Dr. Victoria Maizes: Hi Andy.

Dr. Andrew Weil: Hi Victoria.

Dr. Victoria Maizes: Today we have Dr. Lewis Ignarro, who is a Nobel prize winner

Dr. Andrew Weil: And the discoverer of the great importance of a very simple molecule nitric oxide. One of the bodies signaling molecules, responsible for maintaining our arteries and good health and heart and good health. He's a fascinating man.

Dr. Victoria Maizes: Yes and he sometimes called to his mother's displeasure, the father of Viagra. So I think we'll hear about that too. Okay. Let's welcome him.

Dr. Andrew Weil: Okay.

Dr. Victoria Maizes: Let's welcome him.

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Dr. Victoria Maizes: Dr. Lewis Ignarro earned his doctorate in pharmacology at the University of Minnesota and completed a post-doctoral fellowship at the National Institutes of Health. As a professor at the Tula School of Medicine. Dr. Ignarro began his basic science research into nitric oxide, which he continued as faculty at UCLA.

He discovered that nitric oxide relaxes vascular smooth muscle and is biosynthesized in mammalian cells. His discovery advanced our understanding of heart disease, and he was awarded the Nobel Prize in medicine in 1998 for the discovery that nitric oxide acts as a signaling molecule in the cardiovascular system, he has received numerous other prize and has devoted his life to improving heart health. Welcome Lou.

Luis Ignarro: Thanks very much, Victoria it’s so great to be here.

Dr. Victoria Maizes: Well, we are delighted to have you, and we're going to be talking today about nitric oxide. So can you explain for our listeners, what is it and what does it do in the body?

Luis Ignarro: Sure. I'll try to do that very, very briefly.

First of all, chemically speaking, nitric oxide is a very small molecule and it's actually a gas, just like oxygen. It, it's a gas that's found in our environment. And it's been known for years and years. In fact, Joseph Priestly discovered nitric oxide before he discovered oxygen.

That's how old nitric oxide is, but, no one knew for well over a hundred years that nitric oxide would turn out to play an important role in our bodies. We started off looking at the mechanism of action of nitroglycerin, which is a vasodilator, and we showed that it works by being metabolized to nitric oxide. And so as a pharmacologist, I started studying the pharmacology of nitric oxide and that's when we discovered it was a vasodilator and that it inhibited blood clotting by inhibiting platelet aggregation. And so I was so taken by the incredible pharmacology of this molecule that I thought that perhaps our bodies, especially our arteries, may produce such a molecule.

And so we set out to do that and we made that discovery that our arteries actually produce nitric oxide for the purpose of controlling blood pressure, because it is a vasodilator. And by that mechanism of course it improves blood flow to various organs and by serving as an inhibitor of platelet aggregation, we suspected that the nitric oxide produced by our arteries may play a protective role in preventing unwanted blood clotting.

In other words, preventing stroke and myocardial infarction.

Dr. Andrew Weil: I remember when there the first publicity about the discovery. It just seemed astounding to me because the other signaling molecules we knew about were much larger molecules, more complicated compounds, and here was such a simple molecule and a gas that, that had such a role just seemed very surprising.

Luis Ignarro: Well, it was very surprising. and I mean, nature is very simple it's incredibly simple. I mean, we make nitric that everywhere in our body Not every tissue makes it at the same time. Different signals in different organs, in different regions in different cells will trigger the local formation of nitric oxide, which will do its thing at that particular site.

So that saves a lot of energy. I find it to be incredible that one molecule can produce so many different kinds of effects, but specifically that is not all at the same time, but you're right, Andy, to,the fact that nitric oxide is such a simple molecule, right? One item of nitrogen, one item of oxygen, NO and that is a gaseous molecule…

No one ever thought a gas would play a role as a signaling molecule. That's what took so long to discover that our bodies produce nitric oxide and that NO occurs naturally because this idea came up several years before we made the discovery, but I kept saying to myself, how, how could a gas, like NO, be important?

How could it exist inside of mammalian cells? Number one, it's a gas number two. It's extremely unstable has a half-life of two or three seconds. But, you know, you just, you just move ahead. You just, you know, you never give up you don't let the chemistry slow you down. You just do the work and, and go after it.

Dr. Victoria Maizes: You mentioned that it has these effects of being a vasodilator and a platelet inhibitor, but I know you've also shown that it has anti-inflammatory effects and antioxidant effects and that it's even a neurotransmitter.

