Inhaled nitric oxide improves survival rates during hypoxia in a sickle cell (SAD) mouse model

Ricardo Martinez-Ruiz, Pedro Montero-Huerta, Jonathan Hromi, C. Alvin Head

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Background: The hallmark of sickle cell disease (SCD) is erythrocyte sickling during deoxygenation of the abnormal hemoglobin S (HbS). When HbS is deoxygenated, it aggregates into polymers, resulting in distortion of the erythrocyte structure, producing microvascular thrombosis and ischemia. The transgenic SAD mouse produces three types of human hemoglobin: S, Antilles, and D-Punjab (HbSAD) and provides an animal model for SCD. We studied the effects of nitric oxide (NO) breathing at various doses and time regimens in the presence of severe hypoxia (6% oxygen) using the SAD mouse model. Methods: Age- and sex-matched control and SAD mice were exposed to 6% oxygen breathing in an environmental chamber and assessed for survival up to 1 h. Animals received different inhaled NO concentrations before and/or during hypoxia. Blood was obtained to evaluate the oxyhemoglobin dissociation curve and measure methemoglobinemia. Results: Pretreatment by breathing NO at 20 ppm by volume in air for 30 min, and continuing to breathe 20 ppm NO during hypoxia resulted in improvement in survival rates in the SAD mouse (75%, n = 8) as compared with control SAD mice (11%, n = 9; P < 0.001). Pretreatment alone or breathing lower doses of NO were not protective. Changes in HbSAD oxygen affinity were not detected with NO breathing, and methemoglobin levels were low in all surviving mice. Conclusions: Breathing NO produced a rapid, protective effect to severe hypoxic stress in SAD mice. There appears to be a required loading period between NO breathing and its beneficial effect during hypoxic stress, possibly because of the total amount of NO delivered to SAD hemoglobin, blood cell components, and endothelium. NO breathing may be beneficial as a therapeutic intervention in SCD.

Original languageEnglish
Pages (from-to)1113-1118
Number of pages6
JournalAnesthesiology
Volume94
Issue number6
StatePublished - Jun 15 2001

Fingerprint

Nitric Oxide
Respiration
Sickle Cell Anemia
Sickle Hemoglobin
Oxygen
Erythrocytes
Hypoxia
Abnormal Hemoglobins
Methemoglobinemia
Methemoglobin
Oxyhemoglobins
Cellular Structures
Transgenic Mice
Endothelium
Blood Cells
Polymers
Thrombosis
Ischemia
Animal Models
Air

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Inhaled nitric oxide improves survival rates during hypoxia in a sickle cell (SAD) mouse model. / Martinez-Ruiz, Ricardo; Montero-Huerta, Pedro; Hromi, Jonathan; Head, C. Alvin.

In: Anesthesiology, Vol. 94, No. 6, 15.06.2001, p. 1113-1118.

Research output: Contribution to journalArticle

Martinez-Ruiz, R, Montero-Huerta, P, Hromi, J & Head, CA 2001, 'Inhaled nitric oxide improves survival rates during hypoxia in a sickle cell (SAD) mouse model', Anesthesiology, vol. 94, no. 6, pp. 1113-1118.
Martinez-Ruiz, Ricardo ; Montero-Huerta, Pedro ; Hromi, Jonathan ; Head, C. Alvin. / Inhaled nitric oxide improves survival rates during hypoxia in a sickle cell (SAD) mouse model. In: Anesthesiology. 2001 ; Vol. 94, No. 6. pp. 1113-1118.
@article{0c20b6468c584402bac254cdaf88573b,
title = "Inhaled nitric oxide improves survival rates during hypoxia in a sickle cell (SAD) mouse model",
abstract = "Background: The hallmark of sickle cell disease (SCD) is erythrocyte sickling during deoxygenation of the abnormal hemoglobin S (HbS). When HbS is deoxygenated, it aggregates into polymers, resulting in distortion of the erythrocyte structure, producing microvascular thrombosis and ischemia. The transgenic SAD mouse produces three types of human hemoglobin: S, Antilles, and D-Punjab (HbSAD) and provides an animal model for SCD. We studied the effects of nitric oxide (NO) breathing at various doses and time regimens in the presence of severe hypoxia (6{\%} oxygen) using the SAD mouse model. Methods: Age- and sex-matched control and SAD mice were exposed to 6{\%} oxygen breathing in an environmental chamber and assessed for survival up to 1 h. Animals received different inhaled NO concentrations before and/or during hypoxia. Blood was obtained to evaluate the oxyhemoglobin dissociation curve and measure methemoglobinemia. Results: Pretreatment by breathing NO at 20 ppm by volume in air for 30 min, and continuing to breathe 20 ppm NO during hypoxia resulted in improvement in survival rates in the SAD mouse (75{\%}, n = 8) as compared with control SAD mice (11{\%}, n = 9; P < 0.001). Pretreatment alone or breathing lower doses of NO were not protective. Changes in HbSAD oxygen affinity were not detected with NO breathing, and methemoglobin levels were low in all surviving mice. Conclusions: Breathing NO produced a rapid, protective effect to severe hypoxic stress in SAD mice. There appears to be a required loading period between NO breathing and its beneficial effect during hypoxic stress, possibly because of the total amount of NO delivered to SAD hemoglobin, blood cell components, and endothelium. NO breathing may be beneficial as a therapeutic intervention in SCD.",
author = "Ricardo Martinez-Ruiz and Pedro Montero-Huerta and Jonathan Hromi and Head, {C. Alvin}",
year = "2001",
month = "6",
day = "15",
language = "English",
volume = "94",
pages = "1113--1118",
journal = "Anesthesiology",
issn = "0003-3022",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

