All achievers

Louis Ignarro, Ph.D.

Nobel Prize in Medicine

Seventy percent of Americans suffer from some kind of cardiovascular disease — 95 percent of that is due to poor lifestyle.

Louis Ignarro was born in Brooklyn, New York and raised nearby in the coastal city of Long Beach, one of two sons of working class immigrant parents from Italy. His father worked as a carpenter while his mother worked at home until her sons were grown. Although both parents lacked formal education, they impressed the importance of learning on both of their sons. From an early age, Louis was fascinated by gadgets and machinery. When he was eight years old his parents gave him his first chemistry set and he immediately worked through all of the possible experiments. He built on this rudimentary knowledge with frequent trips to the library, reading everything he could about chemistry and biology. He applied his burgeoning knowledge of chemistry to making explosives and building rockets, while he augmented his knowledge of anatomy by dissecting dead animals that fell into his hands.

Dr. Louis Ignarro addresses the Academy of Achievement at the 2014 Achievement Summit in San Francisco.
Dr. Louis Ignarro addresses the Academy of Achievement at the 2014 Achievement Summit in San Francisco.

For a time, his interest in science had to compete with a passion for building cars and drag racing, but when he won admission to Columbia University, his interest in science won the day. Although his first academic interest was chemistry, his father urged him to enter Columbia’s pharmacy school so he would have the option of working as a pharmacist while pursuing his other interests. Louis Ignarro entered the pharmacy school at Columbia, while taking all of the chemistry courses he could. Following his father’s advice, he worked in pharmacies for two summers during his studies, but the daily filling of prescriptions bored him, and he was convinced that a career in research and teaching was more to his liking. An undergraduate course in pharmacology particularly intrigued him, and following his graduation from Columbia in 1962, he earned his master’s and doctoral degrees in pharmacology at the University of Minnesota.

At Minnesota, Ignarro’s studies focused on learning how the neurons of the heart produce norepinephrine, a hormone and neurotransmitter associated with concentration. He also made an intensive study of enzymology with Dr. Paul Boyer, who would receive the Nobel Prize in Chemistry in 1997. Ignarro’s doctoral research was published in the form of four separate articles in a single issue of the Journal of Pharmacology and Experimental Therapeutics, an unusual achievement for a researcher at any stage of his career.

Louis and Sharon Ignarro enjoy a visit to California's Napa Valley during the 2014 International Achievement Summit. (© Academy of Achievement)
Louis and Sharon Ignarro enjoy a visit to California’s Napa Valley during the International Achievement Summit.

Ignarro, who was now married and starting a family, undertook a postdoctoral fellowship in clinical pharmacology at the National Institutes of Health (NIH). At NIH, he conducted research into the chemistry of adrenergic receptors, the molecules of the cell that respond to the hormone adrenaline. In 1968, Ignarro joined Geigy Pharmaceuticals, heading their research program in anti-inflammatory agents. His work at Geigy led to the development of a new NSAID (non-steroidal anti-inflammatory drug), Diclofenac. While there, he also performed his first studies of cyclic guanosine monophosphate (GMP), one of the components of the RNA molecule. When Geigy merged with Ciba Pharmaceuticals in 1973, Ignarro returned to academic research as an Assistant Professor of Pharmacology at Tulane University School of Medicine in New Orleans.

At Tulane, Ignarro was teaching his medical students the use of nitroglycerin in treating heart disease when one of them raised a perplexing question. In the body, nitroglycerin is known to relax the smooth muscle tissue of the blood vessels, but how it does so was unknown. Since nitroglycerin is also an explosive, the student asked if there was any connection between these two functions. Ignarro knew there was not, but the mystery of nitro’s vasorelaxant effect continued to intrigue him and he decided to pursue the matter.

Dr. Louis Ignarro enjoys an informal afternoon reception with Dr. James D. Watson, the co-discoverer of the DNA molecule, at the Auberge du Soleil in California's Napa Valley during the 2014 International Achievement Summit.
Dr. Louis Ignarro enjoys an informal afternoon reception with Dr. James D. Watson, the co-discoverer of the DNA molecule, at the Auberge du Soleil in California’s Napa Valley during the 2014 International Achievement Summit.

