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Vol. 24, No. 7 Oct. 23, 1998

COLUMBIA'S 59TH NOBEL: Discovery of Nitric Oxide's Role Brings Nobel for Alumnus Louis. J. Ignarro

By Bob Nelson

Louis J. Ignarro, like any inquisitive scientist, had a mystery to investigate: why does nitroglycerin, a volatile explosive, work in treating hypertension and angina-the chest pains that occur when the heart is deprived of oxygen?

Ignarro, a 1962 graduate of the former Columbia College of Pharmacy, found that nitroglycerin is converted to nitric oxide in the smooth muscles that surround blood vessels and control their flow. Nitric oxide, a common pollutant found, for example, in automobile exhaust, apparently causes the smooth muscles to relax, allowing blood vessels to widen and blood pressure to decrease. That could explain why nitroglycerin helps heart patients.

For the discovery of the wide-ranging role that nitric oxide plays within the body, Ignarro and two other pharmacologists were named Oct. 12 to receive the 1998 Nobel Prize in Physiology or Medicine.

The award, along with a physics Nobel shared by Horst Stormer, professor of physics and applied physics at Columbia, brings the number of faculty, former faculty and alumni recognized with a Nobel to 59.

The three pharmacologists, working separately, showed that nitric oxide is a vital messenger molecule in the body and the only gas yet discovered to play that role. Ignarro, who is professor of molecular and medical pharmacology at the UCLA School of Medicine, will share the $938,000 award with Robert F. Furchgott of the State University of New York Health Science Center at Brooklyn, known as SUNY Downstate, and Ferid Murad of the University of Texas Medical School in Houston. The prize will be presented Dec. 10 in Stockholm.

Occurring throughout the body, nitric oxide performs a number of regulatory tasks, including battling infections, preventing formation of blood clots, acting as a signal molecule in the nervous system and controlling blood flow to a number of organs. Ignarro discovered the principle that allowed pharmaceutical researchers to create the anti-impotency drug Viagra.

That nitric oxide could be produced by a cell in the human body, penetrate cellular membranes and regulate the function of other cells came as a shock to the scientific world when it was first reported it 1986. The finding "represents an entirely new principle for signaling in biological systems," said the Nobel committee of the Karolinska Institute in Stockholm, which gives the award. The discovery has spawned an entire medical subfield represented by a new scientific journal, Nitric Oxide, which Ignarro founded and currently edits.

"It's been fun to see the field explode like this," Ignarro told a UCLA publication. In an ironic footnote to its citation, the Nobel committee pointed out that Alfred Nobel, who founded the prize, was the inventor of dynamite, which uses nitroglycerin. When Nobel developed chest pain from heart disease, he refused to take the nitroglycerin his doctor prescribed because he knew it caused headaches. Nobel died in 1896. "It would take 100 years until it was clarified that nitroglycerin acts by releasing NO gas," the committee wrote.

The committee cited Furchgott's 1980 experiment that showed a drug, acetylcholine, could widen blood vessels, but only if the layer of cells lining the vessel was intact. From this, Furchgott concluded that those cells, the endothelium, must product some signal that relaxed the smooth muscle cells in blood vessels.

Furchgott called this signal "endothelium-derived relaxing signal," or EDRF. But it was Ignarro who concluded, after a brilliant series of analyses in 1986, that nitric oxide was the elusive EDRF. Murad was cited for showing that the gas could regulate important cellular functions.