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Extrapulmonary Effects of Inhaled Nitric Oxide

Role of Reversible S-Nitrosylation of Erythrocytic Hemoglobin

Durham Veterans Affairs and Duke University Medical Centers, Durham, North Carolina; and University of Virginia Children's Hospital, Charlottesville, Virginia

Correspondence and requests for reprints should be addressed to Timothy J. McMahon, M.D., Ph.D., Room 0048, CARL Building, Duke University Medical Center, Durham, NC 27710. E-mail: mcmah003{at}duke.edu

ABSTRACT

Early applications of inhaled nitric oxide (iNO), typically in the treatment of diseases marked by acute pulmonary hypertension, were met by great enthusiasm regarding the purported specificity of iNO: vasodilation by iNO was specific to the lung (without a change in systemic vascular resistance), and within the lung, NO activity was said to be confined spatially and temporally by Hb within the vascular lumen. Underlying these claims were classical views of NO as a short-lived paracrine hormone that acts largely through the heme groups of soluble guanylate cyclase, and whose potential activity is terminated on encountering the hemes of red blood cell (RBC) Hb. These classical views are yielding to a broader paradigm, in which NO-related signaling is achieved through redox-related NO adducts that endow NO synthase products with the ability to act at a distance in space and time from NO synthase itself. Evidence supporting the biological importance of such stable NO adducts is probably strongest for S-nitrosothiols (SNOs), in which NO binds to critical cysteine residues in proteins or peptides. The circulating RBC is a major SNO reservoir, and RBC Hb releases SNO-related bioactivity peripherally on O₂ desaturation. These new paradigms describing NO transport also provide a plausible mechanistic understanding of the increasingly recognized peripheral effects of inhaled NO. An explanation for the peripheral actions of inhaled NO is discussed here, and the rationale and results of attempts to exploit the "NO delivery" function of the RBC are reviewed.

Key Words: hemoglobin • nitric oxide • red blood cell • S-nitrosohemoglobin • S-nitrosothiol

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