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Reactions of Nitroxyl and Nitrite in Blood

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abstract
Plasma hemoglobin released during intravascular hemolysis has been associated with numerous deleterious effects that may stem from increased nitric oxide (NO) scavenging. Therapies that oxidize plasma oxyHb to metHb could be beneficial because this species does not effectively scavenge NO. We investigated the effects of Angeli's Salt (AS, Na2N2O3), a nitroxyl (HNO) and nitrite (NO2-) donor, on plasma Hb oxidation, and on the vasoactivity of plasma Hb. Both HNO and nitrite are known to oxidize oxyHb to metHb. We hypothesized that AS could ameliorate hemolysis-associated pathology via its preferential reactivity with plasma Hb, as opposed to red cell encapsulated Hb, and through its intrinsic vasodilatory activity. To test this hypothesis, we infused (1) cell-free Hb and AS, (2) cell-free Hb alone, (3) AS alone, and (4) saline (control) in a canine model. The infusion of Hb alone led to significant increases in blood pressure and symptoms of circulatory distress, as was expected, and infusion of AS alone led to significant decreases in these parameters. Co-infusion of AS with Hb had an additive effect on reversing the effects of Hb alone on the systemic circulation, and led to preferential conversion of plasma Hb to metHb. However, the extent of conversion was lower than anticipated based on the in vivo concentration of AS relative to plasma Hb, likely due to reactions of nitroxyl-derived AS with plasma components such as thiol-containing compounds. In our in vitro efforts to characterize the nature of the reaction of Angeli's salt with blood, and particularly with excess Hb, it was noted that AS reacted with oxyHb to produce more metHb than expected based on the previously understood stoichiometry of the reaction. The reaction rate of HNO with oxyHb is approximately seven orders of magnitude larger than the reaction rate of NO2- with oxyHb, and thus the HNO reaction has conventionally been considered independent of the nitrite reaction. However, this research shows that HNO accelerates the nitrite reaction with oxyHb. This acceleration of the nitrite/oxyHb reaction could affect studies aimed at understanding physiological roles of HNO and nitrite and the use of these agents in therapeutics for conditions such as hypertension, hemolytic anemia, heart failure, and ischemia reperfusion injury.
subject
Angeli's salt
blood
hemoglobin
nitrite
nitroxyl
therapeutic
contributor
Bellavia, Landon S. (author)
Kim-Shapiro, Daniel B. (committee chair)
Bonin, Keith D. (committee member)
Carlson, Eric D. (committee member)
Guthold, Martin (committee member)
date
2013-06-06T21:19:35Z (accessioned)
2013 (issued)
degree
Physics (discipline)
10000-01-01 (liftdate)
embargo
forever (terms)
identifier
http://hdl.handle.net/10339/38558 (uri)
language
en (iso)
publisher
Wake Forest University
title
Reactions of Nitroxyl and Nitrite in Blood
type
Dissertation

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