Cell-Free Hemoglobin as an Oxygen Carrier Removes Nitric Oxide, Resulting in Defective Thromboregulation

Abstract

Development of a clinically safe and effective substitute for erythrocytes that is capable of efficient oxygen delivery in vivo has progressed to the stage where cross-linked hemoglobin preparations are now undergoing clinical trials.1 Such preparations withstand storage for prolonged periods of time, can be administered without the need for cross-matching, and are free of contamination by infectious agents. Utilization of cell-free hemoglobin as an erythrocyte substitute was initially hampered by nephrotoxicity and an affinity for oxygen that prevented efficient oxygen delivery to tissues.2 These disadvantages were overcome when Bunn and Jandl3 chemically cross-linked the hemoglobin molecule to produce stable hemoglobin oligomers that do not pass through the glomerular filtrate. In addition, Benesch and Benesch4 developed reagents that modified the 2,3-diphosphoglycerate binding site of hemoglobin, thereby reducing its oxygen affinity. Administration of cell-free hemoglobin solutions results in systemic vasoconstriction in research animals.5 This is thought to be a consequence of the high avidity of hemoglobin for nitric oxide (NO, endothelium-derived relaxing factor [EDRF]), which it binds and inactivates. The NO-hemoglobin interaction results in rapid formation of nitrite/nitrate and methemoglobin. This blocks vasodilation induced by …