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Characterization of Sickling During Controlled Automated Deoxygenation with Oxygen Gradient Ektacytometry

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Nitric oxide transport on sickle cell hemoglobin: where does it bind?

M T Gladwin¹, F P Ognibene, J H Shelhamer

¹Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. mgladwin@nih.gov

Free Radical Research

|November 8, 2001

Summary

Inhaled nitric oxide (NO) in sickle cell anemia primarily forms nitrosyl hemoglobin (HbFeIINO), not S-nitrosohemoglobin (SNO-Hb). This suggests NO delivery via heme binding is key for potential sickle cell disease therapies.

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Area of Science:

Biochemistry
Hematology
Pulmonary Medicine

Background:

Nitric oxide (NO) inhalation in sickle cell anemia (SCA) increases NO-bound hemoglobin, creating an arterial-venous gradient indicating tissue delivery.
A proposed model suggests NO forms S-nitrosohemoglobin (SNO-Hb) via cysteine 93, facilitating NO release in tissues to modulate blood flow.
Previous studies in healthy individuals showed NO primarily forms nitrosyl hemoglobin (HbFeIINO) during NO breathing, with minimal SNO-Hb.

Purpose of the Study:

To determine if NO is transported as HbFeIINO or SNO-Hb in individuals with sickle cell disease.
To assess the impact of different NO transport mechanisms on sickle hemoglobin polymerization.
To investigate the dose-dependent formation of HbFeIINO and SNO-Hb during inhaled NO therapy in SCA.

Main Methods:

Measurement of HbFeIINO and SNO-Hb levels in three sickle cell volunteers.
Dose escalation of inhaled NO (40, 60, and 80 ppm) administered to participants.
Comparison of NO adducts formed in SCA patients with those previously observed in healthy individuals.

Main Results:

The predominant NO-hemoglobin adduct formed in sickle cell volunteers was HbFeIINO, similar to healthy individuals.
A significant arterial-venous gradient for HbFeIINO was observed, suggesting effective NO transport.
Minimal SNO-Hb formation occurred, indicating it is not the primary NO transport pathway in SCA during NO inhalation.

Conclusions:

NO transport in sickle cell disease during inhalation therapy predominantly occurs via heme binding (HbFeIINO), not S-nitrosylation of cysteine 93 (SNO-Hb).
The rapid reversibility of NO binding to heme supports a revised model for NO delivery in peripheral circulation.
Hemoglobin-mediated NO delivery shows potential as a therapeutic strategy for sickle cell disease.