A 1977 paper by Ferid Murad of the University of Texas demonstrated the effect of nitric oxide and various nitro compounds, including nitroglycerine, on the levels of cyclic GMP in vascular tissue. Ignarro was already familiar with a connection between GMP levels and vascular dilation, and he began to consider the possibility that nitric oxide, mediated by GMP, was the component of nitroglycerin that dilates blood vessels.

In 1979, Ignarro published his first findings, demonstrating that nitric oxide clearly produces the vasorelaxant effect. His next task was to unravel the mechanism by which the muscles convert compounds such as nitroglycerin into pure nitric oxide. Ignarro published the results of this study in the Journal of Pharmacology and Experimental Therapeutics in 1981. A question that remained was why the blood vessels of human beings and other mammals should be so receptive to a substance, nitric oxide, which we know in nature as a toxic gas, an air pollutant, and one component of a powerful explosive. Was it possible that the cells of the body themselves produce nitric oxide in small quantities? The introduction of nitric oxide from outside the body might be elevating the natural response of blood vessels to an agent already present in the body. Robert Furchgott of the State University of New York had independently discovered the presence of a mysterious EDRF (endothelium-derived relaxing factor) that naturally occurs in the blood vessels. In 1984 Ignarro demonstrated that this EDRF was, in fact, nitric oxide.

Nobel Prize winners Dr. Saul Perlmutter and Dr. Louis Ignarro enjoy a conversation at the Achievement Summit.
Nobel Prize winners Dr. Saul Perlmutter and Dr. Louis Ignarro enjoy a conversation at the Achievement Summit.

The following year Dr. Ignarro, recently divorced, moved from Tulane to the University of California, Los Angeles (UCLA) School of Medicine. He continued his work on nitric oxide at UCLA, demonstrating that nitric oxide is the neurotransmitter responsible for the erectile response in mammals, including human beings. It was soon discovered that impotence (erectile dysfunction) is caused by an impaired GMP pathway for processing nitric oxide. Ignarro’s research led to the creation of the first effective drugs for erectile dysfunction — Viagra, Levitra and Cialis — as well as nutritional supplements that improve cardiovascular health and athletic performance. Ignarro himself is an avid cyclist and runner, who has completed more than a dozen marathons. His books on health and nutrition include No More Heart Disease and Health is Wealth. In 1997 Ignarro married Sharon Williams, an M.D. anesthesiologist he met while working at UCLA.

Dr. Steven A. Rosenberg of the National Cancer Institute presents Dr. Louis Ignarro with the Golden Plate Award of the Academy of Achievement at the 2014 International Achievement Summit in San Francisco, California.
Dr. Steven A. Rosenberg of the National Cancer Institute presents Dr. Louis Ignarro with the Golden Plate Award of the Academy of Achievement at the 2014 International Achievement Summit in San Francisco, California.

In 1998, Dr. Ignarro’s achievement was honored with the Nobel Prize in Medicine, an honor he shared with his fellow researchers, Ferid Murad and Robert Furchgott. Today, Dr. Ignarro is Professor Emeritus at UCLA Medical School, where for many years he held an endowed chair in pharmacology. Since retiring from UCLA, he has served as a consultant and advisory board member for numerous health and nutrition companies including Herbalife. Louis Ignarro and Sharon Ignarro have homes near UCLA and in nearby Malibu, California. Dr. Ignarro has one daughter by his previous marriage.

Inducted Badge
Inducted in 2014

Although he is renowned in medical circles as “the father of Viagra,” the discoveries of Louis Ignarro have profound implications for all circulatory conditions, not least heart disease, the leading cause of death around the world.

Nitroglycerin has been used in treating heart disease since the 1870s, but for over a century no one knew what property of the chemical causes constricted blood vessels to dilate. Ignarro determined that nitroglycerin, and other nitrates and nitrites, are metabolized as nitric oxide, relaxing the smooth muscle surface of the blood vessels, and inhibiting the growth of blood platelets. He was the first to observe that nitric oxide is a neurotransmitter mediating erectile function, a discovery that led to the creation of Viagra and other drugs for erectile dysfunction, as well as nutritional supplements that improve cardiovascular health and athletic performance.

Louis Ignarro embarked on his journey of discovery from humble beginnings. Born in Brooklyn, New York to working-class immigrant parents, he received the Nobel Prize in Medicine in 1998. As he told a Congressional committee, “only in America could the son of an uneducated carpenter win the Nobel Prize in Medicine.”

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You were at Tulane University when you began to seriously study nitric oxide. Can you talk about how that came about?

