Full podcast transcripts:

Patrick McKeown  00:04

A conversation here with Dr. Nathan Bryan. I think this conversation had to
happen because our paths have crossed a couple of times, and we were in
Houston. No, it was Austin, actually there, about two or three weeks ago,
Austin in Texas, and I didn't realize you were there, but I went looking for
your stand, and lo and behold, you were there. So, I said, 'Great, why not
strike while the iron is hot? So, what are we going to be talking about here?
We're going to be talking about a gas called nitric oxide. So, people, when
they think about gasses, they think about oxygen and carbon dioxide, but what
about the third gas? What does it do, and where is it formed, you know, why
should we be thinking of it? So we have probably the best expert in the world
in terms of this topic. So it's a pleasure, Nathan. I have plenty of my own
personal questions to ask as well, so you know, I think this is going to be a
good conversation. Can I just ask, how you know, I'll start off like I suppose
a little bit about your background, but I'm more curious, why did you go down
the kind of rabbit hole of nitric oxide? Like, what got you there?

Dr. Nathan Bryan  01:12

Yeah, no, it's a good question, it's a common question, but you know, I, I've always
had an interest in science and medicine, even going back to high school, but
you know, out of high school, I went to the University of Texas at Austin, I
got a bachelor's degree in biochemistry, and then I went to LSU School of
Medicine, and it was there that was introduced this whole field and new science
around nitric oxide. This is a Nobel Prize had just been awarded for the
discovery of nitric oxide, so you know the scientific community was really
excited about this new discovery, a relatively new discovery, and you know,
early on in my PhD work, I met Louie Ignaro, who came and gave a lecture on
nitric oxide. He had just won the Nobel Prize and came to the LSU School of
Medicine and gave a lecture, and kind of his, his story, personal story of
discovery, of you know, how he discovered that EDRF is nitric oxide, you know.
I had a chance to have dinner with him that night, and he made a very profound
statement that I'll never forget. He says, Nathan, he goes, "This is such
an important discovery. He goes, "If, if anybody or any company can figure
out how to restore the production and natural signaling of nitric oxide, it'll
change the world. It, because we know that most chronic diseases are associated
with a loss of nitric oxide production, so there's still a lot of work to be
done, and so I go, "Wow, that's that's really a profound statement. And
you know, I worked with a pharmacologist, Martin Felix, who was my PhD mentor
and advisor, and you know, we got to work, and you know, even as a student, I
think I finished my PhD in about two years, published, I think, six first
author papers, because we'd figured out how to wait to detect nitric oxide gas
at physiological levels, so that gave our research group a very powerful tool
to make new discoveries around nitric oxide. Once it's produced, where does it
go, what does it become, and what does it do? And then I went to Boston, did a
two-year fellowship in BU Medical Center, and really just still trying to
understand the vascular production of nitric oxide, and how do we restore the
production of this? And then from there I was recruited by Fred Mirad, one of
the other guys who won the Nobel Prize, to join the faculty at University of
Texas Medical School in Houston, and you know, we were at a center called the
Institute of Molecular Medicine, where we were charged to really understand the
mechanism of disease to the extent that we could fix it through development of
rational therapies. So, that was, you know, I was introduced to this field in
the late 90s, early 2000s and you know, that's all I've done for the past 25
years.

Patrick McKeown  03:40

Wow,
so nitric oxides, it was you're talking about the late 1990s so the award for
the Nobel Prize for medicine, Ignarro, he received that, I think, in 1998 It's
a really relative recent discovery, but I also believe that when they first
thought about nitric oxide, and when I narrow started giving talks to a
conference, it wasn't always best received. Nitric oxide was, it was kind of
dismissed, really. And then it was embraced.

Dr. Nathan Bryan  04:16

No, for sure. You know, the I go back to the, you know, late 80s, when they first
administered nitric oxide gas to premature babies with pulmonary hypertension,
and you know, I was very fortunate to know Warren Zapol, the anesthesiologist,
and a lot of his team at Mass General and Harvard Medical School, where they
were administering nitric oxide gas, and you know, they said, because if you
have a cylinder of nitric oxide gas, very clearly on that cylinder it has a
skull and crossbones, and it says poison, so you can imagine the general
population when you were going to administer the most vulnerable patient in the
world, a premature baby that's, you know, living on the brink of life or death,
and you're going to administer a gas that. Nearly says poison on it, but you
know now, fast forward, and we know that innovative nitric oxide therapy for
premature babies with pulmonary hypertension is very effective, and it's not
only effective, it's very safe at the doses you administer. So now we know
that, I mean, those are paradigm-changing observations and discoveries, and
that's why nitric oxide is so important because now we need to figure out how
do we deliver this in an outpatient setting and how do we restore the natural
production of nitric oxide. I think that's what you've done such a fantastic
job of doing, is you know, teaching people that just nasal breathing can
activate and stimulate the production of this very important molecule, so you
don't even have to give it through innovative therapy, we can just do the nasal
breathing and deep breathing exercises and naturally produce it,

