Nitric Oxide and Functional Health - with Dr. Nathan Bryan | The Empowering Neurologist EP. 166

my objective is to Open the Eyes of the masses and start people to to realize that hey nitric oxide is important and if you have a poorly managed disease with standard pharmacotherapy then start taking into consideration some of these Common Sense approaches and restore nitric oxide and be able to wean off drugs allow the body to heal itself and that's how humans are designed to react [Music] please [Music] well hello everyone Dr David promoter here welcome again to the program the empowering neurologist there's a lot of talk these days about something called nitric oxide it's

a very very fundamental chemical in the human body it is actually a gas but it plays Incredible roles in metabolic function including things like blood pressure regulation how insulin works it even acts as a neurotransmitter uh we're going to learn a lot more about nitric oxide today on the program and we really should because this is uh really state-of-the-art science that has huge implications as it relates to human health Our Guest is Dr Nathan Bryan who's looked upon really I think as being Center Stage as relates currently to nitric oxide research and development let me

tell you a little bit more about Dr Bryant Dr Nathan Bryan earned his undergraduate Bachelor of Science degree in Biochemistry from the University of Texas at Austin and then went on to get his doctoral degree from Louisiana State University School of Medicine where he was the recipient of the dean's award for excellence in research he then did his postdoc training at Boston University School of Medicine and then was recruited to join the faculty at the University of Texas Health Science Center in Houston by Fareed Murad who ultimately went on to win the 1998 Nobel Prize

as it relates to nitric oxide Dr Brian has been involved in nitric oxide research for the past 20 years and has made a variety of really seminal discoveries in this field these discoveries have resulted in dozens of issued U.S patents as well as international patents and product technology resulting from his discoveries and inventions has improved patient care around the world so we are just delighted as can be to welcome Dr Brian to the program hello Dr Brian Welcome to our program Dr bromato thank you very much for having me it's a great honor and pleasure

to be with you I want to start off by uh saying that you and I spoke several years ago but I think we kindled our friendship or maybe rekindled our friendship uh at the plmi meeting in Chicago and I was very very overwhelmed by your uh presentation which uh you know because I've been thinking about nitric oxide for an awful long time obviously in relationship to uric acid and even obviously prior to that and then the way that you just opened up the whole universe to the implications of this gas this chemical molecule uh was

really breathtaking so I want to jump right in I think that our viewers are probably aware of nitric oxide but certainly not uh the nuances that are coming to light day in and day out so why don't we start just by talking to those who don't know what is nitric oxide and then we'll develop it from there sure well thanks for the kind words and uh yeah it's you know we've been working with this for almost 25 years now but yeah nitric oxide is a signaling molecule it's really a unique molecule produced in the body

of humans in fact all mammals but it's a gas which makes it unique and so once it's produced it's gone in less than a second so it's produced it activates some second messengers and then starts this whole signaling Cascade so it's how cells in the body communicate it's most common recognized function is in vasodilation so when nitric oxide is produced in the lining of the blood vessels it causes the smooth muscles to relax and dilate so you basically get vasodilation normalization of blood pressure regulation of blood flow to every organ tissue and cell in the

body but it's a neurotransmitted in the central nervous system so as you're well aware it's extremely important as a signal in neurocognition deficiencies of which cause neurodegenerative disorders and it's how our immune system fights off invading pathogens from you know bacteria to viruses to you know any type of parasite so it's really you know the the Simplicity of this molecule but yet the number of important roles it plays in human physiology is really fascinating and now that I think there are 195 000 papers published in the scientific literature on nitric oxide so we continue to

learn more each day the reason I'm smiling is because my mind is going a thousand miles an hour right now I mean I don't know where to take this conversation I really don't because you know do we go to cardiovascular health we go to uh sexuality do we go to neurotransmitter production do we go to MTHFR polymorphism it's all over the place and again for our viewers this is really uh incredibly important information I think yeah I would say it's Nobel Prize worthy information but in fact the Nobel Prize has already been awarded uh due

to uh you know the research in identifying uh the roles of nitric oxide but uh interestingly uh I I heard you interviewed talking about that at the time of the uh Nobel Prize that there really weren't any ways to measure nitric oxide really quantify what the heck's going on in the body uh how far have we come in terms recognizing how important this molecule is where are we today 2023 and being able to say well we can measure some things and let you know where you are as it relates to nitric oxide sure well there's

