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Short-term hypoxic vasodilation in vivo is mediated by bioactive nitric oxide metabolites, rather than free nitric oxide derived from haemoglobin-mediated nitrite reduction

Short-term hypoxic vasodilation in vivo is mediated by bioactive nitric oxide metabolites, rather than free nitric oxide derived from haemoglobin-mediated nitrite reduction
Short-term hypoxic vasodilation in vivo is mediated by bioactive nitric oxide metabolites, rather than free nitric oxide derived from haemoglobin-mediated nitrite reduction
Local increases in blood flow - 'hypoxic vasodilation' - confer cellular protection in the face of reduced oxygen delivery. The physiological relevance of this response is well established, yet ongoing controversy surrounds its underlying mechanisms. We sought to confirm that early hypoxic vasodilation is a nitric oxide (NO)-mediated phenomenon and to study putative pathways for increased levels of NO, namely production from NO synthases, intravascular nitrite reduction, release from pre-formed stores, and reduced deactivation by cytochrome c oxidase. Experiments were performed on spontaneously breathing, anaesthetized, male Wistar rats undergoing short-term systemic hypoxaemia, who received pharmacological inhibitors and activators of the various NO pathways. Arterial blood pressure, cardiac output, tissue oxygen tension and the circulating pool of NO metabolites (oxidation, nitrosation and nitrosylation products) were measured in plasma and erythrocytes. Hypoxaemia caused a rapid and sustained vasodilation, which was only partially reversed by non-selective NOS inhibition. This was associated with significantly lower plasma nitrite, and marginally elevated nitrate levels, suggestive of nitrite bioinactivation. Administration of sodium nitrite had little effect in normoxia, but produced significant vasodilation and increased nitrosylation during hypoxaemia that could not be reversed by NO scavenging. Methodological issues prevented assessment of the contribution, if any, of reduced deactivation of NO by cytochrome c oxidase. In conclusion, acute hypoxic vasodilation is an adaptive NO-mediated response that is conferred through bioactive metabolites rather than free NO from haemoglobin-mediated reduction of nitrite.
hypoxia, nitrergic, nitric oxide, hypoxic vasodilation
0022-3751
1061-1075
Umbrello, Michele
2b17d329-9a22-4be9-8b8b-6729c427fe32
Dyson, Alex
e288e219-cdac-4c63-85c6-9c2b6cdb194c
Bollen Pinto, Bernardo
b715bf17-7b8e-49c2-a9c6-b09431cb9394
Fernandez, Bernadette O.
9890aabc-1fe6-4530-a51e-31182e537131
Simon, Verena
e4ed3414-6e1d-43a2-b0a5-8140408ed410
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Singer, Mervyn
87229716-c753-44ab-a382-3f93c1c5441d
Umbrello, Michele
2b17d329-9a22-4be9-8b8b-6729c427fe32
Dyson, Alex
e288e219-cdac-4c63-85c6-9c2b6cdb194c
Bollen Pinto, Bernardo
b715bf17-7b8e-49c2-a9c6-b09431cb9394
Fernandez, Bernadette O.
9890aabc-1fe6-4530-a51e-31182e537131
Simon, Verena
e4ed3414-6e1d-43a2-b0a5-8140408ed410
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Singer, Mervyn
87229716-c753-44ab-a382-3f93c1c5441d

Umbrello, Michele, Dyson, Alex, Bollen Pinto, Bernardo, Fernandez, Bernadette O., Simon, Verena, Feelisch, Martin and Singer, Mervyn (2014) Short-term hypoxic vasodilation in vivo is mediated by bioactive nitric oxide metabolites, rather than free nitric oxide derived from haemoglobin-mediated nitrite reduction. The Journal of Physiology, 592 (5), 1061-1075. (doi:10.1113/jphysiol.2014.255687). (PMID:24396056)

Record type: Article

Abstract

Local increases in blood flow - 'hypoxic vasodilation' - confer cellular protection in the face of reduced oxygen delivery. The physiological relevance of this response is well established, yet ongoing controversy surrounds its underlying mechanisms. We sought to confirm that early hypoxic vasodilation is a nitric oxide (NO)-mediated phenomenon and to study putative pathways for increased levels of NO, namely production from NO synthases, intravascular nitrite reduction, release from pre-formed stores, and reduced deactivation by cytochrome c oxidase. Experiments were performed on spontaneously breathing, anaesthetized, male Wistar rats undergoing short-term systemic hypoxaemia, who received pharmacological inhibitors and activators of the various NO pathways. Arterial blood pressure, cardiac output, tissue oxygen tension and the circulating pool of NO metabolites (oxidation, nitrosation and nitrosylation products) were measured in plasma and erythrocytes. Hypoxaemia caused a rapid and sustained vasodilation, which was only partially reversed by non-selective NOS inhibition. This was associated with significantly lower plasma nitrite, and marginally elevated nitrate levels, suggestive of nitrite bioinactivation. Administration of sodium nitrite had little effect in normoxia, but produced significant vasodilation and increased nitrosylation during hypoxaemia that could not be reversed by NO scavenging. Methodological issues prevented assessment of the contribution, if any, of reduced deactivation of NO by cytochrome c oxidase. In conclusion, acute hypoxic vasodilation is an adaptive NO-mediated response that is conferred through bioactive metabolites rather than free NO from haemoglobin-mediated reduction of nitrite.

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2014 Umbrello J Physiol - just accepted.pdf - Other
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e-pub ahead of print date: 6 January 2014
Keywords: hypoxia, nitrergic, nitric oxide, hypoxic vasodilation
Organisations: Faculty of Medicine

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Local EPrints ID: 361109
URI: http://eprints.soton.ac.uk/id/eprint/361109
ISSN: 0022-3751
PURE UUID: 18a2fa78-1d15-48da-8a49-7348f8037dca
ORCID for Bernadette O. Fernandez: ORCID iD orcid.org/0000-0001-6337-0381
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 14 Jan 2014 11:01
Last modified: 18 Feb 2021 17:20

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Contributors

Author: Michele Umbrello
Author: Alex Dyson
Author: Bernardo Bollen Pinto
Author: Bernadette O. Fernandez ORCID iD
Author: Verena Simon
Author: Martin Feelisch ORCID iD
Author: Mervyn Singer

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