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(Circulation Research. 2008;103:545.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Hypoxic Vasodilation by Red Blood Cells

Evidence for an S-Nitrosothiol–Based Signal

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

From the Departments of Surgery (D.L.D.), Medicine (D.T.H., J.S.S.), and Biochemistry (J.S.S.), Duke University Medical Center, Durham, NC 27710.

Correspondence to Jonathan S. Stamler, MD, Box 2612, Duke University Medical Center, Durham, NC 27710. E-mail staml001{at}mc.duke.edu

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.

Key Words: red blood cell • hemoglobin • nitric oxide • hypoxic vasodilation

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