006

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Background-Recent in vitro studies have shown that disturbed flow and oxidative conditions induce the expression of bone morphogenic proteins (BMPs 2 and 4) in cultured endothelial cells. BMPs can stimulate superoxide production and inflammatory responses in endothelial cells, raising the possibility that BMPs may play a role in vascular diseases such as hypertension and atherosclerosis. In this study, we examined the hypothesis that BMP4 would induce hypertension in intact animals by increasing superoxide production from vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and an impairment of vasodilation responses. Methods and Results-BMP4 infusion by osmotic pumps increased systolic blood pressure in a time-and dose-dependent manner in both C57BL/6 mice (from 101 to 125 mm Hg) and apolipoprotein E-null mice (from 107 to 146 mm Hg) after 4 weeks. Cotreatment with the BMP antagonist noggin or the NADPH oxidase inhibitor apocynin completely blocked the BMP4 effect. In addition, BMP4 infusion stimulated aortic NADPH oxidase activity and impaired vasorelaxation, both of which were prevented either by coinfusing noggin or by treating the isolated aortas with apocynin. BMP4, however, did not cause significant changes in maximum relaxation induced by the endothelium-independent vasodilator nitroglycerin. Remarkably, BMP4 infusion failed to stimulate aortic NADPH oxidases, increase blood pressure, and impair vasodilation responses in p47phox-deficient mice. Conclusions-These results suggest that BMP4 infusion induces hypertension in mice in a vascular NADPH oxidasedependent manner and the subsequent endothelial dysfunction. We suggest that BMP4 is a novel mediator of endothelial dysfunction and hypertension and that noggin and its analogs could be used as therapeutic agents for treating vascular diseases. (Circulation. 2006;113:2818-2825.)

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Apocynin but Not Allopurinol Prevents and Reverses Adrenocorticotropic Hormone-Induced Hypertension in the Rat

Abstract: Apocynin but not allopurinol prevented and reversed ACTH-induced hypertension in the rat. These results suggest superoxide production through NAD(P)H oxidase plays a role in ACTH-induced hypertension.

Cited by 81 publications

References 31 publications

Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

NADPH Oxidase in the Renal Medulla Causes Oxidative Stress and Contributes to Salt-Sensitive Hypertension in Dahl S Rats

Bone Morphogenic Protein-4 Induces Hypertension in Mice

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