Patrick McKeown  05:47

and it was a nice lead in. So, you know, young infant babies who have pulmonary
hypertension, and so they were breathing in the gas, obviously, to increase or
to carry that nitric oxide into the lungs, and the purpose in the lungs was to
help to dilate the little blood vessels to reduce pressure.

Dr. Nathan Bryan  06:08

That's right, so the nitric oxide, so when we're delivering it intranasally, you know,
nitric oxide is a gas, right? So it just diffuses right across the bronchials
into the small blood vessels of the the alveoli, the lower airways, and so the
problem in pulmonary hypertension, and it's, it's a problem in premature
babies, and it's a problem in adults with pulmonary hypertension. So, what
happens in the lungs, and the lungs are a very unique organ, because typically
when you have hypoxia or low oxygen, all other organ systems dilate because we
need to get more oxygen to that tissue, but the lungs are a little bit
different because if you, if they're poorly perfused regions of the lungs, then
you get what's called hypoxic vasoconstriction, so if you have pulmonary
hypertension, certain parts of the lungs aren't being perfused, so you can't
take up oxygen, and babies become hypoxic, they become cyanotic, blue is called
blue baby syndrome, and the nitric oxide completely, you know, corrects that,
because it dilates the pulmonary arteries, it improves oxygen uptake, it
improves oxygen delivery, and that's how it works, and the same mechanism is in
place naturally through nasal breathing and through endothelial nitric oxide
production. The problem in adults is this: they've lost the ability to produce
nitric oxide, so it's no longer generating nitric oxide when we do nasal
breathing, or when we activate the endothelial.

Patrick McKeown  07:36

So, in terms of then nitric oxide coming from the nose, I believe it's produced
locally in the nose, and it's also produced in the paranasal sinuses
surrounding the nasal cavity. And say, for example, we went through COVID, and
I was putting out blog posts about the importance of nasal breathing. You know,
at least in Ireland, all of the emphasis here was about washing hands and
wearing a mask. Nobody was talking about breathing internet through the nose,
and I was thinking about, like, if this is a virus that's transmitted airborne
via water particles, it doesn't really make sense for us to be going around
with our mouth open, either. The person who was infected, because they're
breathing more particles out into the atmosphere, but also for the person that's
close to them, if they have the mouth open, they're bypassing the nose, and
people kind of objected to what I was saying, and I was saying, "Listen,
your nose is kind of the first part of the fence, so will you list the
functions of why this gas is very important? And it was only in 1991 that the
nitric oxide was first identified on the exhale breath of the human being, so
it's still relatively recent, you know. What are the functions in terms of
nasal nitric oxide, and do you think there may be other functions of nitric
oxide when it comes to sleep apnea, but yet people aren't really talking about
them?

Dr. Nathan Bryan  08:57

No. Absolutely. Look, we have to understand the enzymology and the biochemistry of
that reaction, because there's an enzyme, the same enzyme that's found in our
endothelial cells, and those are the cells that line all blood vessel
throughout the body. That enzyme is also found in our epithelial cells. In
fact, the highest concentration of this enzyme is found in our nasal
epithelium. So we have to focus on how does that enzyme become active, so that
when we activate it through nasal breathing, it actually produces nitric oxide
gas, and we understand the enzymology and the biochemistry of that reaction.
So, the problem is in older patients, when we have endothelial dysfunction, you
also have epithelial dysfunction, and you've probably seen this in the published
literature that young, healthy people, if you do nasal breathing, you, you get
exhaled nitric oxide, or you get nitric oxide that we can detect in the exhaled
breath, but if you take older patients with hypertension, diabetes, erectile
dysfunction, they can do nasal breathing, but there's less nitric oxide being
produced that we can detect in the exhaled breath and. The reason for that is
because their enzyme isn't functional, so that's really the work I've been
doing for the past 20 or 25 years. How do we fix the enzyme? How do we restore
the oral microbiome so that the body is optimized to naturally produce this
molecule, and so if we can act, if we can, we can recouple the enzyme. Now,
when we do nasal breathing, we can detect more nitric oxide, and when it's,
when it's produced in the sinuses, again, it's just like giving it through a
nasal cannula. It's delivered into the lower airways, it dilates the blood
vessels, it matches ventilation to perfusion, and it's a normal physiological
response. Now, your question to patients with sleep apnea, you know, for this
enzyme to work, it's, it's really a complex enzyme. It requires eight different
cofactors and substrates in order to convert arginine to nitric oxide gas. One
of those is oxygen. So, if you're having sleep apnea and you become hypoxic,
which is a result of sleep apnea, lack of breathing, then without oxygen your
body can't make nitric oxide, without nitric oxide you can't deliver oxygen, so
it's this feed forward loop that if you don't correct, you know you can get
into really serious conditions, and you know you know the numbers, people with
obstructive sleep apnea have, you know, sometimes a 10 time higher risk of
cardiovascular disease, heart attack, and stroke, so oxygen is important, but I
think nitric oxide is even more important, because as you said during COVID,
you put people on 100% oxygen if they become hypoxic, and many people didn't
improve their blood oxygen saturation, because that revealed to us that they
weren't really out of oxygen, they were out of the ability to produce nitric
oxide to adequately uptake oxygen and then deliver it to every cell in the
body, so nitric oxide is critically important