still kind of a bridge or gap between research and clinical medicine so in the research lab you know we have nitric oxide gas phase analyzers we can measure nitric oxide gas we can measure oxidative metabolites of nitric oxide but clinically there's really still no way to measure nitric oxide so it's you know it's it's unlike say vitamin D or cholesterol which are stable in blood so you can pull blood and measure these molecules in blood nitric oxide is a gas and it's fleeting so it's gone in less than a second so it's really impossible to

measure nitric oxide in blood or in peripheral blood in terms of a diagnostic or prognostic indicator however there are indirect measures and so in 2010 I developed really the first point of care non-invasive salivary diagnostic for nitric oxide so what we're measuring is salivary nitrite and there's a number of different Pathways that lead to accumulation of of salivary nitrite it's the oxidation of endogenously produce nitric oxide or it's the reduction of inorganic nitrate that comes from green leafy vegetables by Oral nitrate reducing bacteria so it gives us what we call kind of a total body

proxy for nitric oxide production but I tell people it's a good tool to have in your toolbox but it's really not the only thing you should be using so really what we rely on in clinical medicine are symptoms and there's there's known symptoms of nitric oxide deficiency the first one is an increase in blood pressure and you know two out of three Americans have an unsafe elevation and blood pressure and really the first sign and symptom of nitric oxide deficiency is erectile dysfunction and that's in both men and women and vascular dementia insulin signaling so

when you lose the ability to regulate blood flow or to increase blood flow improve perfusion to select organs upon need then that's a sign of nitric oxide deficiency and collectively that's referred to as endothelial dysfunction so let me just break this down you've said quite a bit just now in fact it could be an entire podcast that this chemical is difficult to measure because it's life is so darn short but nonetheless it's directly involved in how the endothelium the lining of the blood the cells lining the blood vessels are able to do their job it's

involved in the relaxation of blood vessels allowing blood supply to the various organs and you did mention it's also involved in what is called insulin signaling so that deficiencies of availability or functionality of this chemical nitric oxide relates to things like insulin resistance and type 2 diabetes Now for me where the story gets really incredible and you know I recently did a podcast with a Doctor Mark berhenna who's a dentist we were talking about oral health we were talking about the bacteria in the mouth and the the story is that we can't change food related

nitrate into available nitrite that is necessary for the formation of nitric oxide this incredibly valuable chemical that we've been discussed discussing we depend on bacteria mostly living in the mouth but throughout the gastrointestinal system but there's a lot of studies being done in the mouth that look at how these bacteria convert our food-related nitrate into nitrite that then becomes stored and available for nitric oxide production so in a very real sense then what you've said is that things like blood pressure and risk for diabetes are dependent upon the health and functionality of the bacteria in

the mouth through the mechanism of their role in the creation of this very important chemical called nitric oxide as such if you damage those bacteria there could be hell to pay how do we damage those mouth-related bacteria I'm really setting you up am I not yeah I thought it through I need you to take me with me when uh with my lectures you can set the stage because it's so it's so complicated and one of the things I've always been a big fan of yours is you take really complex Concepts and make them really simple

and easy for patients and consumers to understand so yeah actually is very much a simpleton and so that's the only way I can see the world through you know breaking it down we were one of the first people to demonstrate the role of oral bacteria and the regulation of systemic blood pressure and so now we're finding and we've published I don't know three or four papers on this where if you disrupt the oral microbiome the oral Flora it leads to a down regulation or in decreased production of nitric oxide and we see an increase in

blood pressure and then all the other symptoms that follow nitric oxide deficiency are ensued so so how do you do that well if you use mouthwash any type of antiseptic mouthwash two out of three Americans wake up every morning use antiseptic mouthwash killing the bacteria leading to an increase in blood pressure and also and you lose the protective benefits of exercise if you use mouthwash so that's number one until people if you use mouthwash you have to stop I mean it's a risk benefit analysis and we're finding a science progresses that the the risk of

mouthwash and killing the nitric oxide producing bacteria far outweigh the benefits of killing any gingival carries causing plaque the other is fluoride you know fluorides are neurotoxin it's an antiseptic and it destroys your thyroid function so we have to get rid of fluoride based toothpaste we have to you know filter the fluoride out of Municipal Water Systems uh and then the other you know our antibiotics you know 200 million prescriptions written for antibiotics every year and there's so there's collateral damage you want to kill the Infectious pathogenic bacteria but there's always collateral damage from overuse

of antibiotics and so these are the things and it's really the the mechanism of the oral systemic link and as you know probably in discussing with this dentist that people with poor oral hygiene have a higher incidence of heart attack stroke cardiovascular disease and this is the link and Alzheimer's and Alzheimer's which is Alzheimer's as we now describe it is really fundamentally metabolic it's an insulin people have called it type 3 diabetes it's an insulin resistance basically in the brain insulin requires nitric oxide we can't have adequate amounts of nitric oxide if we don't have

