Background:Intravascular hemolysis produces injury in a variety of human diseases including hemoglobinopathies, malaria, and sepsis. The adverse effects of increased plasma hemoglobin are partly mediated by depletion of nitric oxide (NO) and result in vasoconstriction. Circulating plasma proteins haptoglobin and hemopexin scavenge extracellular hemoglobin and cell-free heme, respectively. Methods:The ability of human haptoglobin or hemopexin to inhibit the adverse effects of NO-scavenging by circulating murine hemoglobin was tested in C57Bl/6 mice. In healthy awake mice, the systemic hemodynamic effects of intravenous co-infusion of cell-free hemoglobin and exogenous haptoglobin, or cell-free hemoglobin and hemopexin were compared to the hemodynamic effects of infusion of cell-free hemoglobin or control protein (albumin) alone. We also studied the hemodynamic effects of infusing hemoglobin and haptoglobin as well as injecting either hemoglobin or albumin alone in mice fed a high-fat diet (HFD) and in diabetic mice. Results:Co-infusion of a 1:1 weight ratio of haptoglobin, but not hemopexin, with cell-free hemoglobin prevented hemoglobin-induced systemic hypertension in healthy awake mice. In mice fed a HFD and in diabetic mice, co-infusion of haptoglobin mixed with an equal mass of cell-free hemoglobin did not reverse hemoglobin-induced hypertension. Haptoglobin retained cell-free hemoglobin in plasma but neither haptoglobin nor hemopexin affected the ability of hemoglobin to scavenge NO ex-vivo. Conclusion:In healthy mice with normal endothelium, co-administration of haptoglobin but not hemopexin with cell-free hemoglobin prevents acute hemoglobin-induced systemic hypertension by compartmentalizing cell-free hemoglobin in plasma. In murine diseases associated with endothelial dysfunction, haptoglobin therapy appears to be insufficient to prevent hemoglobin-induced vasoconstriction.
- Cell-free hemoglobin
- Nitric oxide
- Endothelial dysfunction
- Copyright © 2017, American Journal of Physiology-Heart and Circulatory Physiology