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SEATTLE – Duke University Medical Center researchers have
shown an association between changes in nitrate, a biochemical
marker of nitric oxide production, and physiological changes in
arteries' reaction to stress. They hope their discovery could
eventually lead to a non-invasive method of determining which
patients are at risk for developing cardiovascular disease.

Such a simple diagnostic is important, they said, because up
to half of patients who develop heart disease do not have the
typical risk factors. Furthermore, using this new approach, the
researchers demonstrated that exercise improved the marker in
patients at risk for developing cardiovascular disease.

In their pilot study, the researchers linked the systemic
production of nitric oxide, a chemical known to play a key role
in controlling the ability of arteries to constrict or relax,
with changes in the endothelial lining of arteries after being
stressed.

"This is the first study to attempt to link whole body
production of nitric oxide with regional endothelial function,"
said Jason Allen, Ph.D., who presented the results of the Duke
study today (Nov. 22, 2003) during the 10th annual scientific
sessions of the Society for Free Radical Biology and Medicine.
"Both measures were found to discriminate between healthy
participants and those with diagnosed cardiovascular
disease."

In addition to its ability to dilate arteries, nitric oxide
has other properties that protect against cardiovascular
disease, such as inhibiting blood platelet clumping, preventing
smooth muscle proliferation within the artery and inhibiting
the immune response.

On the other hand, other risk factors, such as diabetes,
high blood pressure, mental stress and smoking can reduce
nitric oxide's protective properties, said the researchers. It
is believed that these patients produce more oxygen free
radicals, impairing the ability of the body to respond
appropriately to nitric oxide. These oxygen free radicals are
highly reactive chemicals that are the potentially destructive
byproducts of the disease process.

In their experiments, the researchers divided 37
participants into three groups – healthy (12), those who had
two or more identified risk factors but without clinical
diagnosed cardiovascular disease (15), and those with known
disease (10).

To determine how arteries responded physiologically under
different circumstances, Allen used ultrasound to visualize the
brachial artery, the major artery of the arm. The ultrasound
images can then be analyzed to detect even the slightest
changes in the diameter of the artery.

The researchers made detailed measurements at three time
points – baseline, while the artery was being occluded by a
tourniquet, and after the tourniquet was released.

"When the tourniquet is loosened, the resulting increased
blood flow causes physical shear stress to the endothelium,"
Allen explained. "A healthy artery should be able to react to
the increased blood by dilating. Conversely, an unhealthy or
diseased artery will not be able to respond as well. This
response of the endothelium is regulated in part by nitric
oxide."

While the diameters of arteries in all three groups
increased, the healthy group saw the largest percentage
increase after 60 seconds, possibly indicating greater
endothelial health and nitric oxide production.

To better understand the biochemical responses in the
patients, Allen then took blood samples from all the
participants at rest, immediately following a strenuous
exercise test, and then ten minutes after exercise
completion.

"The group of healthy participants was the only one that saw
an increase in systemic nitric oxide during the recovery period
after exercise," Allen explained. "We also found that the
reactivity of the brachial artery was greater in the healthy
patients when compared to those with cardiovascular
disease."

Allen then sought to discover whether a sustained program of
exercise had any effect on nitric oxide production and
reactivity of the brachial artery. So, he followed seven of the
participants in the "at-risk" group during six months of
exercise carried out on cycle ergometers, treadmills or
elliptical trainers in a supervised setting. After six months,
the researchers performed the same series of ultrasound and
biochemical tests again.

After the exercise period, the at-risk patients had a
significant increase in nitric oxide metabolite production
during the recovery period after exercise, as well as an almost
doubling of the brachial artery reactivity, Allen said.

"First, it appears that a nitric oxide metabolite measured
in the blood after exercise may discriminate between healthy
patients and those with cardiovascular disease and is related
with a physiological response of the artery diameter," Allen
said. "Also, these biochemical and physiological markers can be
positively influenced by exercise in patients who are at risk
for cardiovascular disease."

This pilot project was funded by Duke's division of
cardiology. Joining Allen was Frederick Cobb, M.D., from Duke,
and Andrew Gow, Ph.D., Children's Hospital of Philadelphia.