good oral health and good oral health means nurturing the oral bacteria to a significant degree not killing 99 of germs which television commercials tell us that's what we should be doing we should be sterilizing the mouth so you're making this connection between the use of mouthwash 200 million Americans do this every day and risk for diabetes and risk for high blood pressure simply by using mouthwash but that's what we were told we needed to do that's right well you know it's probably not surprising to you but a lot of the things the information we get

from the media or the so-called experts aren't always the truth or at least the full truth so we have to rely on you know science and you know real science and what the not only just the basic science but the translation of that basic science into clinical medicine and that's where the true story is revealed but yeah to me and I tell you I know that viewers are watching this right now not in there and say are you telling me that my mouthwash could put me at risk for high blood pressure and it is what

we are saying and it's not just an interesting Association but what you've done Dr Brian is you demonstrated the actual mechanism I.E connecting the scientific dots that make it very understandable as to how this is occurring yeah no doubt it's been really amazing and it's you know it explains a lot it explains resistant hypertension and for the I mean obviously as a physician you know this but if you have high blood pressure and you go to your primary care physician or cardiologist and he puts you on a blood pressure medicine such as an Ace inhibitor

an ARB or calcium channel antagonist you know 50 of those medicated patients don't respond with better blood pressure and why is that because it's a it's a this hypertension may be a symptom of oral dysbiosis and so these types of drugs and their mechanism of action aren't designed to restore the oral Flora uh they're hitting other Pathways that may be that may not be the cause of the underlying hypertension so we have to you know what I tell people is look just stop using the mouthwash allow the diversity of the oral microbiome to repopulate and

what we published on is the higher the diversity the better the blood pressure management and the more these nitrate reducing bacteria are present wow you know I would say who knew or who would know but the reality is uh we should have known uh that that you know in recognizing this a meta organism that we are that there would be a symbiosis between the good guys in our mouths now accepted in the gut that's for sure and on the skin but in the mouth as well and that's right um there is one other area that

seems to be threatening and that is the use of these proton pump inhibiting drugs acid blocking drugs if you will uh and how what's the mechanism there well it's really part of the mechanism of nitric oxide production so the human body makes nitric oxide through two independent and completely separate Pathways one we talked about through the enzyme nitric oxide synthase this found in the endothelial cells the cells that line the blood vessels and the other is through this bacterial reduction of nitrate to nitride and then when we swallow our saliva as long as their stomach

acid you know it becomes protonated and we generate nitric oxide gas interestingly proton pump inhibitors inhibit nitric oxide from both Pathways so these are extremely dangerous drugs and you know they they were never approved for long-term use by the FDA these drugs were only approved for acute use in gastroesophageal reflux disease and now the data showing us that people who have been on ppis for three to five years this is worked by John cook a colleague of mine at Houston Methodist showed that they have a 30 to 40 percent higher incidence of heart attack and

stroke so what's happening is these drugs are inhibiting an enzyme called ddah which lead to an an increase in a metabolite called asymmetric dimethyl L-Arginine or adma and now these are known risk factors for cardiovascular disease so not only is it inhibiting the nitric oxide being produced in the lining of the blood vessel but if we suppress stomach acid production we lose the nitric oxide that's being produced by swallowing our own saliva from this conversion of nitrate to nitrite so these are extremely dangerous drugs and the consequences are are very clear now I wrote a

Blog uh several maybe four or five years ago probably at least actually or even longer than that and I said how Larry the Cable Guy may be giving you dementia that's right and it was because even back then we began to see the literature of about people who are chronically taking these acid blocking drugs having a dramatic increased risk for dementia and as you mentioned stroke as well uh you know the mechanisms that we fell back on were the changes in the pH in the gut how that would change the gut bacteria and might favor

pro-inflammatory array of organisms but now through the understanding of their role in terms of nitric oxide production it really does seem to make sense and you know it seems to be um that it seems to be so valuable to make these considerations and yet you mentioned earlier mainstream pharmacology doesn't really want to go there doesn't really want to embrace the notion of above all Do no harm and we write these blogs we get criticized for it but you know the point is this is good peer-reviewed science that is published and uh people certainly need to

be made aware of it but it's why we do what we do so the nitric oxide made in our bodies from nitrite which is converted from nitrate due to an enzyme that we as humans and all mammals lack but the bacteria in our mouths and elsewhere in our digestive system are able to help us with so we have to be kind to them these nitrates come from the diet so what are good dietary sources then of the nitrates that we should be thinking about well you know it's it's kind of on a generally speaking it's

