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Pharmacological preconditioning with inhaled nitric oxide (NO): organ-specific differences in the lifetime of blood and tissue NO metabolites

Pharmacological preconditioning with inhaled nitric oxide (NO): organ-specific differences in the lifetime of blood and tissue NO metabolites
Pharmacological preconditioning with inhaled nitric oxide (NO): organ-specific differences in the lifetime of blood and tissue NO metabolites

BACKGROUND: Endogenous nitric oxide (NO) may contribute to ischemic and anesthetic preconditioning while exogenous NO protects against ischemia-reperfusion (I/R) injury in the heart and other organs. Why those beneficial effects observed in animal models do not always translate into clinical effectiveness remains unclear. To mitigate reperfusion damage a source of NO is required. NO inhalation is known to increase tissue NO metabolites, but little information exists about the lifetime of these species. We therefore sought to investigate the fate of major NO metabolite classes following NO inhalation in mice in vivo.

METHODS: C57/bl6 mice were exposed to 80 ppm NO for 1 h. NO metabolites were measured in blood (plasma and erythrocytes) and tissues (heart, liver, lung, kidney and brain) immediately after NO exposure and up to 48 h thereafter. Concentrations of S-nitrosothiols, N-nitrosamines and NO-heme products as well as nitrite and nitrate were quantified by gas-phase chemiluminescence and ion chromatography. In separate experiments, mice breathed 80 ppm NO for 1 h prior to cardiac I/R injury (induced by coronary arterial ligation for 1 h, followed by recovery). After sacrifice, the size of the myocardial infarction (MI) and the area at risk (AAR) were measured.

RESULTS: After NO inhalation, elevated nitroso/nitrosyl levels returned to baseline over the next 24 h, with distinct multi-phasic decay profiles in each compartment. S/N-nitroso compounds and NO-hemoglobin in blood decreased exponentially, but remained above baseline for up to 30min, whereas nitrate was elevated for up to 3hrs after discontinuing NO breathing. Hepatic S/N-nitroso species concentrations remained steady for 30min before dropping exponentially. Nitrate only rose in blood, liver and kidney; nitrite tended to be lower in all organs immediately after NO inhalation but fluctuated considerably in concentration thereafter. NO inhalation before myocardial ischemia decreased the ratio of MI/AAR by 30% vs controls (p = 0.002); only cardiac S-nitrosothiols and NO-hemes were elevated at time of reperfusion onset.

CONCLUSIONS: Metabolites in blood do not reflect NO metabolite status of any organ. Although NO is rapidly inactivated by hemoglobin-mediated oxidation in the circulation, long-lived tissue metabolites may account for the myocardial preconditioning effects of inhaled NO. NO inhalation may afford similar protection in other organs.

Journal Article
1089-8603
52-60
Nagasaka, Yasuko
059f8837-21bd-4075-adcd-883f98b8edbf
Fernandez, Bernadette O.
9890aabc-1fe6-4530-a51e-31182e537131
Steinbicker, Andrea U.
c6c31000-151e-4633-9542-a4b09db47b78
Spagnolli, Ester
c43f2755-b3da-44e0-955f-a5ecb5c94790
Malhotra, Rajeev
8ae9ed0d-dd47-4b83-a192-3c2f38f003cc
Bloch, Donald B.
bce63551-89d0-4ccc-b03a-4a2a5278eaf7
Bloch, Kenneth D.
25d43ddf-77d4-448b-b618-079a0492aba1
Zapol, Warren M.
84efe66d-166f-4b1d-8db2-b48586aea27e
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Nagasaka, Yasuko
059f8837-21bd-4075-adcd-883f98b8edbf
Fernandez, Bernadette O.
9890aabc-1fe6-4530-a51e-31182e537131
Steinbicker, Andrea U.
c6c31000-151e-4633-9542-a4b09db47b78
Spagnolli, Ester
c43f2755-b3da-44e0-955f-a5ecb5c94790
Malhotra, Rajeev
8ae9ed0d-dd47-4b83-a192-3c2f38f003cc
Bloch, Donald B.
bce63551-89d0-4ccc-b03a-4a2a5278eaf7
Bloch, Kenneth D.
25d43ddf-77d4-448b-b618-079a0492aba1
Zapol, Warren M.
84efe66d-166f-4b1d-8db2-b48586aea27e
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd

