No scavenging and the hypertensive effect of hemoglobin-based blood substitutes.
The major pathway for nitric oxide scavenging in red cells involves the direct reaction of the gas with HbO2 to form nitrate and the ferric form of the protein, metHb. Because both atoms of O2 are incorporated into nitrate, this process is called NO dioxygenation (NOD). The NOD reaction involves an initial, very rapid bimolecular addition of NO to bound O2 to form a transient Fe(III)-peroxynitrite complex, which can be observed spectrally at alkaline pH. This intermediate rapidly isomerizes at pH 7 (t1/2 <== 1 ms) to metHb and NO3-, which is nontoxic and readily transported out of red cells and excreted. The rate of NO consumption by intracellular HbO2 during normal blood flow is limited by diffusion up to and into the red cells and is too slow to interfere significantly with vasoregulation. In contrast, extracellular HbO2 is highly vasoconstrictive, and the resultant hypertension is a significant side effect of most hemoglobin-based blood substitutes. The major cause of this blood pressure effect seems to be the high rate of NO dioxygenation by cell-free HbO2, which can extravasate into the vessel walls and interfere directly with NO signaling between endothelial and smooth muscle cells. This interpretation is supported by a strong linear correlation between the magnitude of the blood pressure effect caused by infusion of cross-linked recombinant hemoglobin tetramers in vivo and the rate of NO dioxygenation by these proteins measured in vitro.
Olson
John S
JS
Department of Biochemistry and Cell Biology, W. M. Keck Center for Computational Biology, Rice University, Houston, TX 77005, USA. olson@bioc.rice.edu
Foley
Erin W
EW
Rogge
Corina
C
Tsai
Ah-Lim
AL
Doyle
Michael P
MP
Lemon
Douglas D
DD
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001802:Blood Substitutes / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000378:metabolism; D006433:Hemocyanins / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism; D009211:Myoglobin / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D051381:Rats
D001802:Blood Substitutes; D016166:Free Radical Scavengers; D006454:Hemoglobins; D009211:Myoglobin; C021724:oxy-beta-hemocyanin; C017595:oxymyoglobin; D009569:Nitric Oxide; D006433:Hemocyanins; D010100:Oxygen