Patrick McKeown  11:46

In terms of other functions of the gas, so when we're breathing in through the
nose and we're carrying that air with laden with nitric oxide into the lungs,
but when the gas nitric oxide arrives into the lungs, what would you say are
the most important? I'm just thinking about all of the people who had asked me
about everybody in terms of lung health and gas exchange. What do you think
would be the most important functions?

Dr. Nathan Bryan  12:11

Well, it's most important function. Well, it's.. I shouldn't say most important,
perhaps it's most well characterized function is a smooth muscle vasodilator or
smooth muscle relaxant, and so the airways, the upper airways, the lower
airways are surrounded by smooth muscle, right? So, when nitric oxide is
delivered into the lungs, it dilates the smooth muscle, so bronchials dilate,
so now we're eliminating or reducing the resistance in the airways, right, and
gasses follow the path of least resistance, so we're, we're lowering the
peripheral vascular resistance, we're lowering the resistance in the airways,
and when it's delivered into the vasculature, when it, when it diffuses across
the the airways into the circulation, it's now dilating the blood vessels, so
now you're matching ventilation to perfusion, which is a normal respiratory
response. So that's number one, but number two, in terms of our immune system,
nitric oxide inhibits a virus from replicating most respiratory virus, whether
it's a coronavirus, whether it's RSV, whether it's influenza, if our body makes
sufficient nitric oxide and we're breathing nitric oxide, then the virus can't
attach to our cells, it can't propagate and replicate in the cell, and we don't
get sick from virus. You know, I haven't been sick from a viral infection in
more than 20 something years, and all four years of Covid, I never got Covid, I
never wore a mask. I was on an airplane every week. We had 26 clinical sites
for COVID drug study we were involved in. I didn't get the shot, and I've never
had COVID, so that just tells me that if our body's making sufficient nitric
oxide, it specifically with COVID, it down regulates the ACE two receptors,
which is where the spike protein binds to and attaches and enters the cell, so
it makes perfect sense. It improves circulation, we mobilize an immune
response, and we prevent virus from replicating.

Patrick McKeown  14:09

Okay, so keeping that simple, in terms of people who are listening that may not
understand the words, but so really this is a gas that can help open up the
airways, so the sensation that people might have of chest tightness or wheezing
or difficulty in breathing, and we have the bronchial three, which is an
extensive network of airways. I think there's about 23 branches in total. So,
as we're drawing that air, that nitric oxide from the nose and gently carrying
it into the lungs, it's helping to open up the airways, and then the blood
vessels, so when that air then arrives to the small little air sacs in the
lungs for gas exchange take place, nitric oxide crosses the barrier from the
lungs to small air sacs into the blood and then it's dilating the blood vessels,
so that then so nitric oxid is going into the blood and now that blood is going
to the heart, so here's. A question that has always kind of bugged me, and you
know what I'm going to ask you. The heart, then, is pumping that blood, but is
nitric oxide having an impact on that circulation? The answer is no. Sorry,

