Research that helped create the celebrated anti-impotence drug Viagra may
lead to a new treatment for inflammatory arthritis.
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Erections, air pollution and arthritis. Quick - how are these three things
related? If you are like most people, you probably have no clue. The common
thread? A gas called nitric oxide.

A colorless gas that forms when nitrogen burns, as in automobile exhaust,
nitric oxide has long been regarded as little more than a hazard of traffic-
clogged highways. But as researchers have found, it's much more than that.

Thanks to two decades of investigation that earned three researchers the 1998
Nobel Prize for Medicine, that limited view of the gas is giving way to a
better understanding of the human body and how it functions. Increasingly
scientists are realizing that nitric oxide formed by our bodies plays many
diverse roles - both good and bad.

When produced by cells of the immune system, for example, nitric oxide helps
fight infection and ward off cancer. When produced in excess, however, the
result can be a host of inflammatory conditions, including rheumatoid
arthritis and lupus.

The Hard Facts
While scientists have long recognized that nitric oxide is present in the
body, they didn't begin to understand its role until the late 1970s. That's
when Nobel Prize-winner Ferid Murad, MD, PhD, who was then on the faculty at
the University of Virginia, discovered that cardiac drugs such as
nitroglycerin work by causing the release of nitric oxide.

When formed in the linings of blood vessels, Dr. Murad explains, nitric oxide
increases formation of another molecule known as cyclic guanosine
monophosphate (cGMP). This cGMP relaxes smooth muscles in the blood vessels'
lining, causing the vessels to dilate. In this way the gas controls blood
pressure (because the heart doesn't have to pump as hard to force blood
through dilated vessels), for example, and allows blood to fill the erectile
tissues of the penis during sexual arousal, resulting in an erection.

The popular drug sildenafil (Viagra), in fact, promotes blood flow to the
penis by indirectly increasing levels of cGMP.

Too Much of a Good Thing
With nitric oxide, as with any other substance produced by the body, the key
is balance. "It's a matter of magnitude," says Dr. Murad. "When you're making
the right amount of nitric oxide, it's great. If you're making too much,
there are problems."

Problems caused by too much nitric oxide can range from damaging to life-
threatening, says Dr. Murad, who now conducts his nitric oxide research at
the University of Texas - Houston Medical School. A prime example is a rare
but potentially fatal condition, septic shock, which occurs when the body
produces excessive nitric oxide in response to a severe infection.

With inflammatory diseases such as arthritis, the excessive nitric oxide
released from inflammatory cells results in permanent damage to joints and
other tissues. Fortunately, drugs that increase nitric oxide levels in the
blood vessels are not associated with increased production in inflammatory
cells or any worsening of anti-inflammatory diseases.

Sex Sells

Not surprisingly, nitric oxide's role in arthritis, other inflammatory
diseases and even septic shock has taken a back seat to its role in creating
erections - at least in the popular press.

Last fall, when the Nobel Prize winners for medicine were announced, numerous
articles from newspapers and magazines connected the timing of the prize with
last year's FDA approval of Viagra. Some articles suggested or even outright
stated that the popular drug worked by increasing the body's production of
nitric oxide - which isn't exactly true.

"That's almost correct, but not quite," says Dr. Murad, whose research has
very little to do with erections. "Viagra actually works by blocking an
enzyme that destroys cGMP, allowing the cGMP to accumulate in the vessels and
cause dilation, whereas nitric oxide increases cGMP formation." In short,
both nitric oxide and Viagra increase cyclic cGMP - thus the link - but the
way in which they do it is slightly different.

And while Dr. Murad admits that knowledge from nitric oxide research was key
to development of Viagra, he believes the results of such research will save
much more than just sex lives.

In experimental studies, nitric oxide is administered to help open air
passages and aid breathing in premature babies. It is also applied to
vascular grafts to keep life-threatening blood clots from forming on them. In
the future, Murad believes, nitric oxide drugs will be used to treat
infections and cancers.

The Pay-Off for Arthritis
Conversely, drugs that block nitric oxide may be effective in treating
problems - such as septic shock or inflammatory arthritis - in which
excessive nitric oxide is a problem. At present, scientists are conducting
clinical trials of nitric oxide-blocking drugs for septic shock.

Trials of similar drugs for arthritis are likely begin in the next year or
two, predicts Gary Gilkeson, MD, associate professor of medicine at the
Medical University of South Carolina in Charleston, who has studied the role
nitric oxide plays in inflammatory disease. These drugs might be available in
as few as five or seven years.

Both Dr. Gilkeson and Dr. Murad say that new drugs derived from nitric oxide
research will be different from - and perhaps better than - current arthritis
drugs. "In addition to preventing inflammation, these nitric oxide blockers
could also prevent tissue damage, because nitric oxide is toxic to cells,"
says Dr. Gilkeson.

"What we're talking about is an entirely different mechanism for influencing
inflammation," says Dr. Murad. "Maybe [nitric oxide-blocking] drugs could be
used as supplemental therapies. People could take two or three different
drugs that work through different mechanisms and have an augmentative benefit.
On the other hand, these drugs could work alone and could be the only drugs
some people need to control their arthritis."