Luis Ignarro: Yes, it does so many different things once again. Why should the body waste it’s time to produce a different signaling molecule for each of these effects when it can produce just one nitric oxide and the nitric oxide produces all of the effects, but again, the no produces these effects very locally and only when called for, I mean, if, if you make nitric oxide to work as an anti-inflammatory, let's say if you have knee inflammation, you don't want it to cause penile erection, for example, you know, it has to be localized.

Dr. Andrew Weil: What can go wrong with that system are defects in nitric oxide synthesis or deployment responsible for diseases?

Luis Ignarro: Sure. That that's an incredibly good question. And a question that we, “we” meaning the scientific community interested in nitric oxide have been trying to answer for so long. What we see is that there may be localized deficiencies of nitric oxide, for example, in coronary artery disease, where the coronary arteries or arteries associated with the heart develop inflammation and this is going to cause damage to the endothelial cells within the arteries. That's going diminish the NO formation. That's gonna lead to vasoconstriction, blood clotting and so on, but that'll occur locally let's say in the heart, or it could occur in the brain, but may not occur anywhere else.

So when the nerves that go to the that innovate the erectile tissue, for example, in, in males and females, for that matter, when those nerves release nitric oxide, there's a local effect and no effect anywhere else. Males with erectile dysfunction of which there are hundreds of millions patients with a erectile dysfunction have a deficiency of nitric oxide in those nerves that innovate the erectile tissue. They may not have no deficiency anywhere else. So they may suffer from erectile dysfunction and not suffer from other diseases, and you may raise this. So I'm going try to say it first many people with diabetes of course have erectile dysfunction.

So that's a problem with NO formation generally in all the arteries. So those patients with diabetes are of course at a much higher risk for any kind of cardiovascular disease, as you folks know better than I do. And also erectile dysfunction in men and, and a lack of sexual arousal in females. So there are variety of kinds of conditions that can result from a problem with NO production.

Dr. Victoria Maizes: So how do we safely increase our natural production of nitric oxide. And when we do take actions, you know, like changing our diet. Does that have a general effect or does that have a localized effect? Because you've pointed to the localized effect of nitric oxide.

Luis Ignarro: Yes. Well, if you had not mentioned the last part of your statement and you asked me, how can we assure that we have sufficient nitric outside production I was going just say, follow your website and everybody follows your website. We won't have such a problem. And I've been doing that for a long, long time. In all the research that has gone on about asking the question, “how can we boost or maintain our nitric oxide?”, which of course is the obvious question because NO is the good guy and we know what happens when you have a deficiency…so the obvious question is, all right, how do I make more? Can I take a pill? Can I do this? Can I do that? Well, can't take a pill. We don't know of any drugs yet that boost nitric oxide production. I would've thought by now we would have something like that, but, but we don't. And it's hard to get information out of drug industry if they haven't published anything yet.

But I don't think we we're close to having a drug that would boost NO. But what we've learned from the research really, and I say this to so many people and they go, [00:10:00] yeah, yeah tell me another one. I did just don't believe it for some reason, a healthy, balanced nutrition coupled with significant or appreciable or regular physical activity is what you must do to boost nitric oxide.

I mean, it is so well known as you folks know that doing both of those adopting a healthy lifestyle is going boost your nitric oxide. It's going make you healthier and it's going to increase your longevity, but give you a healthy longevity, not just living longer, but living a healthy life as you grow older.

Dr. Andrew Weil: Do we know what is responsible for deficiency of nitrous oxide production?

Luis Ignarro: We know that certain conditions can bring it on what comes first is, is less clear. For example, if someone is not eating a healthy diet, for example, eating a diet. For example that's rich in salt or saturated fats or not eating enough fruits and vegetables, not getting enough antioxidants, which boost NO, the NO will gradually decrease.

Even if you're healthy, young people that eat a poor diet will gradually develop NO deficiency that will gradually be followed by mild cardiovascular disease, mild diabetes, which would then. And less reversed would progress get progressively worse, leading to a vicious cycle of decreased nitric oxide.

So your question is, do we know what causes the decrease in NO, we don't have [00:12:00] a clear cut answer, but as I tell people, since I'm a Nobel Laureate, I think of any answer I want, you know, and get away with it. But I think, I think it's when we abuse our bodies that we cause a decrease in NO. Poor diet sedentary lifestyle that's by definition, you can show this in laboratory animal models and humans. You can show this that leads to decreased NO. Years later, we see the resulting or consequential diseases of that. So for lack of a better answer, I say that not paying attention to your diet and not paying attention to physical activity will cause this decrease in nitric oxide.