Speaker 3  15:14

yeah,

Dr. Nathan Bryan  15:14

the answer is yes, but it's not nitric oxide gas itself. So, in this, these data
were published because it was first thought that if you get insulated nitric
oxide therapy, it was a selective pulmonary vasodilator, but and we did these
studies when I was in Boston, in collaboration with the with Mass General, and
looking at the systemic effects of inhaled nitric oxide, so nitric oxide, once
it's produced, whether it's in the nasal epithelium or whether it's in the
lining of the blood vessels, typically it has a half life intravascular, mean
if it's produced in the lining of the blood vessel has a half life of about two
milliseconds, so 1/5 of a second, right, and then if it's produced outside the
vasculature, like in the in the airways, it has a half life of maybe two
seconds, but what happens, and this was part of our work early on in the early
2000s because I was interested in once nitric oxide is produced, where does it
go and what does it become, and then how is it transported throughout the
vascular tree, and so what we found was there's two main transporters, one it's
oxidized to inorganic nitrite with the dioxygen reaction, and then number two,
it binds to the cysteine of glutathione. Right, so glutathione is a master
antioxidant, it's a tripeptide, three amino acids, and one of those is a
cysteine, which contains a sulfur residue. So nitric oxide binds to the sulfur
residue, and then it's transported throughout, so you know there's millimolar
concentrations of glutathione in the red blood cell, so once nitric oxide is
produced, it binds to it, there's cysteine in the plasma, and then it can be
transported, so to answer your question, if we're breathing in nitric oxide or
producing nitric oxide in the lining of the blood vessel, it's systemic because
it forms inorganic nitride, it forms S. nitroso glutathione, and it transduces
that vascular activity from the side of production, whether it's the lungs or
the side of production, whether it's in the endothelial cells of the sex organs
or the heart or the brain. It goes systemic, and we actually published on that
in 2007 in the Proceedings National Academy of Science, showing for the very
first time that nitric oxide is a hormone, and that's the hormone that's the
endocrine function of nitric oxide. So that was really the eureka moment for me
in science, because I knew that if nitric oxide is a hormone, then in people
who are low in that hormone, which is the aging population, people with
erectile dysfunction, high blood pressure, diabetes, then we had to replace
that hormone, and so all we have to do is generate nitric oxide in a single
compartment, whether that's the upper airways, whether it's the oral cavity,
which is where I focused, or whether it's stimulating through the production of
exercise or through the through dietary changes, and now once we produce nitric
oxide, it goes systemic, and we no longer have to deliver it just in a nasal
cannula in an inpatient setting, especially in a critical care setting. We can
do this in an outpatient setting. We can, we can teach people to do this every
day to replace the missing hormone nitric oxide.

Patrick McKeown  18:16

So, in essence, this is only my interpretation on it, because I got a little bit
lost along the way, so nitric oxide has a half life of about two seconds,
you're saying from the lungs into the blood, so it means that half the gas is
gone within the two seconds and only 50% is remaining, but because the gas
makes some conversion in the blood vessels, it's still able to do a lot of work
throughout the body, so it's irrespective of the short, the short life.

Dr. Nathan Bryan  18:46

Yeah, so let's go back, because once nitric oxide is produced, it by it's called a
messenger molecule, or a signaling molecule. So even in that second or less
that it's around, it activates an enzyme called guanylocyclis, and that enzyme
leads to cyclic GMP, which now is a second messenger. So, once it's produced,
it starts the signaling transduction, and the analogy is, if you've got, you
know, a string of dominoes, and once you hit that first domino, then the
dominoes fall, right? So, you can knock that first domino over in less than a
second, and then all the other dominoes right in line are going to fall. Nitric
oxide is that first dominant, right? So it doesn't have to. All you have to do
is turn it on, and then it activates the second messenger systems. It's
transported, you know, it's it's oxidized by oxygen, it binds to other cysteine
residues, and then it's transported throughout. But it's that first domino in
that cascade,

Patrick McKeown  19:42

but you know this is shocking now, because now I'm beginning to wonder. Okay, we've
been talking about the benefits of nose breathing versus mouth breathing, and
we've isolated everything in terms of the impact of nasal breathing on the
airways and the lungs, which, of course, is very, very important, but what
you're saying is having. Way more effects than just isolated to the lungs, and
my question, then Nathan, is what about mouth readers? I was a chronic mouth
reader for so many years. 20-five to 50% of studied children are mouth readers.
We don't have many stats for adults, because it doesn't get really studied. 50%
of adults breathe through an open mouth during sleep, so we have this gas
that's hugely important in terms of health, but by bypassing the nose, we're
not going to be getting the same benefits of the gas by breathing through the
mouth, because I don't know if I'm correct here, that the production of nitric
oxide in the nose is 100 times that of the lower airways, so the main source,
in terms of the airways, is the upper. So, here's the question: in a general
sense, what would be the more common conditions that may be associated with
mouth breathing? Because that mouth breathing is contributing to, because it's
bypassing the benefits of nasal nitric oxide.