dark green leafy vegetables and typically the darker the green vegetable the higher the nitrate content and this is you know most uh Foods grown in the soil are dependent upon the availability of nitrogen you have to assimilate nitrogen the form of nitrate to really assimilate other nutrients you know there's a misconception you know people people you mentioned nitrate or nitride the first thing people go to is oh hot dogs and bacon and cured meats and the hot dog that's a misconception uh you know again we were we were not told the entire truth over the

past 50 or 60 years and the the Innovations and the progress we've made in science hasn't really been communicated effectively but 85 percent of the nitrate we get comes from green leafy vegetables only five percent comes from cured and processed meats and the other 10 comes from swallowing your own saliva so it's it's really the mechanism of action for a plant-based diet a vegetarian diet the cardio protective benefits of a Japanese diet the dietary approaches to stop hypertension which we published on in 2009 that's the mechanism of how these diets are affording not just the

cardio protective effects of these dietary patterns and certain food choices but also in many cases the anti-cancer effects of many of these dietary patterns well you mentioned just to be clear the DASH diet one other consideration oh well there are many but is the production of nitric oxide requires availability of adequate oxygen so how might it be affected nitric oxide production for example in somebody that has some sort of illness that creates lower oxygen uh hypoxia like sleep apnea for example how does that fall into this discussion well the part of this five electron oxidations

of arginine to make nitric oxide is dependent upon oxygen and so in tissue beds where there's insufficient oxygen then you can't make nitric oxide and it's really this Perpetual cycle because without nitric oxide you can deliver oxygen without oxygen you can make nitric oxide so you have to correct it and it's kind of like the chicken or the egg right you have to get oxygen to make nitric oxide but you have to have nitric oxide to deliver oxygen to every cell in the body and you know we experienced that over the past three years with

covid and it really revealed the importance of nitric oxide and oxygen saturation and oxygen delivery because you know everybody knows that if you get covered you drop your blood oxygen saturation they give you 100 oxygen still didn't improve it they picture the mechanical van it didn't improve it and a lot of times these people die well what the science revealed to us is that nitric oxide is required for oxygen uptake in delivery so in these patients who had increased risk in death of covid these were the patients who couldn't make nitric oxide the hypertensives the

patients with previous heart attacks diabetes uh pulmonary disorders and so when we in our code and our drug covered drug study we could just give our nitric oxide drug and improve blood oxygen saturation from 76 to 98 within eight minutes even just breathing right here or 21 oxygen so you have to fix the underlying disorder and the mechanism of all of these diseases and as you know the common denominator in every major common chronic disease whether it's Alzheimer's cardiovascular disease is insufficient blood flow or ischemia hypoxia to that particular vascular bed well you know it's

interesting because I think the fix for what you're talking about ends up getting back to the what is the universal fix or the fixes it's eating right getting enough sleep breathing right which I think not a lot of people talk about uh you know I'm basically taking care of yourself I think in terms of the dietary recommendations I think you've been very clear that it's just about getting adequate amounts of nitrate through dark green leafy vegetables and it's not necessarily a call for vegetarianism I mean there's no threat to this pathway by consuming animal products

is there No in fact you know I'm not a big fan of these extreme diets whether it's straight carnivore or straight vegan and vegetarian I think we need a diverse food supply to get the many essential vitamins and minerals uh we need but no there's there's no uh disruption in the nitric oxide production from eating animal proteins versus plant proteins but what's clear is that you have to have a sufficient supply of nitrate in order to to keep both of these Pathways functional so that you're optimizing both production pathways one uh this a bit of

it probably no segue here but I guess under the main umbrella of nitric oxide consideration and let me Define this a little bit and people will then get the connection so I've I've mentioned on this program many times that in my genetic profile I have what's called a polymorphism or a variation if you will in something called MTHFR and that's probably maybe 20 to 30 percent of people have a variation as you look at your 23 mirror whatever genome profile you have in something called methylene tetrahydrofolate reductase an enzyme involved in the methylation pathway more

specifically how our bodies are able to deal with something called homocysteine right but you've been able to relate this MTHFR polymorphism again we're talking about perhaps 20 to 30 percent of people to deficiencies in the creation of a particular chemical uh tetrahydro hydro biopterin baptaren and that that may compromise the formation of nitric oxide therefore giving us a better understanding as to the vascular and cognitive uh and even uh mood issues related to carrying this MTHFR polymorphism can you unpack that a little bit for us sure so is it in in Biochemistry you know these

