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Nitric oxide in the human respiratory cycle

Nature Medicine volume 8, pages 711–717 (2002)Cite this article

Abstract

Interactions of nitric oxide (NO) with hemoglobin (Hb) could regulate the uptake and delivery of oxygen (O2) by subserving the classical physiological responses of hypoxic vasodilation and hyperoxic vasconstriction in the human respiratory cycle. Here we show that in in vitro and ex vivo systems as well as healthy adults alternately exposed to hypoxia or hyperoxia (to dilate or constrict pulmonary and systemic arteries in vivo), binding of NO to hemes (FeNO) and thiols (SNO) of Hb varies as a function of HbO2 saturation (FeO2). Moreover, we show that red blood cell (RBC)/SNO-mediated vasodilator activity is inversely proportional to FeO2 over a wide range, whereas RBC-induced vasoconstriction correlates directly with FeO2. Thus, native RBCs respond to changes in oxygen tension (pO2) with graded vasodilator and vasoconstrictor activity, which emulates the human physiological response subserving O2 uptake and delivery. The ability to monitor and manipulate blood levels of NO, in conjunction with O2 and carbon dioxide, may therefore prove useful in the diagnosis and treatment of many human conditions and in the development of new therapies. Our results also help elucidate the link between RBC dyscrasias and cardiovascular morbidity.

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Figure 1: Oxygenation/deoxygenation-dependent NO reactions in human blood and hemoglobin.
Figure 2: Levels of SNO–Hb (▪) and Hb[FeNO] (□).
Figure 3: RBC-mediated hypoxic vasodilation and hyperoxic vasoconstriction.
Figure 4: Simplified 2-state model of the human respiratory cycle: a 3-gas system involving NO, CO2 and O2.

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Acknowledgements

We thank Y. Yan for technical assistance. This work was supported by grants from the NIH (K08 HL04014 to T.J.M.; HL04424-09 to C.A.P.), and NSF (MCB-0091228 to D.J.S.).

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Authors and Affiliations

  1. Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA

    Timothy J. McMahon, Richard E. Moon, Martha S. Carraway, Anne E. Stone, Andrew J. Gow, John R. Pawloski, Claude A. Piantadosi & Jonathan S. Stamler

  2. Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA

    Richard E. Moon, Martha S. Carraway, Bryant W. Stolp, Paula Watke & Claude A. Piantadosi

  3. Department of Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina, USA

    Anne E. Stone & Jonathan S. Stamler

  4. Department of Chemistry, Montana State University, Bozeman, Montana, USA

    Ben P. Luschinger & David J. Singel

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McMahon, T., Moon, R., Luschinger, B. et al. Nitric oxide in the human respiratory cycle. Nat Med 8, 711–717 (2002). https://doi.org/10.1038/nm718

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