Dr. Nathan Bryan  20:59

Well, we know there's a hierarchy of symptoms that develop, and the progression of a
gradual loss of nitric oxide production. First, you see erectile dysfunction,
and this is in both men and women, and you think about this, because if your
body can't produce nitric oxide to dilate the blood vessels of the sex organs,
then we can't get an erection, and that's both a clitoral and a penile
erection, so that's number one, and we call that the canary in the coal mine,
because it's the first sign and symptom. And then number two, your blood
pressure goes up, you know, at least in the US, I think it's probably global
statistics, but two out of three Americans have an unsafe elevation in blood
pressure, right? Because, and we're finding that it's because of a loss of
nitric oxide production, and then the third is you start to get metabolic
disease, nine out of 10 Americans are metabolically unfit, because we, we
published in 2011 that nitric oxide is required for insulin signaling, so tend
to get glucose into the cell, if it cell can't make nitric oxide, you get
insulin resistance, and you get diabetes, and then number four, you start to
develop exercise intolerance, where you tire easily, you get short of breath
walking up a flight of steps, and then if not corrected, then people start to
get heart attack, stroke, vascular dementia, and Alzheimer's. So the
interesting thing about mouth breathing is it you're not only bypassing this
essential pathway to produce nitric oxide, but you're actually inhibiting it
more, so because when you fully oxygenate the the oral cavity, that completely
changes the the ecology of the oral microbiome. It creates a more acidic
environment, your saliva becomes acidic, it changes the ecology, now you have
more opportunistic infectious bacteria, the gingival bacteria prone to cavities
and caries and periodontal disease, gingivitis. So, we have to close the mouth,
change the ecology, do the nasal breathing, not only stop preventing,
inhibiting the nitric oxide production, but promoting it through nasal
breathing, so mouth breathing is one of the worst things we can do for our
cardiovascular nitric oxide production.

Patrick McKeown  23:07

Okay, I'm going to kind of hold with that point in terms of mouth breathing. So,
because the mouth is open, we're taking cold, dry, unfiltered air into the
mouth, and this would dry out the mouth. So, this is what you're saying, is
this is changing, then the bacteria inside the mouth, and of course, then
you're thinking about the connection between the mouth and the gut. So every
time we swallow, or the food that we eat, we're carrying this bacteria then
from the mouth into the gut, so it's affecting the gut microbiome. So, what's
happening there? Just a little bit about that, so that's one question to tease
that out a little bit, because again, nobody seems to talk like there's a lot
of talk about gut microbiome at the moment, but there's not so much talk about
breathing in and out through your nose to help with the gut microbiome.

Dr. Nathan Bryan  23:56

Yeah, so we and others identified these, what we call the oral nitrate reducing
bacteria that live on the dorsal part of the tongue, so these non-pathogenic
commensal bacteria are part of our natural production of nitric oxide, so and
it explains the benefits of certain diets, a Japanese diet, a Mediterranean
diet, the dietary approaches to stop hypertension, so when we consume it's
primarily green leafy vegetables that contain inorganic nitrate. When we
consume these foods, 90 minutes later, the nitrate is concentrated in our
salivary glands. So now each time we salivate, if we have normal salivary flow,
then it's providing these bacteria on the dorsal part of the tongue nitrogen to
respire on, because they're they're facul of anaerobes. If they don't have
oxygen, they use nitrogen in the form of nitrate, and they reduce that to
nitrate. So now we swallow our own saliva, we get a nitride becomes protonated
in the in the lumen of the stomach. So now we're getting nitric oxide being
produced in the lumen of the stomach every time we swallow our saliva, and that
nitric oxide has been shown to. Kill H. pylori, the ulcer causing bacteria,
kill E. coli, Salmonella, botulinum, Clostridium, all of these food-borne
pathogens, and it's increasing gastric mucosal blood flow, because similar to
nitric oxide delivered in the lungs, the nitric oxide delivered in the stomach
dilates the blood vessels, it diffuses across the mucosum, and now we're
enhancing nutrient absorption, but if you, if you're not eating a good diet, if
you don't have the right oral bacteria, because you have your mouth breather,
because you're using fluoride toothpaste, or using antiseptic mouthwash, or
you're taking antacids, which is a huge problem, then you're completely
eliminating this natural production cycle of nitric oxide, and we know you know
if you use mouthwash and kill the bacteria, your blood pressure goes up. So all
of this is very well characterized in the published and the basic science in
the clinical literature that this is an absolutely essential pathway, and if we
abandon it, you know, we do it to our own demise.