metabolites feed that some of them metabolite from one reaction feeds into another so the MTHFR I mean most as you said recognize it as a methylating enzyme involved in kind of a methylation cycle and deep are defects of such but part of what this enzyme does is it reduces bioctron to tetrahydrobacter so it's redox cycling and if you can't reduce biopter into tetrahydramopter and then the availability of bh4 or tetrahedron is the rate limiting step in nitric oxide production so if you have an MTHFR snip then it leads to an inefficient reduction to to bh4

and then that's the rate limiting step and it uncouples the NOS enzyme and you're no longer able to produce nitric oxide so this this really is a is a risk factor and I think as you said it it really explains a lot of these previously unexplained symptoms that were typically unrelated to a methylation issue well you know and and I learned about bh4 in the context of my nitric oxide production but also recognized that it's fundamental in the production of of a variety of neurochemicals norepinephrine dopamine uh and even serotonin and the the fix for

me and I guess others who would be to add higher levels of folenic acids what I what I'm using and then we're facilitating the methylation pathway and hopefully bypass it's a bit of biochemistry that's for sure but you know I have to admit that this kind of stuff isn't going to enter into your your typical interaction 15-minute interaction with your general physician I mean it's it's a little bit intense but you know it's good to know what your genetic uh predispositions are right so getting back to how do we correct this with food you're talking

about green leafy vegetables there's a real Trend these days to maybe in the interest of convenience or time to spend this your vegetables down uh in a blender of sorts and and suck it down and and be on your way and uh to me if we're depending upon having the mouth be able to expose itself to levels of nitrate in order for these reactions to happen it would seem to me that that's not a good plan that chewing your vegetables might be a a better idea than being on your way well you know I think

it's part of this is It's recycled so it's taken up in the gut and then concentrated back in our salary glands but you make a very good point one of the first steps in digestion is the mastication and having a certain resident time in the mouth for these bacteria to metabolize a lot of food food nutrients and the one we focus on is is nitrate so there has to be a resident time in the mouth for these bacteria to respire and reduce the nitrate to nitrite so you know I think it's not only important to

masticate and chew your food to allow that Resident time but also to break it up into smaller parking so you increase the surface area and it just leads to better digestion so there's a number of reasons to do this but it has to have a certain resident time for these bacteria to utilize it now we uh our ability to make nitric oxide is age dependent it declines as we get older doesn't it well the the function of the NOS enzyme so half of the pathway to make nitric oxide and so this has been well well

studied now for probably 30 years looking at this age-dependent loss of endothelial function or the ability of the enzyme and the endothelial cells to produce nitric oxide and that's just kind of on a on a population-based studies but as you know you know there are 20 25 year old kids who have a vascular age in a nitric oxide production of a 60 or 70 year old and to the contrary you know I'll be 50 this year but I have a vascular age of a 36 or 37 year old so you know we we know that

we can shift this curve to the left and to the right but kind of when you look at population-based studies there seems to be about a 10 to 12 percent decline in our nitric oxide production per decade so by the time we're 40 years old you know we only have about 50 of the nitric oxide we had through that enzyme when we were younger but the this the dietary pathway doesn't seem to be affected by age but but it certainly is affected by the foods we eat and it's certainly affected by the presence or absence

of these essential bacteria in the mouth and uh there there are ways of otherwise aside from the foods we eat uh what else can a person do to increase the availability of of oral nitrate to to boost nitric oxide production well number one you have to get rid of mouthwash and start the collateral damage from killing not only the bad guys but you know the killing a lot of good guys and so um you know it's really very simple it's a complex science but you made a good point earlier it's really just good diet exercise

in lifestyle and a lot of this is going to be money saving because you know if you stop using mouthwash that's going to save you money if you get rid of fluoride you know there's some fluoride free toothpaste out there and this this we're not asking you to do anything more a lot of this is just eliminating certain practices so we're going to simplify your life so I tell people you have to get rid of mouthwash get rid of fluoride throw in some more green leafy vegetables and then just moderate physical exercise and exposure to

sunlight you know there's certain wavelengths of light that stimulate or release nitric oxide when exposed to the skin so these are these are just common sense real world approaches to improve nitric oxide it's not rocket science I have to say that every guest on the program that indicates what you just indicate about fluoride every time we do that there's always comments oh fluoride's so important my dentist says I have to have fluoride treatments my children have to have fluoride treatments and gosh I'm I'm in a position or the position that would indicate that that's bad

advice not not what we should be doing for a number of reasons we'll do actually we just did a podcast on that um Viagra Works in a sense to improve endothelial function via the nitric oxide Pathway to help with erectile dysfunction in men and women for that matter and uh one would think then if there is a way we could be looking at the large data sets to determine things like Alzheimer's risk you would think Alzheimer's having a vascular component and a insulin component that that might be affected by people who frequently use Viagra so

