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Mixed S-Nitrosylated Polymerized Bovine Hemoglobin Species Moderate Hemodynamic Effects in Acutely Hypoxic Rats

¹ Cardiovascular Pulmonary Research Group, School of Medicine, University of Colorado Health Science Center, Denver, Colorado; ² Laboratory of Biochemistry and Vascular Biology, Office of Blood Research and Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland; ³ Department of Cell Biology, Duke University Medical Center, Durham, North Carolina; Nicholas School of the Environment, Duke University Marine Laboratory, Beaufort, North Carolina; ⁴ Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado; and ⁵ Department of Anesthesiology, University of Colorado Health Science Center, Aurora, Colorado

Correspondence and requests for reprints should be addressed to David Irwin, Ph.D., University of Colorado Health Science Center, Cardiovascular Pulmonary Research Laboratory, School of Medicine, 4200 East 9th Avenue, Denver, CO 80262. E-mail: david.irwin{at}uchsc.edu

Hemoglobin (Hb)-based oxygen carriers (HBOCs) are being developed as a potential therapy for increasing tissue oxygenation, yet they have not reached their full potential because of unwanted hemodynamic side effects (vasoconstriction, low cardiac output, and oxygen delivery) due in part to nitric oxide (NO) scavenging by cell-free Hb. It may be possible to overcome the NO scavenging effect by coinfusing S-nitrosylated (SNO) HBOC along with unmodified HBOC. SNO-HBOC, like free Hb, may act as an NO donor in low-oxygen conditions. We hypothesized that an unaltered HBOC, polymerized bovine Hb (PBvHb), coinfused with an SNO-PBvHb, would improve hemodynamics and oxygen delivery during hypoxia. Vascular oxygen content and hemodynamics were determined after euvolemic rats were infused (3 ml) with lactated Ringer's solution, PBvHb, SNO-PBvHb, or PBvHb plus SNO-PBvHb (1:10) during normoxia or acute hypoxia (fraction of inspired oxygen = 10%, 120 min). Hemodynamic side effects resulting from PBvHb infusion (vasoconstriction, elevated pulmonary blood pressure, and reduced cardiac output) were offset by SNO-PBvHb in acute hypoxic, but not normoxic, conditions. These data support the potential use of HBOC mixed with SNO-HBOC for the treatment of conditions in which acute hypoxia is present, such as tumor oxygenation, wound healing, hemorrhagic trauma, and sickle cell and hemolytic anemia.

Key Words: S-nitrosylation • hemoglobin-based oxygen carrier • oxygen delivery • cardiac output • blood pressure

CLINICAL RELEVANCE Hemoglobin-based oxygen carriers (HBOCs) are being developed for blood substitutes, as well as for a wide variety of therapies for other conditions. However, due to unwanted hemodyanmic side effects, HBOCs have not yet reached their full potential. We show here that infusing a mixture of S-nitrosylated and normal HBOCs mitigates these adverse hemodynamic side effects.