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Nitric Oxide: Key to Cardiovascular and Pulmonary Function and Drug Effectiveness

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Duke Health News 919-660-1306

DURHAM, N.C. -- A naturally occurring molecule in the body
appears to control whether certain medications, such as beta
adrenergic receptor agonists used in acute heart failure or in
inhalers for asthma, lose their effectiveness over time.

Nitric oxide is a molecule produced by the body that
controls many functions, including the contraction or dilation
of blood vessels.

New experiments conducted by Duke University Medical Center
and Howard Hughes Medical Institute researchers have shown that
specialized forms of nitric oxide called SNOs may be the key to
a problem that has stumped physicians for years -- why specific
drugs for such diseases as heart failure or asthma lose their
effectiveness over time.

Almost half of all drugs on the market today, as well as
many hormone and neurotransmitters, target a specific family of
cell surface receptors known as G-protein coupled receptors.
The researchers believe that the presence or absence of nitric
oxide or SNOs determines whether these receptors continue to
function properly. This action is controlled by the ability of
nitric oxide to inhibit a key regulatory system which
ordinarily shuts the receptors off after they are
stimulated

The researchers reported their latest findings on Friday,
May 4, in the journal Cell.

"This work is significant in that it demonstrates how two of
the most pervasive physiological systems -- G-protein coupled
receptors and nitric oxide -- come together to influence one
another," said Erin Whalen, Ph.D., who spent six years focusing
on the link between the two biological systems. Whalen is a
postdoctoral fellow in the laboratory of Robert Lefkowitz,
M.D., a Howard Hughes Medical Institute investigator at Duke
who first cloned these receptors in 1986. The link was cemented
through a collaboration with Matt Foster, a post-doctoral
fellow in the laboratory of Jonathan Stamler M.D.

G-protein coupled receptors reside on the cell surface where
they interact with all manner of stimuli, including circulating
factors such as adrenaline, as well such diverse sensory
signals as odorants and light. The activation of these
receptors leads to the propagation of intracellular signals.
Once activated the receptors are quickly turned-off by an
enzyme called a G protein-coupled receptor kinase. This process
is called desensitization and can limit the effectiveness of
many drugs, such as opiates for pain and adrenaline for asthma,
and is further associated with numerous diseases including
those of the cardiovascular and pulmonary systems. If activated
for a long period of time the receptors are carried into the
cell and are "turned off."

In animal, cellular and biochemical experiments, the
researchers found that a lack of nitric oxide leads to a
decrease in beta adrenergic receptor number and function. Also,
the researchers found that when SNO compounds were administered
to mice they could prevent the receptors from being "turned
off" by the drugs.

The researchers said these findings, if confirmed in humans,
open up new avenues for the development of non-desensitizing
drugs not only for heart failure and asthma but also for other
conditions such as pain and high blood pressure.

"We demonstrated that when one of the systems goes awry, so
does the other," said Stamler, whose laboratory has made many
fundamental discoveries about the role of nitric oxide in human
biology, including the discovery of SNOs' ubiquitous role in
human health and disease. "When nitric oxide function is
impaired by disease, therapeutic agents like beta-agonists in
asthma and adrenergic stimulants in heart failure will work
less well. The key now is to determine how best to manipulate
these ubiquitous receptors, together with nitric oxide for the
treatment of human diseases."

"In broad terms, the results of these experiments present a
novel role for nitric oxide in regulating the activity of
G-protein coupled receptors," Lefkowitz said. "Also, the
findings point to the possibility that deficiencies in the
activity of nitric oxide, which occurs in common disorders such
as high blood pressure, diabetes, atherosclerosis, cystic
fibrosis and neurodegenerative conditions, as well as in aging,
may interfere with the G-protein coupled receptor
signaling."

Other Duke members of the team were Akio Matsumoto, Kentaro
Ozama, Jonathan Violin, Loretta Que, Chris Nelson, Moran Benhar
and Howard Rockman. Yehia Daaka of the Medical College of
Georgia, and Janelle Keys and Walter Koch, both of Jefferson
Medical College, in Philadelphia, were also members of the
team.

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