Transport and Peripheral Bioactivities of Nitrogen Oxides Carried by Red Blood Cell Hemoglobin: Role in Oxygen Delivery

Abstract

The biology of NO (nitric oxide) is poorly explained by the activity of the free radical NO ((.)NO) itself. Although (.)NO acts in an autocrine and paracrine manner, it is also in chemical equilibrium with other NO species that constitute stable stores of NO bioactivity. Among these species, S-nitrosylated hemoglobin (S-nitrosohemoglobin; SNO-Hb) is an evolved transducer of NO bioactivity that acts in a responsive and exquisitely regulated manner to control cardiopulmonary and vascular homeostasis. In SNO-Hb, O(2) sensing is dynamically coupled to formation and release of vasodilating SNOs, endowing the red blood cell (RBC) with the capacity to regulate its own principal function, O(2) delivery, via regulation of blood flow. Analogous, physiological actions of RBC SNO-Hb also contribute to central nervous responses to blood hypoxia, the uptake of O(2) from the lung to blood, and baroreceptor-mediated control of the systemic flow of blood. Dysregulation of the formation, export, or actions of RBC-derived SNOs has been implicated in human diseases including sepsis, sickle cell anemia, pulmonary arterial hypertension, and diabetes mellitus. Delivery of SNOs by the RBC can be harnessed for therapeutic gain, and early results support the logic of this approach in the treatment of diseases as varied as cancer and neonatal pulmonary hypertension.

Evolution of adverse changes in stored RBCs

“…In patients with pulmonary arterial hypertension and hypoxemia, RBC SNO-Hb formation was deficient, and both the depressed RBC bioactivity and pulmonary vascular resistance were improved when RBC SNO-Hb was replenished in vivo (30). Thus, the in vitro RBC bioassay model recapitulates in vivo O 2 -sensitive function of the RBC in blood flow regulation in humans in health (21,37), disease (44), and in corrective therapy.…”

The dual roles of red blood cells in tissue oxygen delivery: oxygen carriers and regulators of local blood flow

“…above) seems to allow the NO group transfer from SNO-Hb to a reactive cysteine residue in band 3 (Pawloski et al, 2001). The NO species transferred is formally analogous to NO + and is protected from heme scavenging and inactivation (Sonveaux et al, 2007). Further transnitrosation processes may subsequently be involved in transmitting the NO signal from the RBC to the vessel wall.…”

Tissue Hypoxia: Implications for the Respiratory Clinician

“…Governing this distribution of oxygen delivery are both global factors (eg, adrenergic tone, systemic inflammatory mediators) and local factors, including local hypoxia, local cytokine production, local nitric oxide, vascular factors, and Hb properties. [8][9][10][11] …”