Dr. Victoria Maizes: Well, let me ask you about another possible mechanism. We had James Nester who wrote the book Breath on Body of Wonder some months ago. And he was particularly interested in how breathing influences nitric oxide levels. And he postulated that breathing through your nose was going to be much more beneficial than breathing through your mouth.

Luis Ignarro: Yes. I agree a hundred percent. I've spoken with him. I've read that. On other podcasts, I've talked about that. And this comes from an incredible series of simplistic experiments conducted by a group of researchers at the Karolinska Institute in Stockholm, Eddie Whitesburg and, and John Lundberg. I know them fairly well for years.

Well, before this study, and what they showed is that, that nasal mucosa, but not the mouth produce nitric oxide. And they, it produces lots of nitric oxide, which can diffuse out of the nasal mucosa as a gas into the airway system. So if you inhale through your nose, you're going to bring in the [00:14:00] nitric oxide into your lungs.

So what these researchers postulated, was that the physiological reason for your nose making the nitric oxide is that by breathing in we can relax the airway smooth muscle, right? Cause bronco dilation. The NO goes into the lungs, causes the small pulmonary arteries and branches to dilate.

That means more blood flows into the lungs. And that's great for your pulmonary function, because then you could bring more air, therefore more oxygen into the lungs. You have more blood flow to pick up the oxygen and deliver it to the tissues and carry the carbon dioxide away as well.

And so it, it just seems reasonable to speculate, cause it's really never been proven. It's, it's hard to prove that, but you one could speculate that breathing through your nose especially inhaling through your nose is, is the best way to go. And you know, people who have been practicing yoga for hundreds and hundreds of years have all this breathing in your nose.

All these kinds of things that you do during yoga. I don't do yoga because my body just doesn't move in that direction. But my, my wife does lots of yoga and breathing is very important in yoga and not only breathing let's carry that further. Even humming, humming making vibrations in your nose. We're shown by the same group at the Karolinska Institute to increase the No production by the nasal NIOSA 10 to 15 fold.

And so in many different kinds of yoga, you know, you hum and you breath in through the nose and you know, and it just makes you feel better. Now that part of yoga I can do and I've done that and it does feel great, very relaxing.

Dr. Victoria Maizes: I've been really intrigued that there's now some research going on using nitric[00:16:00] oxide nasal sprays for COVID.

And there is some evidence that nitric oxide can have antimicrobial effects in antiviral effects.

Luis Ignarro: Absolutely. You're correct. There's no question about that. Inhaled nitric oxide… I think a year and a half ago, maybe two years ago. The late Warren C. Paul from Massachusetts General hospital, who first used inhaled nitric oxide 20 years ago to give to infants with persistent pulmonary hypertension treated these newborns very successfully with the inhaled NO.

Very safe. It, it just relieved their pulmonary hypertension and these babies right before your eyes. And I saw this in the intensive care for neonates because Warren showed me this, these kids are purple and after about a minute and a half, two minutes of breathing in nitric oxide, they turn pink.

Let me tell you something. I'm not a physician. So, you know, I, I don't see people who get cured or whatever, but looking at something like that, just brought tears to my eyes. It's just unbelievable. But one thing led to another and when COVID came out the same group, plus other groups decided to try to see if inhaled nitric oxide could be effective in treating COVID. And as you said, Victoria, nitric oxide as antiviral antimicrobial activity in general, when someone gets COVID, the principle cause of death is a massive thrombus formation in the lungs. Intensive pulmonary blood clotting, vasoconstriction because the virus destroys the endothelial cells of the pulmonary arteries.

And so the idea was, okay, well, let's give the nitric oxide back, you know, by inhalation and we can restore that. And so some of the [00:18:00] early clinical trials showed that nitric oxide was effective in humans. In fact, the first study I think, was done with pregnant females and, and it was a miraculous success.

I know that there are about four or five clinical trials still in progress. I'm surprised the results are not out yet, but I hear that it's quite effective in keeping patients with COVID out of the intensive care unit. So therefore freeing up beds and oxygen and so on. Here's another example where nitric oxide can do something else. I mean, it, it, it really is incredible if I must say so myself, how many effects nitric oxide has. And I wouldn't be surprised if, NO was a great treatment for the effects of, of the flu influenza virus. There are products available, which claim…okay..mow I'm going to use the word claim. That doesn't, I'm not putting them down and I'm not praising them. I'm just saying that they say they claim that these sprays deliver nitric oxide. Well, the advertising is not good because you can't deliver nitric oxide since it's a gas with the half-life of two seconds.

