Just Say NO
Research into the properties of nitric oxide
may lead to treatments for hypertension, stroke, male impotence and more
 Chosen as Science
magazine’s “Molecule of the Year” in 1992, nitric oxide has come a long
way since 1980, when it was the focus of only 12 academic papers. It is
a simple hormone like chemical; yet it is one of the most powerful known
biological substances. Nitric oxide (NO) controls a seemingly limitless
range of essential bodily functions, including blood pressure and various
activities of the brain, lungs, liver, kidneys, stomach, gut and genitals,
among other organs. In 1996, research on NO yielded more than 5,000 papers,
according to Louis J. Ignarro, a professor of pharmacology at the
UCLA School of Medicine who has spent the past 19 years studying the chemical.
Synthesized from the amino acid L arginine, nitric oxide is found in
cells from head to foot. The brain uses it to send messages and store memories.
The immune system uses it to fight viral, bacterial and parasitic infections,
as well as tumors. NO assists the action of almost every orifice, from
swallowing to defecation. But it can also be destructive. Excessive amounts
of nitric oxide are linked to massive cell destruction in cancer and other
diseases, and to the progression of neurological diseases such as multiple
sclerosis.
The surge in interest in the simple molecule, composed of one atom of
nitrogen (N) and one of oxygen (O), began after researchers discovered
that, rather than being a mere nuisance compound contributing to air pollution
and acid rain, NO is also the regulator of the tone of vascular tissue.
“It’s been fun to see the field explode like this,” says Ignarro who, in
addition to conducting his own research supported by grants from the National
Institutes of Health, is responsible for designing the pharmacology curriculum
for second year medical students. He has also received the American Medical
Student Association’s Golden Apple award for teaching for the past 10 consecutive
years and a UCLA School of Medicine award for Excellence in Education.
Ignarro began his nitric oxide work in 1978. He wondered why, since
the Victorian era, nitroglycerin had proven so effective in the treatment
of hypertension and angina -- the chest pains that occur when the heart
muscle is deprived of oxygen. His subsequent research showed that nitroglycerin
is converted to nitric oxide inside vascular tissue. His experiments found
further that NO causes vascular smooth muscle relaxation and inhibition
of blood clotting.
“The discovery of the mechanism of action in nitroglycerin also led
to the discovery that the body produces nitric oxide, which lowers blood
pressure and prevents stroke,” says Ignarro. “It’s only been a decade since
we learned our cells produce NO.
“The drugs now used to treat high blood pressure can have toxic side
effects, such as dizziness, headaches and swelling,” he continues. “We
want to find out the precise cause of hypertension and strokes so we can
use limited treatment to remedy the problem.”
Presently, nitric oxide can’t be delivered pharmaceutically to NO deficient
areas of the body. Ignarro, along with collaborator Jacob Rajfer, a UCLA
professor of urology, has also identified NO deficiency as the physiological
cause of 70 to 80 percent of the 10 million cases of impotence among American
men. NO initiates a series of events, including dilation of blood vessels,
that causes the penis to become engorged with blood and stay erect. Using
strips of penile tissue obtained from men receiving penile implants due
to impotence, Ignarro and Rajfer found that, when stimulated by NO, the
smooth muscle tissue that encircles blood vessels relaxed instantly, freeing
the flow of blood that enables erection. “Before 1990, the physiological
basis for erectile function was completely unknown,” says Ignarro.
Ignarro’s discovery made headlines from The New York Times to Italy’s
la Repubblica, and today drug companies are looking for ways to put NO
“donors” on patches that can be attached directly to the penis, eliminating
the use of scarring and stinging injections of relaxants into the organ.
Nitric acid is produced in tiny amounts, for fractions of a second,
throughout the body. “As soon as it’s produced,” Ignarro explains, “NO
elicits its effects and then it’s gone, which is the safest way for the
body to use a chemical.” Ignarro’s research into the transient molecule
has garnered him numerous awards, among them the 1994 Roussel Uclaf prize
for “original and significant research in the field of cell communication
and signaling,” and the 1995 CIBA award for Hypertension Research.
“I’m hoping that we can utilize our discovery to develop novel therapeutic
drugs to treat hypertension, stroke and impotence,” says Ignarro. “That
would probably be enough for one career.”
— Rachel Marcus
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