Louis Ignarro: Others were doing work on nitric oxide — had just started to do work on nitric oxide — which is a very unstable poisonous gas in the earth’s atmosphere. So I was wondering, “Why are these people…” there were only two of them — “Why are they studying nitric oxide?” So I was following what they were doing, talking to them. And then I realize, “Oh, you know, maybe certain drugs that we take to treat disease may work through a nitric oxide mechanism.” And I was thinking of that. And then one day, while teaching the pharmacology of blood pressure-lowering drugs in class at Tulane Medical School, one of the medical students after my lecture asked me — I had just talked about nitroglycerine. Nitroglycerine is a drug. It comes as a little tablet which you put under your tongue if you feel that you’re having a heart attack, and it can actually save your life by preventing that heart attack, relieving chest pain. So this medical student asked me what was the mechanism of action of nitroglycerine. I had talked about what it does, but I did not talk about how it worked.

So the student asked me — she said, “You didn’t explain to us the mechanism of action of nitroglycerine. I understand nitroglycerine is also an explosive.” And she said, “Well, certainly it couldn’t work by causing explosions.” I remember the class laughing. And I said, “No, of course not.” I said, “But you know, I’m not certain about the mechanism of action. It may not be known. That’s why I haven’t told you why. Let me look it up.” So, I spent the rest of the afternoon reading up on nitroglycerine. The mechanism was completely unknown. Being a chemist, I looked at the chemistry of nitroglycerine. It’s nitro. So it has actually three nitro groups — NO2 groups they’re called — on this little molecule, and I’m thinking, “Hmm, I just wonder whether one or more of those NO2 groups in the body maybe is converted to NO, which is nitric oxide.” So a couple of days later, we began to do those experiments in a laboratory. And after about two months of work, sure enough we found that our arteries metabolize or convert nitroglycerine to nitric oxide. So then we purchased some authentic nitric oxide gas, and we tested that pharmacologically, and we found that it produces all the identical effects of nitroglycerine. So we concluded that nitric oxide is the active species in the drug nitroglycerine. We published that, and then many people repeated that work and now we know how nitroglycerine works.

How did you relate that discovery to the cardiovascular system, which led to your Nobel Prize?

Louis Ignarro: Once we ordered the authentic nitric oxide and we found that it was a vasodilator — it dilated the arteries just like nitroglycerine — we then tested this nitric oxide further. And we found that it could lower the blood pressure. We found that it could prevent stroke. It could actually prevent — we have certain cells or elements in the blood called platelets, and when they aggregate or clump together they could block arterial blood flow. And if that occurs in the brain, that’s a stroke. If it occurs in the heart, it’s a heart attack. So we found that nitric oxide was very, very powerful in preventing that. Okay. Then we synthesized some chemical molecules that make it a lot easier to test nitric oxide. Nitric oxide is a gas. Very hard to add gases to your testing systems. So we had a solid material that had the nitric oxide built into it. So when you put it in solution, it releases the NO or the nitric oxide. So we could do a lot of experiments with that. So we had published many papers showing how powerful nitric oxide was to prevent all the cardiovascular diseases that we knew about: heart attack, stroke, it drops the blood pressure. We also found that it could prevent or slow down the development of atherosclerosis or cholesterol plaques in arteries.

So then, if I remember, it was a Friday afternoon, 1985. We were thinking and discussing in the laboratory. I brought up to my group, I said, “Why do our bodies react so sensitively to an outside chemical like nitric oxide?” I mean, we don’t have nitric oxide in the body, we didn’t think. So why do our bodies have all this ability to react to this noxious outside chemical that could protect us against cardiovascular disease? That was the first time I thought, “Well, maybe our arteries — our bodies — produce nitric oxide.” It’s just that we don’t know that yet. Nobody’s tested that. So we set aside a series of experiments, very difficult experiments. It took a year, and we finally showed that our arteries can produce nitric oxide. So then it became clear that yes, we have nitric oxide, and that we make it in order to protect ourselves against cardiovascular disease. That is the principal reason I was awarded the Nobel Prize. So it started with nitroglycerine and then wound up with that discovery.

How did your discoveries about nitric oxide lead to such drugs as Viagra?

