Regulation of nitric oxide consumption by hypoxic red blood cells

doi:10.1073/pnas.2133409100

Regulation of nitric oxide consumption by hypoxic red blood cells

Departments of ^*Chemical Engineering, ^‡Medical and Molecular Pharmacology, and ^§Obstetrics and Gynecology, University of California, Los Angeles, CA 90095; and ^†Department of Medical Physiology, Texas A&M University System Health Science Center, College Station, TX 77843

Edited by Louis J. Ignarro, University of California School of Medicine, Los Angeles (received for review June 4, 2003)

Abstract

The homeostasis of nitric oxide (NO) is attained through a balance between its production and consumption. Shifts in NO bioavailability have been linked to a variety of diseases. Although the regulation of NO production has been well documented, its consumption is largely thought to be unregulated. Here, we have demonstrated that under hypoxic conditions, NO accelerates its own consumption by increasing its entry into RBCs. When RBCs were exposed to NO (1:400 NO/heme ratio) under hypoxic conditions to form HbFe(II)NO, the consumption rate of NO increased significantly. This increase in NO consumption converted the bioactivity of serotonin from a vasodilator to a vasoconstrictor in isolated coronary arterioles. We identified HbFe(II)NO as a potential mediator of accelerated NO consumption. Accelerated NO consumption by HbFe(II)NO-bearing RBCs may contribute to hypoxic pulmonary vasoconstriction and the rebound effect seen on termination of NO inhalation therapy. Furthermore, accelerated NO consumption may exacerbate ischemia-mediated vasospasm and nitrate tolerance. Finally, this phenomenon may be an evolved mechanism to stabilize the vasculature in sepsis.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: liaoj{at}ucla.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: HPV, hypoxic pulmonary vasoconstriction; EPR, electron paramagnetic resonance; 5-HT, 5-hydroxytryptamine (serotonin); Hct, hematocrit; NONOate, 2,2′-(hydroxynitrosohydrazino; Sp/NO, spermine/NONOate.