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Nitroxyl, the novel redox sibling of NO, suppresses cerebrovascular NADPH oxidase

Background

Nitroxyl (HNO), the reduced and protonated congener of nitric oxide (NO), is emerging as a novel entity with distinct pharmacology and therapeutic advantages over NO [1]. Importantly, HNO has vasoprotective actions with the potential to serve as an antioxidant. Here we explored the ability of HNO to modulate cerebrovascular NADPH oxidase activity, a major source of superoxide (.O2-) in the vasculature.

Materials and methods

Intracranial (pooled middle cerebral and basilar) and extracranial (carotid) cerebral arteries from male C57BL/6J mice were treated with angiotensin II (10 nM) acutely (30 min) and chronically (24 h), respectively, in the absence and presence of the HNO donor, Angeli's salt (AS). NADPH (100 μM)-stimulated .O2- production was then measured using lucigenin (5 μM)-enhanced chemiluminescence.

Results

AS (1 μM) did not scavenge .O2- generated in a cell free xanthine (100 μM)/xanthine oxidase (0.05 U/ml) activity assay (control: 447.9 ± 90.8; AS 507.1 ± 113.3 counts, n = 4). In contrast, acute and chronic treatment with AS (0.01–1 μM) caused a concentration-dependent decrease in NADPH oxidase-derived .O2- production by intracranial and extracranial cerebral arteries, respectively (carotid 0.59 ± 0.05; AS 0.1 μM 0.33 ± 0.08; AS 1 μM 0.16 ± 0.03 103 counts/s/mg, P < 0.05, n = 8). The effects of AS were reversed by the HNO scavenger, L-cysteine (3 mM) but unchanged in the presence of the NO scavenger carboxy-PTIO (200 μM) and sGC inhibitor, ODQ (10 μM).

Conclusion

HNO suppresses vascular NADPH-oxidase activity both acutely and chronically, possibly via a cGMP-independent mechanism. Such antioxidant actions of HNO may confer therapeutic advantages in the treatment of cerebrovascular disorders.

References

  1. 1.

    Irvine JC, Ritchie RH, Favaloro JL, Andrews KL, Widdop RE, Kemp-Harper BK: Nitroxyl (HNO): the Cinderella of the nitric oxide story. Trends Pharmacol Sci. 2008, 29: 601-8. 10.1016/j.tips.2008.08.005.

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Correspondence to Barbara Kemp-Harper.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Kemp-Harper, B., Ravi, R., Bullen, M. et al. Nitroxyl, the novel redox sibling of NO, suppresses cerebrovascular NADPH oxidase. BMC Pharmacol 9, P31 (2009). https://doi.org/10.1186/1471-2210-9-S1-P31

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Keywords

  • Nitric Oxide
  • Antioxidant Action
  • Angiotensin
  • Cerebral Artery
  • Xanthine