Pharmacologic Targeting of Red Blood Cells to Improve Tissue Oxygenation.
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.
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Journal articlePermalink
https://hdl.handle.net/10161/16052Published Version (Please cite this version)
10.1002/cpt.979Publication Info
Reynolds, James D; Jenkins, Trevor; Matto, Faisal; Nazemian, Ryan; Farhan, Obada;
Morris, Nathan; ... Stamler, Jonathan S (2017). Pharmacologic Targeting of Red Blood Cells to Improve Tissue Oxygenation. Clin Pharmacol Ther. 10.1002/cpt.979. Retrieved from https://hdl.handle.net/10161/16052.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Richard Edward Moon
Professor of Anesthesiology
Research interests include the study of cardiorespiratory function in humans during
challenging clinical settings including the perioperative period, and exposure to
environmental conditions such as diving and high altitude. Studies have included gas
exchange during diving, the pathophysiology of high altitude and immersion pulmonary
edema, the effect of anesthesia and postoperative analgesia on pulmonary function
and monitoring of tissue oxygenation. Ongoing human studies include the effect of
Claude Anthony Piantadosi
Professor Emeritus of Medicine
Dr. Piantadosi's laboratory has special expertise in the pathogenic mechanisms of
acute organ failure, particularly acute lung injury (ALI), with an emphasis on the
molecular regulatory roles of the physiological gases— oxygen, carbon monoxide, and
nitric oxide— as they relate to the damage responses to acute inflammation. The basic
science focuses on oxidative processes and redox-regulation, especially the molecular
mechanisms by which reactive oxygen and nitrogen species transmit b
Jonathan Solomon Stamler
Adjunct Professor in the Department of Medicine
Biochemistry of nitric oxide and related nitro (so)-compounds Biochemistry and metabolic
functions of biological sulfhydryls Free radical mechanisms in biology
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