Patrick McKeown  25:59

Okay, so my daughter went to a dentist, and he advised her to start taking mouthwash,
and of course I was at your talk at the AAPMD, and here's this going off in my
head, this is not the right solution, and so because I remember you talking
about that people who were taking mouthwash, it drove up their blood pressure.
How quickly did it happen? And also, if then somebody say, is that just
mouthwash or is it the fluoride that's in normal toothpastes? Um, is it the
fluoride that's in the water that we're drinking? So, you know,

Dr. Nathan Bryan  26:33

yeah, because fluoride, look, there's there's chemical antiseptics like
chlorhexidine, which is used by dentists for chronic halitosis and dysbiosis.
There's alcohol-based mouthwash, that's again antiseptic, and you see it on the
TV commercials. It kills 99.99% of the oral bacteria. I mean, 100 years ago,
maybe that was a good idea, but that was long before we knew that there was a
microbiome bacteria that lived in and on our body that regulated many human
processes, so we know that if you take an antibiotic, in fact, there's no
physician today that would recommend anybody take an oral antibiotic every day
for the rest of their life, sometimes twice a day, because now we know that it
kills the good bacteria in the gut, causes systemic disease, and so by the same
argument, why would any dentist recommend you use a stringent antiseptic twice
a day in the form of a mouthwash? Because we're killing the microbiome, we're
shutting down nitric oxide production, blood pressure goes up, and you're on a
very slippery slope to the onset of cardiovascular disease, and the frightening
thing is it's not just the antiseptic mouthwash, it's the fluoride that's in
toothpaste, it's the fluoride that's in many municipalities in their drinking
water. Why do they put fluoride in the drinking water to kill the bacteria in
the pipes? Well, when we bathe in this, we cook in it, we drink the water, it's
killing the bacteria in our pipes in our GI system in our mouth, it's awful,
and we have to do better because the science has advanced to the extent that
you cannot ignore the data, and now I think, at least in the US, this is part
of the conversations now with policy makers to get fluoride out of the drinking
water, you know, I spoke before the American Dental Association last year, and
I think we're finally getting the attention of the American Dental Association
to change their practice, because you can't do things today that you did 100
years ago and ignore the new science and the news. In fact, the higher courts
in the US have recently ruled that fluoride exposure poses an unreasonable
risk. In fact, it's lowering IQ in young kids, so it provides no benefit in
terms of oral health, and it's all risk. And you can't subject the general
population to unreasonable risk, and it must be removed from the water supply,
it must be removed from toothpaste and mouth rinses. I think we have to, we
have to get rid of these

Patrick McKeown  29:02

point two that you made was say erectile dysfunction, and I'm sure there's plenty of
men my age, and I think you're in close enough age to myself, age 50 is, but
even age 40 plus, and of course this is going to grab their attention, you
know, and so you were talking about nitric oxide and the role, but you said
that it's the canary in the coal mine. So, what does it mean? So, if a man,
say, for example, is waking up in the morning, but he doesn't have an erection,
and normally it should be that a man is waking up that they have morning wood
to have an erection, but if he doesn't, what's the bigger picture there?

Dr. Nathan Bryan  29:40

Well, that means he has systemic disease, because again, if you're not dilating the
blood vessels of the sex organs, and that tells us that that vascular bed and
those blood vessels can't make nitric oxide, but it's not unique to the
vascular bed of the sex organs, if you have endothelial dysfunction in the
blood vessels that. Perfuse the sex organs, that same dysfunction occurs in the
blood vessels of the heart, the brain, the liver, the kidneys. It's a systemic
problem, and so we have to, and if you treat it as a lifestyle disorder, then
you're, it's grossly under appreciating the systemic nature of that disease,
and so we have to focus, and we have to get physicians and urologists and
endocrinologists and primary care docs to recognize that as a symptom of nitric
oxide deficiency. And today there's enough data showing that men with erectile
dysfunction have a higher incidence of heart attack, stroke, and rapid
progression of cardiovascular disease, and it is the canary in the coal mine,
because you know that analogy goes back to you know, if there's you know
poisonous gas deep in these mines that send a canary in there, the canary died,
they're more sensitive to it than it tells us, well, you know, we might not be
responsive to it or notice it, but there's something bad happening, and we
must, you know, mitigate the situation,

Patrick McKeown  30:58

So the entire is it 50,000 miles of blood vessels in the human body are
influenced, that in other words, they're not as dilated, or they're there, may
be, is there an accumulation of plaque? Is it like, what's a little bit more..

