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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Published Version (Please cite this version)

10.1002/cpt.979

Publication Info

Reynolds, James D, Trevor Jenkins, Faisal Matto, Ryan Nazemian, Obada Farhan, Nathan Morris, John M Longphre, Douglas T Hess, et al. (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.

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