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Citations to this article

Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin
Peter C. Minneci, … , Mark T. Gladwin, Steven B. Solomon
Peter C. Minneci, … , Mark T. Gladwin, Steven B. Solomon
Published December 1, 2005
Citation Information: J Clin Invest. 2005;115(12):3409-3417. https://doi.org/10.1172/JCI25040.
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Research Article Vascular biology Article has an altmetric score of 9

Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin

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Abstract

During intravascular hemolysis in human disease, vasomotor tone and organ perfusion may be impaired by the increased reactivity of cell-free plasma hemoglobin (Hb) with NO. We experimentally produced acute intravascular hemolysis in a canine model in order to test the hypothesis that low levels of decompartmentalized or cell-free plasma Hb will severely reduce NO bioavailability and produce vasomotor instability. Importantly, in this model the total intravascular Hb level is unchanged; only the compartmentalization of Hb within the erythrocyte membrane is disrupted. Using a full-factorial design, we demonstrate that free water–induced intravascular hemolysis produces dose-dependent systemic vasoconstriction and impairs renal function. We find that these physiologic changes are secondary to the stoichiometric oxidation of endogenous NO by cell-free plasma oxyhemoglobin. In this model, 80 ppm of inhaled NO gas oxidized 85–90% of plasma oxyhemoglobin to methemoglobin, thereby inhibiting endogenous NO scavenging by cell-free Hb. As a result, the vasoconstriction caused by acute hemolysis was attenuated and the responsiveness to systemically infused NO donors was restored. These observations confirm that the acute toxicity of intravascular hemolysis occurs secondarily to the accelerated dioxygenation reaction of plasma oxyhemoglobin with endothelium-derived NO to form bioinactive nitrate. These biochemical and physiological studies demonstrate a major role for the intact erythrocyte in NO homeostasis and provide mechanistic support for the existence of a human syndrome of hemolysis-associated NO dysregulation, which may contribute to the vasculopathy of hereditary, acquired, and iatrogenic hemolytic states.

Authors

Peter C. Minneci, Katherine J. Deans, Huang Zhi, Peter S.T. Yuen, Robert A. Star, Steven M. Banks, Alan N. Schechter, Charles Natanson, Mark T. Gladwin, Steven B. Solomon

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Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 Total
Citations: 1 9 7 6 8 8 11 6 5 6 7 8 9 14 6 7 7 8 4 7 144
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Citations to this article in year 2009 (7)

Title and authors Publication Year
Sequestration within haptoglobin complex is effective in treating hypertensive and oxidative effects of extracellular hemoglobin
Felicitas S. Boretti Paul W. Buehler Felice D’Agnillo Katharina Kluge Tony Glaus Omer I. Butt Yiping Jia Jeroen Goede Claudia P. Pereira Marco Maggiorini Gabriele Schoedon Abdu I. Alayash Dominik J. Schaer
Journal of Clinical Investigation 2009
Haptoglobin halts hemoglobin’s havoc
Gregory J. Kato
Journal of Clinical Investigation 2009
Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2009
Hemoglobin-based red blood cell substitutes and nitric oxide
B Yu, KD Bloch, WM Zapol
Trends in Cardiovascular Medicine 2009
Prevention of the pulmonary vasoconstrictor effects of HBOC-201 in awake lambs by continuously breathing nitric oxide
B Yu, GP Volpato, K Chang, KD Bloch, WM Zapol
Anesthesiology 2009
Endogenous nitric oxide synthase inhibitors in sickle cell disease: abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and death
GJ Kato, Z Wang, RF Machado, WC Blackwelder, JG 6th, SL Hazen
British Journal of Haematology 2009
Relationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavailability and perfusion in severe falciparum malaria
TW Yeo, DA Lampah, E Tjitra, R Gitawati, E Kenangalem, K Piera, DL Granger, BK Lopansri, JB Weinberg, RN Price, SB Duffull, DS Celermajer, NM Anstey
The Journal of Infectious Diseases 2009

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