Now, when I go look up these products, I can't find out because they're patented and so on. I don't know what's in those products. So, if it's an ingredient that somehow gets into your nose and reacts with something to form nitric oxide. Ah, that's great. And I'm hoping that's how it works because wouldn't it be something, if you could just use a nasal spray when you feel symptoms coming on and if you get catch it early enough, it could be useful in alleviating some of the [00:20:00] symptoms.

I'm all for that. But you know, I, I have to wait and see how that works out. I mean, there's so far as I know, there's no prescription compounds that have been submitted to the FDA for approval and spraying in your nose is considered for external use only really. And the FDA does not control supplements and drugs like that.

So may be possible to purchase those. And it could be a great benefit. I I'm hoping that they will be of great benefit, but I, I need to see more information which I haven't seen.

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Dr. Victoria Maizes: I want go back and ask you one thing I'm confused about one thing you said that there's no pill to deliver nitric oxide. And yet most people consider a Viagra, a pill that does that for erectile dysfunction right.

I realize that's one effect. And then you described the use of inhaled nitric oxide in babies who had pulmonary hypertension and a potential use of inhaled in COVID. So it sounds like we do have some mechanisms to deliver nitric oxide, at least in particular situations.

Luis Ignarro: Yeah. Well, thanks very much for actually correcting me on that.

That that's true. You know, because when you said, is there a way to, when I said there's no pill that we can increase nitric oxide, I meant generally systemically. when you administer a nitric oxide gas, mixed with air or oxygen by inhalation you're delivering the nitric oxide into the lungs and nowhere else once, but it does a great thing in the lungs could save your life, could prevent inflammation you know, and so on.

Once that nitric oxide diffuses into the pulmonary circulation, it's instantaneously destroyed by the blood. Oxyhemoglobin, you know, hemoglobin with oxygen bound to it can destroy nitric oxide in less than 10 milliseconds. That's how quick it is. So NO cannot produce a downstream effect.

Let's say that it works locally. Okay. So that answers that. Now Viagra, luckily has a very selective effect. Viagra, without getting into the details, Viagra or sildenafil and then the other drugs related to that work only in the erectile tissue, the way Viagra works is nitric oxide produces all these effects, right. But, nitric oxide produces many of these effects by triggering another signaling molecule, which then produces the effects that signaling molecule is cyclic GMP. You know, we have cyclic amp in the body. We have cyclic GMP, nitric oxide. Stimulates the enzyme that makes cyclic GMP and it's the cyclic GMP that is a vasodilator, a smooth muscle relaxant, an inhibitor of platelet aggregation, and so on. Well, cyclic GMP is always rapidly degraded in the body by another enzyme called phosphodiesterase. Phosphodiesterase destroy cyclic GMP. You don't want signaling molecules to be around for more than a second or two.

Otherwise the effect is too prolonged in patients with erectile dysfunction, the problem is that they're not making a lot of nitric oxide. The nerves are not releasing a lot of nitric oxide because those nerves may be damaged either because of diabetes or other problems. The Phosphodiesterase that's present is going to destroy the cyclic GMP as soon as it's increased.

And so there's no erectile function. If you give an inhibitor, if you give a drug, that's an inhibitor of the phosphodiesterase the cyclic GMP has time to accumulate. To the level that can produce an erectile response. That's how Viagra works. So it's not really delivering NO it's increasing the action of NO it's boosting the effects of NO.

Dr. Andrew Weil: And how about, how about inhaled, amal nitrate or sublingual nitroglycerine What's the mechanism of action there?

Luis Ignarro: Yeah. Sublingual nitroglycerine works precisely through an NO mechanism. That was one of the first experiments on nitric oxide [00:28:00] we conducted let's see when was that? 1980. I remember 1980, it seems like a long time ago and of course it is a long time ago. and so nitroglycerin is a nitro compound. It actually has three nitro groups on it. And so what we showed is that the nitroglycerin when it gets into the arteries is actually in the smooth muscle of the arteries. Nitroglycerine is very lip lipid soluble. So it permeates the blood vessels. And when it gets into the smooth muscle of the arteries it's metabolized. And one of those nitro groups, one of the three nitro groups on nitroglycerin comes off and is converted to nitric oxide. So that was our first experiment with nitric oxide. Nitroglycerin works by being converted to nitric oxide.

Amal nitrate works by being converted to NO. Sodium nitropresside, which is used in the OR to control blood pressure, right. That is metabolized to NO. So all these different nitro compounds are called nitro vasodilators. To distinguish them from all, all the other ones. And then there are other ones I'm sure you aware of osozorbite, dinitrate. There, there, there are several of them. They all work the same way. They are metabolized to NO and then the no produces locally that vaso dilator action. And, and that's why NO is. That's why nitroglycerine is so exquisitely potent in relieving Angio pectus, right? In patients with an impending heart attack you put it under the tongue, it gets absorbed.

