Possible usefulness of apocynin, an NADPH oxidase inhibitor, for nitrate tolerance: prevention of NO donor-induced endothelial cell abnormalities

Fukatsu, Atsushi; Hayashi, Toshio; Miyazaki-Akita, Asaka; Matsui-Hirai, Hisako; Furutate, Yukie; Ishitsuka, Asako; Hattori, Yoshiyuki; Iguchi, Akihisa

doi:10.1152/ajpheart.01141.2006

Cited by 27 publications

(18 citation statements)

References 38 publications

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“…BH 4 levels are upregulated by H 2 O 2 -mediated induction of GTP cyclohydrolase (36,37), and we speculate that dismutation of superoxide to H 2 O 2 by rhSOD may account for the increase in BH 4 (15). Conversely, apocynin inhibits superoxide generation by NADPH oxidase and has been reported to scavenge H 2 O 2 in vitro (17,19). Ventilation with NO also reduced superoxide levels in PPHN PA but had less pronounced effects on eNOS expression and did not affect BH 4 or BH 2 levels (15).…”

Section: Discussionmentioning

confidence: 80%

“…The dose of apocynin was calculated with the assumption of an immediate volume of distribution of fetal lung liquid volume (ϳ20 -30 ml/kg) (33) and a target concentration of 0.5-1 mM in the lung liquid. This concentration has been shown to be effective in various cell studies (17,19). We chose the intratracheal route because of our prior success with intratracheal rhSOD (24) and because we wished to induce selective pulmonary vasodilation without systemic hypotension.…”

Section: Discussionmentioning

confidence: 99%

“…However, the mechanisms of apocynin-mediated decreases in Nox2 activity in ventilated PPHN lambs are unknown. It has been argued that apocynin functions as an antioxidant, rather than an NADPH oxidase inhibitor, in vascular cells in vitro, in part because these cells lack the myeloperoxidase activity required to convert apocynin to its active inhibitory form (17,19). However, others have shown that vascular endothelial cells take up myeloperoxidase released by white blood cells (42,45), and other peroxidases expressed in vascular cells also have the potential to influence apocynin activity (42).…”

Section: Discussionmentioning

confidence: 99%

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Apocynin improves oxygenation and increases eNOS in persistent pulmonary hypertension of the newborn

Wedgwood

Lakshminrusimha

Farrow

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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RH. Apocynin improves oxygenation and increases eNOS in persistent pulmonary hypertension of the newborn. Am J Physiol Lung Cell Mol Physiol 302: L616 -L626, 2012. First published December 23, 2011 doi:10.1152/ajplung.00064.2011.-NADPH oxidase is a major source of superoxide anions in the pulmonary arteries (PA). We previously reported that intratracheal SOD improves oxygenation and restores endothelial nitric oxide (NO) synthase (eNOS) function in lambs with persistent pulmonary hypertension of the newborn (PPHN). In this study, we determined the effects of the NADPH oxidase inhibitor apocynin on oxygenation, reactive oxygen species (ROS) levels, and NO signaling in PPHN lambs. PPHN was induced in lambs by antenatal ligation of the ductus arteriosus 9 days prior to delivery. Lambs were treated with vehicle or apocynin (3 mg/kg intratracheally) at birth and then ventilated with 100% O2 for 24 h. A significant improvement in oxygenation was observed in apocynin-treated lambs after 24 h of ventilation. Contractility of isolated fifth-generation PA to norepinephrine was attenuated in apocynin-treated lambs. PA constrictions to NO synthase (NOS) inhibition with N-nitro-L-arginine were blunted in PPHN lambs; apocynin restored contractility to N-nitro-L-arginine, suggesting increased NOS activity. Intratracheal apocynin also enhanced PA relaxations to the eNOS activator A-23187 and to the NO donor S-nitrosyl-N-acetyl-penicillamine. Apocynin decreased the interaction between NADPH oxidase subunits p22 phox and p47 phox and decreased the expression of Nox2 and p22 phox in ventilated PPHN lungs. These findings were associated with decreased superoxide and 3-nitrotyrosine levels in the PA of apocynin-treated PPHN lambs. eNOS protein expression, endothelial NO levels, and tetrahydrobiopterin-to-dihydrobiopterin ratios were significantly increased in PA from apocynin-treated lambs, although cGMP levels did not significantly increase and phosphodiesterase-5 activity did not significantly decrease. NADPH oxidase inhibition with apocynin may improve oxygenation, in part, by attenuating ROS-mediated vasoconstriction and by increasing NOS activity. reactive oxygen species; NADPH oxidase inhibition; nitric oxide signaling WHEN THE PULMONARY CIRCULATION fails to respond to various stimuli at birth, such as increased PO 2 and ventilation, it does not undergo the shift from the high-resistance, low-flow state in utero to the low-resistance, high-flow system postnatally (16,25). This failure results in persistent pulmonary hypertension of the newborn (PPHN) and is associated with impaired pulmonary gas exchange and oxygenation. Clinical strategies, such as mechanical ventilation with high concentrations of O 2 to correct hypoxemia and inhaled nitric oxide (NO), are commonly used to promote pulmonary vasodilation, but sustained improvement is not observed in ϳ40% of patients with PPHN (21). Hyperoxic ventilation also promotes formation of reactive oxygen species (ROS), such as superoxide anions, increases pulmonary artery (PA) contra...