there is a study that demonstrated that what what's what does that reveal to us well it shows us that really it's it's if you can restore blood flow or maintain blood flow then you know a lot of times you don't get this chronic dysfunction that leads to chronic disease so Viagra are what we call phosphodiesterase Inhibitors are dependent upon nitric oxide production so these aren't nitric oxide generating drugs they potentiate nitric oxide basically so if you if you if you're able to produce a little bit of nitric oxide and then it activates an enzyme called

guanocyclase leads to an increase in cyclic GMP and then these pd5 Inhibitors permit the breakdown of that second messenger so you can actually you know sensitize the system and that's why they work for improving erectile dysfunction the problem is you know these drugs were approved I believe in 1998 so we're 25 years on the market and you know they only work in about 40 to 50 percent of the men in which they're prescribed so these non-responders mechanistically are non-responders because their body is not making any nitric oxide to activate the system for these drugs to

work on so we can now if you restore nitric oxide you can turn non-responders into responders and then the end result is vasodilation in vasodilation leads to increase in oxygen and nutrient delivery to every organ tissue and cell in the body so to get back to your question the results of this study that you mentioned people who have been on you know pd5 inhibitors for a number of years now have lower incidence of Alzheimer's vascular dementia a lot of these neurocognitive disorders so why is that well it's because they're not experiencing this focal ischemia or

hypoxia to certain regions of the brain and you get the good stuff in you take the bad stuff out you don't get build up of amyloid or Tau Tangles and you get normal cellular function all of it's dependent upon sufficient regulation of blood flow so erectile dysfunction in in men in their 50s and 60s is really a a a surrogate marker for a systemic issue related to nitric oxide and it's a very very big deal and I'm sure there's psychogenic issues uh that could explain erectile dysfunction as well but um in general if it's a

vascular issue I mean we know it's correlated with cardiovascular risk that's for sure but this becomes the unifying mechanism okay so the the uh the results of the study you mentioned were can be explained by increase in in blood flow in preventing this focal ischemia hypoxia to certain regions of the brain so the take-home message for this is if you can maintain normal blood flow and circulation to every organ including the brain then the data tell us that you can prevent the onset and progression of many of these disorders including Alzheimer's and vascular dementia well

important that you mention that both men and women and so uh no that's right it is the canary in the coal mine because again we have to regulate blood flow upon demand right so when we're stimulated or so there's both the neural connection through these non-adrenergic non-cholinergic nerve endings in the erectile tissue but also the blood vessels you know when we dilate the blood vessels of the the sex organs we get engorgemen it shuts off the outflow and that's what's responsible for erections in both men and women so for us go ahead both men and

women yeah whether it's a penile erection or a clitoral erection you know it's all about increasing blood supply which is dependent upon nitric oxide that's right to get the increase in pressure in the engorgeous so without that if so if you can't regulate blood flow to the sex organs you also have that same vascular dysfunction in the coronary arteries the heart in the brain in the kidney in the liver so this is really a systemic disease but it first manifests itself in the sex organs now you are working on pharmaceutical interventions that Target this pathway

and um so we have great hope that uh you know we're soon going to be able to uh dramatically change the playing field as it relates to this whole Paradigm in a in a country where some 83 million people are either diabetic or pre-diabetic now that we understand the relationship to nitric oxide and Insulin functionality this becomes a big deal the relationship to hypertension it becomes a huge deal in fact you know I remember in your lecture there was probably nothing off the table in terms of what you'd relate nitric oxide to one of the

areas that was so compelling in your talk was wound healing and so you've developed some topical uh Delivery Systems for nitric oxide that are effective in wound healing yeah that's right so you know I've said field for I guess going on 25 years now and most at the time I entered in the late 90s every major pharmaceutical company had a nitric oxide drug pipeline trying to develop nitric oxide drugs every single one of them failed and I think they failed because they didn't understand the mechanism of production and how to create nitric oxide or recapitulate

nitric oxide signaling that would basically mimic endogenous production and you know I'm proud to say that we cracked that code I have several dozen issued patents and so as you mentioned we've now licensed my patents from the University of Texas through our Drug Company where we're commercializing this and yeah the wound care I think is I mean it for me it's personal because my dad who's a paraplegic we've dealt with you know decubitus pressure ulcers for most of my childhood and adult life and so I've been treating wounds and ulcers since I was 10 years

