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DURHAM, N.C. -- Dr. Jonathan Stamler and his colleagues at
Duke University Medical Center shook up conventional views of
how blood delivers oxygen last year when they discovered
hemoglobin also distributes nitric oxide. Now they have put the
pieces of the oxygen-delivery puzzle back together by solving
three apparent paradoxes that have left scientists perplexed
for years.

The researchers report in the June 27 issue of the journal
Science that hemoglobin is an exquisitely tuned biosensor that
adjusts blood flow to provide exactly the right amount of
oxygen to tissues and organs. The research was funded by grants
from the National Institutes of Health and the Pew Charitable
Trust. Working with Stamler were Duke researchers Li Jia, Jerry
Eu, Timothy McMahon, Ivan Demchenko, Kim Gernert, Joseph
Bonaventura and Dr. Claude Piantadosi.

"Most doctors believe blood flow is regulated by the
expansion or contraction of the blood vessels themselves," said
Stamler, the study's lead investigator. "But we've shown that
hemoglobin in the blood itself can sense how much oxygen a
tissue needs and change blood flow to meet that need."

The findings may open up a whole new avenue of treatment for
diseases such as stroke and heart attacks, in which blocked
blood vessels are deprived of oxygen, or tissue injury after
balloon angioplasty, in which reopened arteries can get too
much oxygen too quickly, Stamler said.

In addition, the findings have implications for treatment of
sickle cell disease, lung injury and development of effective
blood substitutes, the researchers say. For example, the
current generation of blood substitutes behave as though the
tissue is getting too much oxygen, and actually decrease oxygen
delivery to tissues to compensate. A thorough understanding of
how blood senses oxygen content in tissues could help
researchers design more effective substitutes.

"We are beginning to understand that hemoglobin is designed
to deliver precisely the right amount of life-sustaining oxygen
where it's needed," said Piantadosi, a circulatory
physiologist.

Mechanically, the body regulates blood flow by changing the
width of blood vessels; rings of muscle in the vessel wall can
expand or contract to increase or decrease blood flow.
Scientists thought this process was controlled by hormones and
other factors in the lining of the blood vessel wall, said
Stamler. And they are right -- hormones such as adrenaline can
cause vessels to dilate or constrict in response to stress or
excitement, he says.

But over the past several years scientists have further
refined their understanding to show that hormones and other
factors work by using nitric oxide (NO), long known as a
noxious gas in the atmosphere. They believe that NO is released
by cells on the inside of vessel walls, where it migrates to
nearby muscle cells and relaxes them, opening the vessel.

Now Stamler and his colleagues found that hemoglobin in red
blood cells -- not the vessel wall -- actually plays the major
role in regulating blood flow. It does so by changing shape and
releasing a souped-up molecule of nitric oxide called
s-nitrosothiol (SNO), which it carries along with oxygen,
through the blood stream. Thus, hemoglobin simultaneously
releases SNO to dilate blood vessels and delivers oxygen to
nourish tissue. When oxygen levels are high, hemoglobin
scavenges excess oxygen and NO, constricting blood vessels and
reducing blood flow.

The findings also provide an explanation for a long-standing
paradox. In 1959, Dr. Max Perutz and his colleagues solved the
three-dimensional structure of hemoglobin, showing each
hemoglobin molecule carries four oxygen molecules when it
leaves the lung. In the tissue, hemoglobin changes shape,
allowing it to release the oxygen. But, on average, it returns
to the lung still carrying three oxygen molecules. Thus,
hemoglobin did not seem to be efficiently releasing oxygen.

Other studies show hemoglobin paradoxically loses most of
its oxygen before it reaches the capillaries. It has always
been a mystery why most of the oxygen is lost in flow
controlling arteries and is shunted back to the lung before
hemoglobin completes its trip through the tissues, Stamler
said. Textbooks gloss over the paradox entirely, he said, and
teach that oxygen release happens in capillaries.

"I'm a cardiologist and pulmonologist, and neither I, nor my
colleagues had any idea when we embarked on this project last
year that most oxygen is not released in the capillaries,"
Stamler said. "Our studies explain why hemoglobin releases much
of its oxygen in the small flow-controlling arteries that feed
capillary beds, not in the capillaries themselves."

The loss of oxygen is a switch that releases nitric oxide in
the arteries to dilate blood vessels and increase blood flow so
that the remaining oxygen can be delivered to tissue. Then, on
the return trip to the lungs, the oxygen that was lost in the
arteries is recaptured in the veins, giving the appearance of
inefficient oxygen delivery.

"This makes complete sense," Stamler added, "if one
appreciates that blood flow is the major determinant of oxygen
delivery."

The researchers measured blood flow and oxygen concentration
in several regions of rat brain while the rats breathed air
with varying oxygen levels. They showed that hemoglobin
releases SNO in the small arteries that regulate blood flow,
thus promoting oxygen delivery. When the animals breathed
oxygen under higher air pressure, oxygen levels increased in
tissue, and hemoglobin compensated by halting SNO release and
contracting blood vessels.

The finding also clears up another puzzle. In test tube
experiments, hemoglobin scavenges NO and constricts blood
vessels. Yet in the body, hemoglobin does not have this effect
under normal conditions.

"This tendency to constrict blood vessels seems to oppose
hemoglobin's job of delivering oxygen," Stamler said. "Our
findings explain why hemoglobin doesn't constrict blood vessels
in the body. It releases NO in the arteries to counteract the
NO it scavenges."

The findings build on previous research, published in the
March 21, 1996, issue of the British journal Nature, by Stamler
and colleagues, which showed for the first time that nitric
oxide, combined with hemoglobin, is a major regulator of gas
exchange in the circulatory system.

The research should help pharmaceutical companies design
more effective blood substitutes and NO-based therapeutics,
Stamler said. Specifically, an understanding of hemoglobin's
relationship with NO could help in designing a new generation
of oxygen and NO delivery molecules for treating the damage
caused when tissue is deprived of oxygen, as in heart disease
and stroke, and the many diseases, such as sickle cell anemia,
in which ineffective oxygen delivery or NO delivery underlies
the disease, he said.