October 17, 2003

Nobel laureate Ignarro delivers entertaining Sutherland lecture

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Louis J. Ignarro, Ph.D./Dana Johnson

Nobel laureate Ignarro delivers entertaining Sutherland lecture

Louis J. Ignarro, Ph.D., could have easily opened his own drag-racing shop on Long Island rather than pursuing chemistry studies at Columbia University, he told an overflowing crowd last week at the Earl W. Sutherland lecture. He thought long and hard before choosing the route that would ultimately take him to Stockholm to receive the 1998 Nobel Prize in Physiology or Medicine.

In a lecture frequently interrupted by bursts of laughter, Ignarro recounted the experiments leading to the discovery that nitric oxide, a simple gas, acts as a signaling molecule and shared his photographs of the Nobel award festivities.

“I knew nothing about the Nobel Prize until I went to Stockholm to receive it. People just don’t talk much about it,” Ignarro said. “I like to talk about it; it gives me a chance to see the slides over and over again.”

Ignarro, professor of Molecular and Medical Pharmacology at the University of California, Los Angeles, was the fourth Nobel laureate in the Sutherland lecture series. The department of Molecular Physiology & Biophysics established the series in 1997 to honor Dr. Earl W. Sutherland, professor of Physiology at Vanderbilt from 1963 to 1973 and recipient of the Nobel Prize in Physiology or Medicine in 1971. The series highlights important advances in cell signaling.

Ignarro and colleagues published the first demonstration that nitric oxide relaxes vascular smooth muscle. The experiments, which involved “squirting bubbles of nitric oxide” into a tissue bath holding strips of coronary arteries, were a long shot, Ignarro said.

“People thought we were crazy; I thought we were crazy.”

The experiments worked. Nitric oxide caused the arteries to relax, and the effect was blocked by hemoglobin, which inactivates nitric oxide, and by methylene blue, which had been shown by others to be an inhibitor of guanylate cyclase. Combined with other data accumulating in the field, it became clear to Ignarro that nitric oxide was likely responsible for the vasorelaxant effects of the cardiovascular drug nitroglycerin, and that cyclic GMP, the product of guanylate cyclase, was probably the ultimate mediator of relaxation.

The investigators wondered why there are receptors for nitric oxide, an air pollutant and metabolite of nitroglycerin, Ignarro said.

“Did God know we would eventually take nitroglycerin to treat angina and therefore equip us with these receptors? My mother would answer yes to that question, but we thought perhaps we also have endogenous compounds like nitric oxide,” he said.

The hunt for nitric oxide-like compounds in the body came together with other studies in the laboratory that were focused on a mysterious substance called EDRF, endothelium-derived relaxing factor. Even though the data were right in front of them, Ignarro said, he and his colleagues failed to realize for several years that EDRF is nitric oxide (NO).

“People in my laboratory would always ask me, ‘do you know what EDRF is,’ and I would always respond by saying ‘NO’. Finally it all came together, and we realized that EDRF is in fact, NO,” Ignarro said.

“Once we published our findings, it seemed like everybody in the cardiovascular field jumped into this area, because here we had a new player on the block.

“I think that nitric oxide is probably one of the most important molecules in the body generated by a normal, healthy endothelium that protects us against the early stages of atherogenesis and atherosclerosis, and that’s what we’re studying at this time,” he said.

Within a few years of their initial studies, Ignarro said, many other effects of nitric oxide were discovered, and it became a very widespread signaling molecule. Nitric oxide participates in regulating blood pressure, signaling in the nervous system and fighting infections.

Ignarro’s team demonstrated that nitric oxide is the neurotransmitter released by nerves that innervate the penis and signal relaxation of the smooth muscle, leading to erection. The work laid the foundation for the development of the drug Viagra to treat impotence. Following this discovery, the journal Science named nitric oxide the molecule of the year in 1992.

“Interesting that they waited until this work to declare it molecule of the year,” Ignarro quipped.