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Apocynin improves oxygenation and increases eNOS in persistent pulmonary hypertension of the newborn

Wedgwood

Lakshminrusimha

Farrow

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Finally, data obtained with apocynin, a polyphenols structural analogue, reported by Fukatsu et al (2007) indicated that this compound, pharmacologically known to be able to prevent the increase in protein expression of NADPH oxidase, a source of superoxide anions, could be a means of protection against nitrate tolerance.…”

Section: Discussionmentioning

confidence: 98%

In vitro preventive effects of nitrate tolerance by a polyphenol-enriched extract of Hibiscus sabdariffa

Sarr

Sar²,

Diao³

et al. 2013

J. Clin. Med. Res.

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Treatment failure or tolerance, which rapidly leads to a reduced hemodynamic effects and therapeutic efficacy is the major limitation of long-term use of nitrates, including nitroglycerin (NTG) in the treatment of coronary artery disease. These effects are most often associated with oxidative stress. Thus, in this work, we were interested in the prevention of nitrate tolerance by the antioxidant compounds from Hibiscus sabdariffa L. crude extract, a plant from the Senegalese Pharmacopoeia, rich in polyphenols. Thoracic aorta segments without endothelium were taken from rats and incubated in isolated organ chambers. The vessels were then pre-exposed with the H. sabdariffa polyphenolic extract (HSE, 5.10 -2 g/l) or antioxidants such as N-acetyl cysteine (NAC, 10 -3 M) or vitamin C (VIT C, 10 -2 M), taken as reference. After a 30 min treatment, aortic segments were exposed to NTG (50 μM, 1 h) to induce tolerance state before being contracted to adrenaline (10 -8 to 10 -5 M), and then relaxed with NTG (10 -9 to 10 -5 M). Polyphenols from H. sabdariffa potentiated the relaxant response to NTG, whatever the state of vascular tolerance; the HSE partially corrected the in vitro nitrate tolerance. This work suggests interesting therapeutic perspectives by improving the response to treatment with nitrates in coronary patients.

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“…Furthermore, because of the development of tolerance to NO donors such as nitroglycerin, their long-term use would be difficult as we described elsewhere. 82 We investigated cellular senescence in human aorta obtained by autopsy and in HUVEC. 72 We demonstrated cellular senescence with SA-b-gal-positive staining in atherosclerotic lesions of the luminal side of human thoracic aorta.…”

Section: Relationship Between Endothelial Cell Senescence and Nomentioning

confidence: 99%

Possibility of the regression of atherosclerosis through the prevention of endothelial senescence by the regulation of nitric oxide and free radical scavengers

Hayashi

Iguchi

2010

Geriatrics Gerontology Int

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In the elderly, atherosclerotic diseases such as stroke and myocardial infarction occupy a major part of their causes of death and care. The elderly always have atherosclerosis in their aorta and other arteries and are exposed to risk of attacks. It is the elderly who should receive its safe, harmless and advanced treatment. Advanced stage of atherosclerosis in the elderly is progressed by complicated risk factors such as dyslipidemia and diabetes mellitus and specific risk factors for the elderly, aging (and menopause). Treatment of atherosclerotic disease may need special ones targeted for the elderly. Recent studies reported that frequencies of dyslipidemia were not decreased in the older oldest. In the elderly, impaired glucose tolerance occurrs and it progresses atherosclerosis. Endothelial dysfunction like impairment of nitric oxide (NO) bioavailability also progresses atherosclerosis. Although we tried to regress the high cholesterol diet-induced atherosclerosis in rabbit aorta with a normal diet with or without statin, regression could not be achieved. NO targeting gene therapy (adenovirus endothelial nitric oxide synthase [eNOS] gene vector) regressed 20% of atherosclerotic lesions through reduction of lipid contents, however, a more integrated strategy is important for complete regression. We paid attention to NO bioavailability and developed two ways of increasing it in atherosclerosis: citrulline therapy and arginase II inhibition by estrogen. Further, we found a close relation between atherosclerosis and endothelial senescence and that NO can prevent it, especially in a diabetic model. Taken together, regression of atherosclerosis can be achieved by not only regulation of various risk factors but regulation of the cross-talk of NO and free radicals. Geriatr Gerontol Int 2010; 10: 115-130.

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Possible usefulness of apocynin, an NADPH oxidase inhibitor, for nitrate tolerance: prevention of NO donor-induced endothelial cell abnormalities

Cited by 27 publications

References 38 publications

Apocynin improves oxygenation and increases eNOS in persistent pulmonary hypertension of the newborn

Apocynin improves oxygenation and increases eNOS in persistent pulmonary hypertension of the newborn

In vitro preventive effects of nitrate tolerance by a polyphenol-enriched extract of Hibiscus sabdariffa

Possibility of the regression of atherosclerosis through the prevention of endothelial senescence by the regulation of nitric oxide and free radical scavengers

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