TY - JOUR

T1 - Inhaled nitric oxide improves survival rates during hypoxia in a sickle cell (SAD) mouse model

AU - Martinez-Ruiz, Ricardo

AU - Montero-Huerta, Pedro

AU - Hromi, Jonathan

AU - Head, C. Alvin

PY - 2001/6/15

Y1 - 2001/6/15

N2 - Background: The hallmark of sickle cell disease (SCD) is erythrocyte sickling during deoxygenation of the abnormal hemoglobin S (HbS). When HbS is deoxygenated, it aggregates into polymers, resulting in distortion of the erythrocyte structure, producing microvascular thrombosis and ischemia. The transgenic SAD mouse produces three types of human hemoglobin: S, Antilles, and D-Punjab (HbSAD) and provides an animal model for SCD. We studied the effects of nitric oxide (NO) breathing at various doses and time regimens in the presence of severe hypoxia (6% oxygen) using the SAD mouse model. Methods: Age- and sex-matched control and SAD mice were exposed to 6% oxygen breathing in an environmental chamber and assessed for survival up to 1 h. Animals received different inhaled NO concentrations before and/or during hypoxia. Blood was obtained to evaluate the oxyhemoglobin dissociation curve and measure methemoglobinemia. Results: Pretreatment by breathing NO at 20 ppm by volume in air for 30 min, and continuing to breathe 20 ppm NO during hypoxia resulted in improvement in survival rates in the SAD mouse (75%, n = 8) as compared with control SAD mice (11%, n = 9; P < 0.001). Pretreatment alone or breathing lower doses of NO were not protective. Changes in HbSAD oxygen affinity were not detected with NO breathing, and methemoglobin levels were low in all surviving mice. Conclusions: Breathing NO produced a rapid, protective effect to severe hypoxic stress in SAD mice. There appears to be a required loading period between NO breathing and its beneficial effect during hypoxic stress, possibly because of the total amount of NO delivered to SAD hemoglobin, blood cell components, and endothelium. NO breathing may be beneficial as a therapeutic intervention in SCD.

AB - Background: The hallmark of sickle cell disease (SCD) is erythrocyte sickling during deoxygenation of the abnormal hemoglobin S (HbS). When HbS is deoxygenated, it aggregates into polymers, resulting in distortion of the erythrocyte structure, producing microvascular thrombosis and ischemia. The transgenic SAD mouse produces three types of human hemoglobin: S, Antilles, and D-Punjab (HbSAD) and provides an animal model for SCD. We studied the effects of nitric oxide (NO) breathing at various doses and time regimens in the presence of severe hypoxia (6% oxygen) using the SAD mouse model. Methods: Age- and sex-matched control and SAD mice were exposed to 6% oxygen breathing in an environmental chamber and assessed for survival up to 1 h. Animals received different inhaled NO concentrations before and/or during hypoxia. Blood was obtained to evaluate the oxyhemoglobin dissociation curve and measure methemoglobinemia. Results: Pretreatment by breathing NO at 20 ppm by volume in air for 30 min, and continuing to breathe 20 ppm NO during hypoxia resulted in improvement in survival rates in the SAD mouse (75%, n = 8) as compared with control SAD mice (11%, n = 9; P < 0.001). Pretreatment alone or breathing lower doses of NO were not protective. Changes in HbSAD oxygen affinity were not detected with NO breathing, and methemoglobin levels were low in all surviving mice. Conclusions: Breathing NO produced a rapid, protective effect to severe hypoxic stress in SAD mice. There appears to be a required loading period between NO breathing and its beneficial effect during hypoxic stress, possibly because of the total amount of NO delivered to SAD hemoglobin, blood cell components, and endothelium. NO breathing may be beneficial as a therapeutic intervention in SCD.

UR - http://www.scopus.com/inward/record.url?scp=0034989750&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034989750&partnerID=8YFLogxK

M3 - Article

C2 - 11465605

AN - SCOPUS:0034989750

VL - 94

SP - 1113

EP - 1118

JO - Anesthesiology

JF - Anesthesiology

SN - 0003-3022

IS - 6

ER -