Volume 104, Issue 3 p. 553-563
Article

Pharmacologic Targeting of Red Blood Cells to Improve Tissue Oxygenation

James D. Reynolds

James D. Reynolds

Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA

Department of Anesthesiology & Perioperative Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

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Trevor Jenkins

Trevor Jenkins

Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

Division of Cardiology, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

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Faisal Matto

Faisal Matto

Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

Division of Cardiology, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

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Ryan Nazemian

Ryan Nazemian

Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

Department of Anesthesiology & Perioperative Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

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Obada Farhan

Obada Farhan

Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

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Nathan Morris

Nathan Morris

Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

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John M. Longphre

John M. Longphre

Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, North Carolina, USA

Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA

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Douglas T. Hess

Douglas T. Hess

Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

Division of Cardiology, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

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Richard E. Moon

Richard E. Moon

Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, North Carolina, USA

Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA

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Claude A. Piantadosi

Claude A. Piantadosi

Center for Hyperbaric Medicine and Environmental Physiology, Duke University Medical Center, Durham, North Carolina, USA

Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA

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Jonathan S. Stamler

Corresponding Author

Jonathan S. Stamler

Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA

Division of Cardiology, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

Correspondence: Jonathan S. Stamler ([email protected])Search for more papers by this author
First published: 14 December 2017
Citations: 11

Abstract

Disruption of microvascular blood flow is a common cause of tissue hypoxia in disease, yet no therapies are available that directly target the microvasculature to improve tissue oxygenation. Red blood cells (RBCs) autoregulate blood flow through S-nitroso-hemoglobin (SNO-Hb)-mediated export of nitric oxide (NO) bioactivity. We therefore tested the idea that pharmacological enhancement of RBCs using the S-nitrosylating agent ethyl nitrite (ENO) may provide a novel approach to improve tissue oxygenation. Serial ENO dosing was carried out in sheep (1–400 ppm) and humans (1–100 ppm) at normoxia and at reduced fraction of inspired oxygen (FiO2). ENO increased RBC SNO-Hb levels, corrected hypoxia-induced deficits in tissue oxygenation, and improved measures of oxygen utilization in both species. No adverse effects or safety concerns were identified. Inasmuch as impaired oxygenation is a major cause of morbidity and mortality, ENO may have widespread therapeutic utility, providing a first-in-class agent targeting the microvasculature.

CONFLICT OF INTEREST

Dr. Reynolds has a financial interest in Miach Medical Innovations. Dr. Stamler has financial interests in Nivalis Therapeutics (formerly Nitrox), Adamas Pharma, LifeHealth, and Vindica Pharm. Drs. Moon, Piantadosi, Reynolds, and Stamler hold patents related to renitrosylation of blood, some of which have been licensed for commercial development. Both institutions are aware of these conflicts and appropriate management plans are in place. None of the other authors have relevant conflicts to disclose.