All you need is a fractional amount of NO to produce a powerful vasodilate effect. So, so that how that works, but I think I know what you're getting at Andy… You can't take the nitroglycerin to deliver NNO generally in the body. [00:30:00] Because what'll happen is that two things. One you'll get a profound and fatal drop in blood pressure.

You'll decrease perfusion of the brain and that'll be it. I mean, that's a very powerful vasodilator also. You have to put the nitroglycerin under the tongue sublingually to work because the, as you know, the circulation sublingually avoids going to the liver first circulates throughout the body.

If you take something orally and swallow it, whatever gets absorbed. Goes into the circulation that goes first to the liver before it goes anywhere else. Remember the liver is a detoxifying organ. It's a huge organ in your body. Whatever you eat that gets into the blood, goes to the liver first. So the liver can, can try to kill or inactivate, whatever poisons you've ingested.

Same thing for nitroglycerin. When you take nitroglycerin orally, it doesn't work because the nitroglycerin is destroyed in what we call a first pass, hepatic metabolism.

You know, I, I love your questions and, you know, I wish I could say yes, we have a way of increasing nitric, oxide, systemically and all that. Believe me. So many people have thought about this and much to my dismay we've not made it yet, but you know, I'm retired and whenever I give talks I have a lot of young people ask me you know, is it still a good idea to work in the field of nitric oxide?

They argue that a Nobel prize has already been awarded for nitric oxide. So why should I work in that field? I said, well, well, first of all, you're not working to get a Nobel prize. Okay. don't ever put that on your mind because you'll never get it. If that's what you want to do. I always tell them that, you know, my principle the reason I worked so [00:32:00] hard with nitric oxide was not to get a Nobel.

I never thought about it. It was to keep my job at UCLA. That's why. But I encourage them to continue working on nitric oxide because there's so many things that are yet unknown. For example, developing a drug that could boost. The enzyme NO synthase that makes nitric oxide, maybe they can make a more specific drug.

You know, antibody technology is incredible. People have learned chemists and biologists have learned to link drugs to certain antibodies that could take the drug to specific sites in the body. And then, then if you have the right linker, the right chemistry, one could remove the antibody and then the drug could act right there, perhaps in stimulating NO formation or even releasing NO there, there's so many ideas.

And since I've retired, I can't do any of those. But what I could do is try to convince other people to do that.

Dr. Andrew Weil: Lou you recently published a book about your life called Dr. NO, a wonderful title. Dr. NO. Can you tell us about that?

Luis Ignarro: Yes. This was a, a book a long time coming. It's a memoir about my life. Starting from the time I was a, a little toddler to the time after I won the Nobel prize in Stockholm, it's a book I wanted to do for many, many year.

I've written so many scientific articles. I wasn't sure how to write a memoir, such that lay public would understand. But many of my colleagues, my scientific colleagues who knew me personally said, you know, so many things happened in your life, Lou, that you have to write about it, so that, so that other scientists, other professionals can read it.

But also other young people can read it because it may be motivational for them. And so I I hired a writing coach who was able to help me write in a way that did not read like a review article in Nature or something. So that was very helpful.

You know, I’m the son of Italian immigrants, my parents were born in Italy. They met each other in Brooklyn, New York.

They never went to school. Not even kindergarten, nothing. They never went to school. They got married. I came along and my English was terrible. When I entered the first grade, the teacher told my parents that I was going have a lot of trouble in elementary school because my English was terrible very quickly, of course, how to speak and understand English.

And so what I'm trying to say is from that point on I developed a, a tremendous interest in science. But despite all the handicaps and language barriers, I was able to make it to the top of my profession in medicine and be awarded the Nobel prize. So, you know, when you have the motivation and passion to do something nothing can keep you back.

It was a one hell of a roller coaster ride. And that's what I try to describe in the book. And I hope that that's motivational to many other, people, teenagers, people in their twenties who read that book and understand that, you know, if I could do it, there's no reason why they can't do it.

Dr. Victoria Maizes: Well, I wanna thank you so much for coming on body of wonder and sharing your journey to developing the science behind nitric oxide, helping us understand the physiology and the various mechanisms and encouraging our listeners to be that scientist who figures out how to discover a drug that might systemically raise nitric oxide in appropriate ways.

Luis Ignarro: Yes. Yes. Thank you. It's been fun. Thank you.

Dr. Victoria Maizes: Thank you so much for being on with us.