Louis Ignarro: That’s a fascinating story. I find that more young kids have heard of Viagra than have heard of Mickey Mouse! Anyway, after we had made the discovery that our arteries and many other parts of the body produce nitric oxide for the purpose of preventing cardiovascular problems, we had been studying a variety of other effects of nitric oxide.

I remember, one day in 1990, a urologist friend of mine at UCLA asked me if I knew what the neurotransmitter was that stimulated erectile function. Okay. So every nerve releases a chemical, and that chemical stimulates something on the other side to produce an effect, a response. So there are nerves that go to the erectile tissue, both men and women. But the neurotransmitter, the chemical that incites that action, was not known. That’s why in 1990, for example, there were no drugs available whatsoever to treat erectile dysfunction. So when he asked me what the neurotransmitter was, I said, “You know what? I don’t know, but you’re the urologist. You should know. You tell me what it is.” And he said it’s not known. He asked me if it was possible to be nitric oxide. And I remember telling him, “Nah, it’s impossible. Nitric oxide is a gas. There’s no evidence that any neurotransmitter could ever be a gas,” and I let it go. Then I caught myself a few days later thinking inside the box. And I thought it was important to think outside the box. That’s what I had done before to show that nitric oxide was made by our arteries. So I thought about what he said, and I went and I read all about neurotransmitters, and believe me, there was no evidence that a gas could ever be a neurotransmitter. So despite all that, I said, “We’re going to do the experiments anyway.” So I went back to my urologist friend, who gave us samples of erectile tissue from humans and animals, and we did the experiments. And within a couple of months we found that the neurotransmitter was nitric oxide, and we published that. I remember the study on humans was published in 1992, and that stimulated a lot of attention. I was conducting interviews for two days from every newspaper and magazine and TV station you can think of, because it was obvious that was an important finding, because the major question was “Okay, now that we know what the neurotransmitter is, could this lead to orally useful drugs to treat erectile dysfunction?” And at the time, my answer was, “No, probably not, but hopefully it will.”

Six years after that — that was in 1992 — six years after that, in 1998, Pfizer announced that the FDA had approved the marketing of sildenafil. It was called Viagra. Viagra is the trade name. The reason I bring that up is because Viagra works by increasing the action of nitric oxide. Years before we published our paper in 1992, Pfizer had developed this compound called sildenafil to elevate nitric oxide in the arteries to lower the blood pressure. So when they tested that clinically, they found that it did lower the blood pressure, but you had to push the dose pretty high to lower the blood pressure. What they found is that when they elevated the dose, it caused erections in the male volunteers. So when the clinics reported that back to Pfizer, Pfizer didn’t know what to do with that. They immediately stopped further testing and put the drug back on the shelf and said, “We can’t deal with this.” So they stopped developing that drug. Then when we published our finding in 1992 about nitric oxide being the neurotransmitter, they realized, “Oh my goodness. Our sildenafil works by increasing nitric oxide in the erectile tissue!” So they went back to the FDA. They filed a new drug application. They then tested the drug for the treatment of ED (erectile dysfunction). The FDA fast-tracked that development in 1996. Viagra was developed. So that’s why I’m often referred to as the father of Viagra, which I can tell you was always humorous to everyone except my mother. She did not like that at all.

Was there a day in the lab when you realized suddenly that nitric oxide is a neurotransmitter? Or was it a gradual realization?

Louis Ignarro: I had made the decision to test a hypothesis that nitric oxide was a neurotransmitter. That’s where it all starts, even before doing the experiments. Then you have to do the experiments. Then you test nitric oxide. You add authentic nitric oxide. It produces a vasodilation of the erectile tissue. That’s what the erectile response is. So we’re happy with that. And there were other experiments we were happy with, but the key thing, and the most difficult thing to show, is that when the nerves attached to that erectile tissue are stimulated electronically with electrodes, will the nerve release nitric oxide? We had to set up experiments to capture the neurotransmitter to stabilize it and identify it. That first experiment that we attempted to do, that worked positively, and we could see in the experiment we were doing that it was nitric oxide. So at that point I was ecstatic and I knew we had something. The laboratory celebrated. And then it took an hour to plan the next three years of experiments. That’s how simple it was. I mean, once you knew it was a neurotransmitter, you knew. You know, we’re scientists. We knew exactly what we had to do. So one of my graduate students and two of my technicians then proceeded to do experiments. The experiments took two to three years, but what I’m trying to say is it became obvious what we had to do to prove the whole story, and it was great.