old and what we found was about 15 years ago that nitric oxide would completely lead to an increase in blood flow and not only caused the hyperemia to the ischemic wound bed and get tissue granulation but nitric oxide at the doses we're producing is antimicrobial so it actually kills the infection that's common in most of these non-healing ulcers so to me it does everything you need to heal a very complex wound get blood supply to the wound kill the infection allow for granulation tissue growth and the body heals itself and and as you know there's

been no Innovations in wound care for 50 years we still treat wounds the same way we did in 1960 through negative pressure and through trying to kill the infection well I think hyperbaricose very excited it has been effective and now that I think about it that might be enhancing nitric oxide availability well there was a study I believe it was in the late 90s early 2000s showing that the mechanism of action of hyperbaric oxygen was through the production of nitric oxide which then mobilized stem cells to go to the site uh of the wound and

basically Hill itself so there are stimulants and and activators of this pathway that are clinically proven hyperbaric oxygen is one but what we do is we just add nitric oxide directly to the wound bed and we've seen three and four-year-old non-healing ulcers completely heal with just the nitric oxide topical drug uh in a period of three to four well we do have an image here of a it looks like a woman with a lesion on her face maybe you can walk us through what we're looking at and what's on the right side yeah this was

a patient of Dr Greg chernoff who's a triple board certified plastic surgeon and so he did a facelift on this patient and she went back and started smoking and I guess sitting at her desk she's smoking and applying pressure with her thumb here and developed a full thickness ulcer within a period of days and obviously they were very concerned about scarring and kind of suturing this up so in His Infinite Wisdom he said well let me try a topical nitric oxide that we had sent him and he applied that topically twice a day for 10

days and got complete closure with very little scar formation and really no suturing for the wound itself and so that was really eye-opening not only for him in these complex patients and try to mediate you know scar formation and preventing infections in these patients and so that was really an eye-opening experience and really started our way on filing the the investigative new drug applications for the FDA because it was it was an amazing result back in the day I remember at the gym Arginine was popularized for a while I was popular for uh as a

you know a way to increase your nitric oxide production but I think you made it clear that that really is not what we want to be doing now you know this this became popular in 1998 this was the year the Nobel Prize was awarded for the discovery of nitric oxide and then it was recognized that this enzyme actually converts Arginine to nitric oxide the nitric oxide synthase enzyme so that's in young healthy people with normal vascular function and now the clinical data has shown us that if you have patients with endothelial dysfunction and what that

means is the NOS enzyme is uncoupled so it can no longer convert Arginine to nitric oxide and now if you give high-dose Arginine to these patients it leads to superoxide production and it basically exacerbates the underlying condition so two studies that I know have been published one in post-infared patients you give high-dose L-Arginine higher mortality than Placebo they stop the trial this was published in 2006. several years later they tried the same experiment giving L-Arginine to patients with peripheral artery disease again another vascular dysfunction and these patients on Arginine actually got worse intermittent claudication increased

inpatient outcomes got worse so this told us and really told the entire scientific and medical community that arginine is not the solution for nitric oxide in fact it should be contraindicated in patients with endothelial dysfunction so we have to recouple the enzyme and then the body can actually utilize endogenous Arginine you know arginine is a semi-essential amino acid meaning we get part of it from the breakdown of proteins but the other part comes from the urea cycle so we're never deficient in arginine so it doesn't make sense to supplement Arginine the body already makes enough

to saturate that enzyme you um made it clear that we need available oxygen to produce nitric oxide and the time we really need nitric oxide to make sure we have blood supply to our muscles is when we're exercising but we can get to a point where we begin to engage anaerobic or our metabolism that's not using oxygen producing lactate and one would think that might threaten then nitric oxide production well no you're exactly right so once you reach that anaerobic threshold an oxygen becomes limiting then you shut down nitric oxide production and you run out

of fuel and then you lead to you know anaerobic metabolism lactic acid production soreness and poor recovery what we're finding is that in well-trained individuals when you begin to exercise before you reach that anaerobic threshold they're producing a lot of nitric oxide and this builds up as nitrate and nitrite and now when you reach that anaerobic threshold and oxygen availability becomes limiting then the nitrite that's accumulated in the plasma from the production of nitric oxide gas is especially reduced back to nitric oxide in a schema in a hypoxic or low oxygen conditions so what you

do is you create this buffer and really the ability to produce nitric oxide predicts your Exercise capacity or how well you can perform so if you have good an ethelial function you start exercising you build up this buffer of nitrite and then when you reach that anaerobic threshold that nitride becomes nitric oxide you extend the anaerobic threshold you improve mitochondrial efficiency and you get less lactic acid buildup better recovery so as it is so important and you're doing your work uh that will hopefully have a clinical application or obviously already does is that why is