Dr. Nathan Bryan  31:12

Well, the blood vessels are vaso reactive, right? So the blood vessel dilation is a
balance of vasodilators versus vasoconstrictors. Nitric oxide is the main
vasodilator, so if we lose the ability to produce it, we no longer dilate the
blood vessels. So now we have basically adults have a finite amount of blood
volume of blood pumping through these 50,000 miles of blood vessels, and so if
we're chronically constricted, then we've got that same fluid going through
smaller pipes, and that's just basic physics, right? Pressure will go up,
pressure has to go up, it's fundamental laws of physics. So, if we can restore
the production of nitric oxide, we can dilate the blood vessels, then we've got
the same volume of blood going through wider pipes, pressure comes down, and
high blood pressure is the number one risk factor for the number one killer of
men and women worldwide, which is still cardiovascular disease. So, nitric
oxide fixes the physics problem of hypertension, and that's why it's so
important, because if we can eliminate the number one risk factor for the
number one killer of men and women worldwide, think about what that does for
public health,

Patrick McKeown  32:22

It's huge. So, coming back to nasal breathing, we talked about nose breathing, and
when people think about breathing in and out through the nose, they're thinking
about, well, when I'm watching TV, my mouth is closed, or if I'm at work, my
mouth is closed. Do you have any thoughts in terms of doing moderate intensity
physical exercise? Should it be through the nose or mouth? Would that be
beneficial? The 50% of people, of adults that sleep with their mouth open,
could the six to eight hours of sleep with their mouth open, waking up at a dry
mouth in the morning. I assume that that's going to have just as big as an
implication is if they have their mouth open during the day.

Dr. Nathan Bryan  33:01

No, absolutely. I mean, whether you're asleep or awake, that oxygen is getting in,
it's changing the ecology, the microbiome, creating an acidic saliva, creating
dry mouth, which again changes the entire ecology of the oral microbiome. But
yeah, what I do, and I look, I'm probably like you, I practice kind of
different things to figure out what works, so I like the high intensity
interval training, only doing nasal breathing right. So every morning when I
get up, I do 100 push-ups and 100 squats, and sometimes, wow, look, it's
amazing the effects you feel, and how it starts your day, because you get your
blood going, you're fully oxygenating, you get your heart rate going and you're
starting the day with a boost of nitric oxide and so I think it's a very good
exercise, whether you have to tape your mouth. What I do is I get a device, an
appliance I put in my mouth that forces me to do nasal breathing while I'm
doing the high intensity interval training, and I encourage everybody to do
that, because you know we used to say 20 to 30 minutes of moderate physical
exercise is enough to stimulate and activate nitric oxide production. Then
people go, well, I don't have 20 or 30 minutes today, anybody has three to four
minutes, right? I can do 100 push-ups and 100 squats in less than four minutes,
and look, it's intense, right? Your heart rate goes up, I start to sweat, your
breath rate increases, so you don't have an excuse anymore. And even if you're
brushing your teeth for two minutes, you know, I used to do squats while I'm
brushing my teeth, it's two minutes, anybody can do that. So, what we call
stack the hack, right? You have to be multi multitask,

Patrick McKeown  34:39

Yeah. And I think, like, if somebody is kind of new to this and they're hearing this
for the first time, it might have to use a nasal dilator. So, for example, I
have a deviated septum, so I use a nasal dilator, and also at the start, kind
of just push yourself, but at an intensity at which you can sustain comfortable
nasal breathing, because I'm sure when you start. Started, you didn't manage
100 press ups and 100 squats the first time you did it, but you were able to
over a period of time, so that's amazing, that's brilliant. Um, so sleep, so
this is all new, you know, this is great stuff for us as well, in terms of the
application going one step further with nasal nitric oxide. Um, here's another
question I have for you, and I'm often kind of wondering about the nitrate, so
say for example people with asthma, which is typically characteristic of
inflammation in the airways, that the walls of the bronchioles have swelled up,
and that one gage of inflammation in the lower airways would be nitric oxide on
the exhale breath, so the fraction of expired nitric oxide, is it pheno, as, as
an inflammatory, you know, a marker of inflammation. What's your take on that?
Because I'm kind of confused on that.

Dr. Nathan Bryan  35:54

Yeah, I think, look, it's the, the exhaled nitric oxide is a clinical measure of the
severity of asthma, you know, those those exhaled nitric oxide analyzers have
been around or detectors for probably 20 or 25 years, so but the problem is
it's the compartmentalization of the nitric oxide, so that what we're detecting
in the the exhaled breath of asthmatic patients is a reflection of the systemic
or the the local inflammation in the airways and I believe we published on
this, I believe in 2004 in chronic inflammatory disease, which is what asthma
is. We were looking at inflammatory bowel disease, relative colitis, and
looking at the acute overproduction of nitric oxide in an inflamed tissue, and
what we're finding is that it completely inhibits the vascular in the
constitutive forms of nitric oxide, so chronically inflamed patients, or
chronically inflamed conditions, have maybe more nitric oxide being produced at
the local site of inflammation, but systemically it completely shuts down its
production.

