Hypoxic vasodilation by red blood cells: Evidence for an s-nitrosothiol-based signal

Diana L. Diesen, Douglas T. Hess, Jonathan S. Stamler

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Abstract

Red blood cells (RBCs) have been ascribed an essential role in matching blood flow to local metabolic demand during hypoxic vasodilation. The vasodilatory function of RBCs evidently relies on the allosteric properties of hemoglobin (Hb), which couple the conformation of Hb to tissue oxygen tension (Po2) and thereby provide a basis for the graded vasodilatory activity that is inversely proportional to Hb oxygen saturation. Although a large body of evidence indicates that the Po2-coupled allosteric transition from R (oxy)-state to T (deoxy)-state subserves the release from Hb of vasodilatory nitric oxide (NO) bioactivity, it has not yet been determined whether the NO-based signal is a necessary and sufficient source of RBC-mediated vasoactivity and it has been suggested that ATP or nitrite may also contribute. We demonstrate here by bioassay that untreated human RBCs rapidly and substantially relax thoracic aorta from both rabbit and mouse at low Po2 (≈1% O2) but not at high Po2 (≈21% O2). RBC-mediated vasorelaxation is inhibited by prior depletion of S-nitroso-Hb, potentiated by low-molecular-weight thiols, and dependent on cGMP. Furthermore, these relaxations are largely endothelium-independent and unaffected by NO synthase inhibition or nitrite. Robust relaxations by RBCs are also elicited in the absence of endothelial, neuronal or inducible NO synthase. Finally, contractions that appear following resolution of RBC-mediated relaxations are dependent on NO derived from RBCs as well as the endothelium. Our results suggest that an S-nitrosothiol-based signal originating from RBCs mediates hypoxic vasodilation by RBCs, and that vasorelaxation by RBCs dominates NO-based vasoconstriction under hypoxic conditions.

Original languageEnglish (US)
Pages (from-to)545-553
Number of pages9
JournalCirculation Research
Volume103
Issue number5
DOIs
Publication statusPublished - Aug 29 2008

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Keywords

  • Hemoglobin
  • Hypoxic vasodilation
  • Nitric oxide
  • Red blood cell

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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