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From the Department of Molecular Physiology and Biological Physics (T.C.S.K., C.M., M.C., M.P., M.Y., B.E.I.), Robert M. Berne Cardiovascular Research Center (T.C.S.K., J.T.B., G.B.B.-F., C.M., L.J.D., X.S., A.K.B., M.E.G., B.E.I.), Department of Pharmacology (L.J.D.), Division of Nephrology, Department of Medicine (S.C., T.H.L.), and Division of Endocrinology, Department of Medicine (E.B.), University of Virginia School of Medicine, Charlottesville; Department of Physiological Sciences, Federal University of Espirito Santa, Brazil (G.B.B.-F., A.S.P.); Departments of Pediatrics and Biochemistry, Washington University in Saint Louis, MO (S.R., A.D.); Department of Biomedical Engineering (B.N., S.M.P., S.H.) and Department of Chemistry (J.N.M., L.C.), University of Virginia, Charlottesville; and College of Pharmacy, Dalian Medical University, Dalian, China (X.S.).
Published: December 2016
AI Article Synopsis
Article Abstract
The ability of hemoglobin to scavenge the potent vasodilator nitric oxide (NO) in the blood has been well established as a mechanism of vascular tone homeostasis. In endothelial cells, the alpha chain of hemoglobin (hereafter, alpha globin) and endothelial NO synthase form a macromolecular complex, providing a sink for NO directly adjacent to the production source. We have developed an alpha globin mimetic peptide (named HbαX) that displaces endogenous alpha globin and increases bioavailable NO for vasodilation. Here we show that, in vivo, HbαX administration increases capillary oxygenation and blood flow in arterioles acutely and produces a sustained decrease in systolic blood pressure in normal and angiotensin II-induced hypertensive states. HbαX acts with high specificity and affinity to endothelial NO synthase, without toxicity to liver and kidney and no effect on p50 of O binding in red blood cells. In human vasculature, HbαX blunts vasoconstrictive response to cumulative doses of phenylephrine, a potent constricting agent. By binding to endothelial NO synthase and displacing endogenous alpha globin, HbαX modulates important metrics of vascular function, increasing vasodilation and flow in the resistance vasculature.
