Nitrite reductase activity of hemoglobin as a systemic nitric oxide generator mechanism to detoxify plasma hemoglobin produced during hemolysis.
Hemoglobin (Hb) potently inactivates the nitric oxide (NO) radical via a dioxygenation reaction forming nitrate (NO(3)(-)). This inactivation produces endothelial dysfunction during hemolytic conditions and may contribute to the vascular complications of Hb-based blood substitutes. Hb also functions as a nitrite (NO(2)(-)) reductase, converting nitrite into NO as it deoxygenates. We hypothesized that during intravascular hemolysis, nitrite infusions would limit the vasoconstrictive properties of plasma Hb. In a canine model of low- and high-intensity hypotonic intravascular hemolysis, we characterized hemodynamic responses to nitrite infusions. Hemolysis increased systemic and pulmonary arterial pressures and systemic vascular resistance. Hemolysis also inhibited NO-dependent pulmonary and systemic vasodilation by the NO donor sodium nitroprusside. Compared with nitroprusside, nitrite demonstrated unique effects by not only inhibiting hemolysis-associated vasoconstriction but also by potentiating vasodilation at plasma Hb concentrations of <25 muM. We also observed an interaction between plasma Hb levels and nitrite to augment nitroprusside-induced vasodilation of the pulmonary and systemic circulation. This nitrite reductase activity of Hb in vivo was recapitulated in vitro using a mitochondrial NO sensor system. Nitrite infusions may promote NO generation from Hb while maintaining oxygen delivery; this effect could be harnessed to treat hemolytic conditions and to detoxify Hb-based blood substitutes.
Department of Surgery, The Children's Institute for Surgical Science, The Children's Hospital of Philadelphia, PA, USA.
Peter C
PC
Minneci
Katherine J
KJ
Deans
Sruti
S
Shiva
Huang
H
Zhi
Steven M
SM
Banks
Steven
S
Kern
Charles
C
Natanson
Steven B
SB
Solomon
Mark T
MT
Gladwin
D000818:Animals; D015374:Biosensing Techniques; D001794:Blood Pressure / Q000187:drug effects; D001802:Blood Substitutes / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects*; D006454:Hemoglobins / Q000378:metabolism*; D006461:Hemolysis / Q000187:drug effects*; D007262:Infusions, Intravenous; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism*; D009572:Nitrite Reductases / Q000097:blood*; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012977:Sodium Nitrite / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D001802:Blood Substitutes; D006454:Hemoglobins; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D009572:Nitrite Reductases; D012977:Sodium Nitrite