Nagasaka, Yasuko, Fernandez, Bernadette O., Steinbicker, Andrea U., Spagnolli, Ester, Malhotra, Rajeev, Bloch, Donald B., Bloch, Kenneth D., Zapol, Warren M. and Feelisch, Martin (2018) Pharmacological preconditioning with inhaled nitric oxide (NO): organ-specific differences in the lifetime of blood and tissue NO metabolites. Nitric Oxide, 80, 52-60. (doi:10.1016/j.niox.2018.08.006).

Record type: Article

Abstract

BACKGROUND: Endogenous nitric oxide (NO) may contribute to ischemic and anesthetic preconditioning while exogenous NO protects against ischemia-reperfusion (I/R) injury in the heart and other organs. Why those beneficial effects observed in animal models do not always translate into clinical effectiveness remains unclear. To mitigate reperfusion damage a source of NO is required. NO inhalation is known to increase tissue NO metabolites, but little information exists about the lifetime of these species. We therefore sought to investigate the fate of major NO metabolite classes following NO inhalation in mice in vivo.

METHODS: C57/bl6 mice were exposed to 80 ppm NO for 1 h. NO metabolites were measured in blood (plasma and erythrocytes) and tissues (heart, liver, lung, kidney and brain) immediately after NO exposure and up to 48 h thereafter. Concentrations of S-nitrosothiols, N-nitrosamines and NO-heme products as well as nitrite and nitrate were quantified by gas-phase chemiluminescence and ion chromatography. In separate experiments, mice breathed 80 ppm NO for 1 h prior to cardiac I/R injury (induced by coronary arterial ligation for 1 h, followed by recovery). After sacrifice, the size of the myocardial infarction (MI) and the area at risk (AAR) were measured.

RESULTS: After NO inhalation, elevated nitroso/nitrosyl levels returned to baseline over the next 24 h, with distinct multi-phasic decay profiles in each compartment. S/N-nitroso compounds and NO-hemoglobin in blood decreased exponentially, but remained above baseline for up to 30min, whereas nitrate was elevated for up to 3hrs after discontinuing NO breathing. Hepatic S/N-nitroso species concentrations remained steady for 30min before dropping exponentially. Nitrate only rose in blood, liver and kidney; nitrite tended to be lower in all organs immediately after NO inhalation but fluctuated considerably in concentration thereafter. NO inhalation before myocardial ischemia decreased the ratio of MI/AAR by 30% vs controls (p = 0.002); only cardiac S-nitrosothiols and NO-hemes were elevated at time of reperfusion onset.

CONCLUSIONS: Metabolites in blood do not reflect NO metabolite status of any organ. Although NO is rapidly inactivated by hemoglobin-mediated oxidation in the circulation, long-lived tissue metabolites may account for the myocardial preconditioning effects of inhaled NO. NO inhalation may afford similar protection in other organs.

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Accepted/In Press date: 10 August 2018
e-pub ahead of print date: 13 August 2018
Published date: 1 November 2018
Keywords: Journal Article

Identifiers

Local EPrints ID: 423541
URI: http://eprints.soton.ac.uk/id/eprint/423541
ISSN: 1089-8603
PURE UUID: ca08ebdf-d540-468b-b823-f8f1080adaf0
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: 25 Sep 2018 16:30
Last modified: 26 Nov 2021 03:00

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Contributors

Author: Yasuko Nagasaka
Author: Bernadette O. Fernandez ORCID iD
Author: Andrea U. Steinbicker
Author: Ester Spagnolli
Author: Rajeev Malhotra
Author: Donald B. Bloch
Author: Kenneth D. Bloch
Author: Warren M. Zapol
Author: Martin Feelisch ORCID iD

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