Published online before print May 5, 2005, doi: 10.1161/01.RES.0000168740.04986.a7
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Submitted on September 21, 2004
Revised on December 10, 2004
Accepted on April 26, 2005
Oxygen Regulation of Tumor Perfusion by S-Nitrosohemoglobin Reveals a Pressor Activity of Nitric Oxide
Pierre Sonveaux ;
From the Department of Radiation Oncology (P.S., A.M.K., S.A.S., R.A.R., L.I.C.-N., R.D.B., M.W.D.), Howard Hughes Medical Institute (J.S.S.) and Department of Medicine (J.R.P., T.J.M., J.S.S.), Duke University Medical Center, Durham, NC; Nicholas School of the Environment and Earth Sciences, Duke University Marine Laboratory, and University of Puerto Rico NIH COBREII Protein Research Center, Beaufort, NC and Mayaguez PR00681 (J.B.); and Tumor Microcirculation Group, Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex, UK (G.M.T).
* To whom correspondence should be addressed. E-mail: dewhirst{at}radonc.duke.edu.
In erythrocytes, S-nitrosohemoglobin (SNO-Hb) arises from S-nitrosylation of oxygenated hemoglobin (Hb). It has been shown that SNO-Hb behaves as a nitric oxide (NO) donor at low oxygen tensions. This property, in combination with oxygen transport capacity, suggests that SNO-Hb may have unique potential to reoxygenate hypoxic tissues. The present study was designed to test the idea that the allosteric properties of SNO-Hb could be manipulated to enhance oxygen delivery in a hypoxic tumor. Using Laser Doppler flowmetry, we showed that SNO-Hb infusion to animals breathing 21% O2 reduced tumor perfusion without affecting blood pressure and heart rate. Raising the pO2 (100% O2) slowed the release of NO bioactivity from SNO-Hb (ie, prolonged the plasma half-life of the SNO in Hb), preserved tumor perfusion, and raised the blood pressure. In contrast, native Hb reduced both tumor perfusion and heart rate independently of the oxygen concentration of the inhaled gas, and did not elicit hypertensive effects. Window chamber (to image tumor arteriolar reactivity in vivo) and hemodynamic measurements indicated that the preservation of tissue perfusion by micromolar concentrations of SNO-Hb is a composite effect created by reduced peripheral vascular resistance and direct inhibition of the baroreceptor reflex, leading to increased blood pressure. Overall, these results indicate that the properties of SNO-Hb are attributable to allosteric control of NO release by oxygen in central as well as peripheral issues.
Key words: nitric oxide • hemoglobin • oxygen • hemodynamics • blood flow
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