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