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Nitric Oxide Key to Respiration

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Duke Health News 919-660-1306

DURHAM, N.C. -- Investigators from Duke University Medical
Center and the Howard Hughes Medical Institute (HHMI) have
demonstrated that red blood cells play a crucial and active
role in responding to the oxygen needs of tissues and that
furthermore, the chemical nitric oxide is key to this process,
leading the researchers to conclude that the chemical should be
considered as the third major blood gas -- along with oxygen
and carbon dioxide -- to be monitored in patients.

In their studies, the scientists tested the responses of the
circulatory systems of human subject in specialized chambers
where the scientists could control atmospheric pressure and gas
concentrations. The scientists raised or lowered oxygen levels
in the chambers and analyzed the response of the subjects'
blood cells. From such analyses, the scientists demonstrated
that nitric oxide in the blood cells is an active regulatory
molecule that causes the oxygen-carrying hemoglobin molecules
in red blood cells to undergo subtle shape changes in response
to varying concentrations of oxygen in tissues. Nitric oxide
works by relaxing or contracting blood vessels.

The researchers are publishing their findings in the July
2002 edition of Nature Medicine, which posted the study as an

advance online publication
today (June 3, 2002.

The scientists said that their discoveries help explain why
some treatments -- such as blood transfusions or drugs like
erythropoietin that boost red blood cell production -- either
don't work, or even lead to death. The findings could also
explain why there is a direct relationship between high red
blood cell counts and stroke, heart attack and hypertension,
said the scientists. Additionally, the findings could offer new
avenues of research in treating a whole range of those
disorders, as well as sickle cell disease and pulmonary
hypertension.

"One of the prevailing precepts of biology is that every
cell regulates its major function," said Jonathan Stamler,
M.D., HHMI investigator at Duke and senior member of the
research team. "For red blood cells, their function is the
delivery of oxygen to tissues, so the fact that it couldn't
regulate blood flow, as was previously thought, seemed to me to
make no sense. Now, we see the crucial role nitric oxide plays
in the respiratory cycle, which is the basis of life for all
mammals."

According to the paper's first author, Duke University
Medical Center pulmonologist Timothy McMahon, M.D., "The
ability to monitor and manipulate nitric oxide along with
oxygen and carbon dioxide should prove to be very useful in the
diagnosis and treatment of many human diseases. Specifically,
the knowledge that nitric oxide is intimately involved with red
blood cells in blood flow regulation opens up huge new fields
of research.

"As we develop further understanding of nitric oxide's role
in oxygen delivery, these insights will be integrated into
routine care of our patients," McMahon added.

The research effort was supported by the National Institutes
of Health and the National Science Foundation.

The results of the teams' experiments provide insight into
two long-running paradoxes faced by physicians: first, found
the scientists, the oxygen content of blood often doesn't
always correlate with the actual delivery of oxygen to the
tissues. And secondly, the results provide a mechanism for
well-known ability of blood vessels to respond to oxygen
tension. The key finding, they said, is that individual red
blood cells can respond quickly and locally to the oxygen needs
of cells in the body's tiny capillaries, or
microvasculature.

Hemoglobin, the molecule to which oxygen binds in red blood
cells, occurs in two shapes, known as the R and the T shapes,
that differ in their affinity for the three gases. Hemoglobin
changes shapes in response to local oxygen concentrations, with
nitric oxide playing the key role in either relaxing the
capillaries to allow a more ready exchange of gas, or
constricting the capillaries, found the scientists.

"Instead of the total oxygen saturation of blood in the
circulatory system, the key determinant of the efficiency of
oxygen delivery is the flow of blood in the microvasculature,"
Stamler said.

"Our data raises the possibility that the level of nitric
oxide in the blood may provide physicians a keen insight into
the state of a patient's microcirculation," Stamler continued.
"The ability to monitor and manipulate levels of nitric oxide
in red blood cells should be useful in assessing blood gases,
in the diagnosing and treating disease of the heart, lung and
blood, and in the rational development of therapeutics."

The findings help explain why many patients, especially
those with heart disease, may not always benefit from blood
transfusions and why some may actually be hurt. Recent data has
even suggested increased deaths in a subset of these patients,
Stamler said. Typically, heart patients with a hematocrit
(concentration of red blood cells in a sample of blood) of less
than 30 are automatically given transfusions in hopes of
improving the ability of oxygen-starved tissues to be
nourished, even though there is no generally accepted threshold
for transfusion therapy, Stamler said.

"There is more to the story than just improving the amount
of oxygen in the system -- if the mechanisms moderated by
nitric oxide are not functioning properly, the oxygen can never
leave the red blood cells and enter the tissue needing oxygen,"
Stamler said.

The Duke team has initiated small clinical trials to test
their findings, particularly in disease states characterized by
abnormal functioning of endothelial cells lining blood
vessels.

"We will be trying to correlate the pathophysiology of these
disorders with the activity of the red blood cells to get a
better idea of how nitric oxide participates in these
diseases," McMahon said. "We hope this will allow us to develop
better ways of diagnosing and treating these diseases."

Currently, the technology to measure the levels of nitric
oxide in the blood is complicated and time-consuming, the
researchers say, and is not yet ready for clinical application.
However, the researchers believe that technology used to
measure nitric oxide in red blood cells can easily be adapted
for future use in clinical settings and research.

Most of the sophisticated measurements made by the team took
place in Duke's specialized hyperbaric chambers, in which
researchers can change the pressures and concentrations of
atmospheric gases and measure their effects on blood gas
exchange.

"The hyperbaric chamber allowed us to manipulate oxygen
levels of human volunteers," McMahon said. "By studying blood
samples during hypoxia (too little oxygen) through hyperoxia
(too much oxygen), we were able to measure the shape changes in
hemoglobin and correlate them with the oxygen uptake and
delivery by the red blood cells."

Duke pulmonary specialist Claude Piantadosi, M.D., directed
the hyperbaric chamber studies.

Other members of the team were, from Duke, Richard Moon,
M.D., Martha Carraway, M.D., Anne Stone, Bryant Stolp, M.D.,
Andrew Gow, Ph.D., John Pawloski, M.D., and Paula Watke. Ben
Luschinger, Ph.D., and David Singel, Ph.D., Montana State
University, were also members of the team.

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