there more research at other pharmaceutical companies are engaged in based on the platform that uh that you're aware of and you think might have promise I mean let's say you know the use of nitroglycerin for example is a vasodiler or something probably goes back who knows how long 80 years at least so the understanding of the ability to dilate blood vessels via this pathway I think has been you know well described for an awful long time but where are we now in the research well you know the problem with Organic nitrates which as you mentioned

been used over 100 years for the treatment of acute angilum have limitations you know patients develop tolerance to these drugs outcome data long-term studies or long-term use of organic nitrates lead to poor outcome so this certainly isn't the solution you know in 2001 the nitric oxide field took a big hit there was a company called nycox out of France who was developing a cox-2 inhibitor with a Nitro Ester Bond on it so it could produce nitric oxide and selectively inhibit cox-2 and at that time you know a lot of these cox2 Inhibitors were causing increase

in heart attacks and strokes and the Black Box mornings were put on Celebrex and vioxx and the whole approach was can we modify these drugs and we were doing a lot of the pharmacokinetics from any of these inner hybrid drugs in in on naproxen which was the first one to go before the FDA was denied approval and that really put the pharmaceutical company really the pharmaceutical industry in a in a tailspin because everybody had a Nitro Ester or an Inno modified drug and then you know when we came out with our technology I don't know

probably 10 or 15 years ago where we deliver a solid dose form of nitric oxide then that really changed the whole Paradigm and now we're taking the same technology and I was the first person to to develop a solid dose form of a bioactive gas so to me that solves the riddle um I'm not aware of any well in covid there were a couple of companies making a nebulized uh kind of a nasal spray for covet to kill the the coronavirus in early exposure and I think it would probably be effective during acute symptoms or

acute infection but the problem with covet is a systemic disease right once it attaches it attaches dates receptors on every cell in the body and causes systemic disease so that's not going to be effective you need a systemic drug so I'm not aware of anybody any pharmaceutical company where we are in phase three clinical trials for our oral drug uh you know we've got a drug study going on for ischemic heart disease ischemic non-obstructive coronary disease as you know we're about to enter into an Alzheimer's drug study we've gotten very good preliminary results with that

and then our topical drug for diabetic ulcers and non-healing wounds so I'm not aware of any company that's as far Advanced as we are wonderful in Nitric oxide-based drug development exciting uh are we able to talk about what's upcoming for you in the uh in the future uh in the literature Department sure um for me spent 20 years in basic science published hundreds of peer-reviewed scientific papers and as you're aware most lay people don't read the scientific literature and so what we try to do and I think that's why it's so important what you do

is help communicate science to the masses and what we've done now is you know I've just I signed with a major publisher last year but I've got a book called The Secret of nitric oxide coming out probably late fall early winter and really the point is it's twofold so it's going to tell the story of it's not autobiographical but kind of it tells the story of discoveries we made and how that changed the way we thought about nitric oxide and how this led to development of what I hope by the end of the year we

have safe and effective drugs approved by the FDA and on the market but number two it's really to inform the reader on how important nitric oxide is and really discussing the topics we discussed today on you know what are you doing that you may not be aware of that's disrupting nitric oxide production I mean for when I give these lectures when I talk about mouthwash it's like they're the light goes off I go oh well I had no idea and so my objective is to Open the Eyes of the masses and start people to to

realize that hey nitric oxide is important and if you have a poorly managed disease uh with standard pharmacotherapy then start taking into consideration some of these Common Sense approaches and restore nitric oxide and be able to wean off drugs allow the body to heal itself and that's how humans are designed to to react who knew what a concept right just get out of the way and let good things happen that's what it's all about by the hills itself give the body what it needs the body heals itself so thank you for for sharing uh your

time with us today this is incredibly valuable and enlightening information and uh we're gonna follow the the development of this story very very closely over the years to come and certainly uh I think you and I have a lot more to talk about moving forward so again thanks absolutely that was quite a program wasn't it uh nitric oxide no we're going to be learning so much more about it but how incredible it is that this chemical in our bodies does so much and yet is highly influenced by the functionality of the bacteria living in the

mouth it makes uh a lot of things a little bit clearer the relationship between oral health for example and things like Alzheimer's diabetes and elevated blood pressure what a fascinating uh interview that was I urge you to learn more about nitric oxide uh his he has a new book coming out can't wait for that but for now I'm Dr David Perlmutter and I want to thank you for joining us today on the empowering neurologist we'll be back soon bye for now [Music] foreign [Music] [Applause] [Music]