NITRIC OXIDE BINDING TO CROSS-LINKED HUMAN FERRIHEMOGLOBINS

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Intravascular administration of stroma-free hemoglobin appears to be strongly correlated with a rise in pulmonary and systemic blood pressure. This hypertensive response has been attributed to interactions between hemoglobin and the endothelium-derived relaxing factor (EDRF), which is now believed to be nitric oxide (NO). We have explored the interactions between NO and oxidized human hemoglobin, comparing the behavior of unmodified HbAo with that of two chemically cross-linked hemoglobins. The latter are promising blood substitute candidates due to their lower oxygen affinity and greater stability of tetrameric structures. The modified forms examined were HbA=-DBBF, cross-linked between the alpha chains with bis (3,5-dibromosalicyl) fumarate, and HbA-FMDA, modified between the beta chains with fumaryl mono-dibromoaspirin. Biphasic kinetics of NO binding to the ferric hemes were observed, attributable to differing reactivities of alpha and beta chains. The rates of the two phases were altered in the modified hemoglobins, indicating that interdimeric cross-linking changes both alpha and beta chain heme pockets. In a much slower subsequent process, the ferric hemes of (FeIII-NO) complex became reduced, as shown by appearance of the (FeII-NO) spectrum. The reduction occurred at differing rates for the hemoglobins studied, with the fastest time courses shown by the modified forms. If the vasoconstrictive effects of extracellular hemoglobin involve cycling between oxidized an reduced forms in response to exposure to NO, the differences in rate constants observed for the modified hemoglobins may prove to be of physiological significance.