Patrick McKeown  36:57

Okay, and

Dr. Nathan Bryan  36:57

So in asthmatics you get the local inflammation in the airways, but it's shutting
down the perfusion of that part of the lungs, and you're getting a mismatch in
ventilation to perfusion. Patients become as hypoxic or anoxic in worse
conditions, and so if you can give nitric oxide, it dilates the pulmonary
arteries. Nitric oxide actually is a very potent anti-inflammatory molecule. In
fact, one of my patents on a method of reducing inflammation as we measure by
C-reactive protein in chronically inflamed patients. So, it's a
compartmentalization issue. So, even though they're exhaling more nitric oxide
reflective of the severity of asthma, the underlying problem is really a loss
of nitric oxide in the endothelium in the pulmonary circulation, that's what's
leading to a mismatch in ventilation to perfusion and lack of oxygenation.

Patrick McKeown  37:48

Okay, I need to kind of tease that out from my own head now. So, is it a matter of
how the nitric oxide is produced through there's different isoforms? So, there
is a nitric oxide that originates because of inflammation called inducible
nitric oxide, and this is a bad guy, whereas we have neuronal nitric oxide and
the Telen nitric oxide are good guys. So, if we have inflammation in the lungs,
we're producing a lot of the bad guy, and that's impacting the good guy. Is it

Dr. Nathan Bryan  38:19

Absolutely? No, you're right, so that the inducible, the inducible nitric oxide is there,
and it's a very important mechanism, because now we can knock out these, these
specific isoforms in mice, and so if you, if you knock out the inos in mice,
they become more susceptible to to infections, in fact, they're completely
immunocompromised, so think about this when we're exposed to a bacterium or a
virus, and our body recognizes that we mobilize an immune response, we activate
monocytes, neutrophils, macrophages, and we go to that site of infection,
right? And then those macrophages are producing a lot of nitric oxide over a
short period of time, and that's a very important because that nitric oxide is
toxic to the infectious bacteria, binds to the iron sulfur signals, centers,
and shuts down the respiration, and as we discussed, it prevents the virus from
attaching and replicating and propagating throughout the body, and then it also
it activates what's called m1 macrophages, so that's the part that goes in and
kills the infection, in this, it's elicits a wound response or wound healing,
but then what happens is that that enzyme is only supposed to be active for
several hours, and then you turn it off because you've gone there, you've
isolated the infection, isolated the wound response, and now you switch the m1
macrophages to m2 which are anti-inflammatory, and what we call the Hill
response, and then constitutive isoforms up regulate, but the problem in
chronically inflamed patients, there's a chronic upregulation of inos, it never
shuts off, it shuts down the constitutive isoforms, so now you have systemic
nitric oxide deficiency, you're chronically inflamed, you have. Immune
dysfunction, and you have oxidative stress, and those are the hallmarks of all
chronic disease. But if we can restore the production of nitric oxide, we can
down regulate eye mass, mitigate the inflammation, shut down the oxidative
response, and repair the immune dysfunction we see in chronic autoimmune
disease, and including asthma.

Patrick McKeown  40:22

Okay, so the next aspect. Then, okay, we talked about nasal nitric oxide. We were
talking about the benefits of, say, nitric oxide that's produced inside the
blood vessels. We were talking about the impact of it, and the production of
nitric oxide, then, is typically derived from the foods that we eat, and that's
also going to influence nitric oxide that's produced locally in the nose and
the paranasal sinuses, but also in the blood vessels.

Dr. Nathan Bryan  40:52

Let me just make a point of clarity, these are two separate and independent
mechanisms to produce nitric oxide. Right, I think there is some cross talk
between it. One can affect the other, but these are two separate independent
pathways. That one is dependent upon the function of the enzyme in the
epithelium through nasal breathing and the endothelial cells. The other is
dependent upon the food we eat and the oral bacteria and stomach acid
production, but one can compensate for the other, but when you lose the ability
to produce nitric oxide from both, which unfortunately a lot of people suffer
from, then that's when you start to develop problems.

Patrick McKeown  41:29

Okay, so we lose the ability, see, over time, then as we age, we're losing the
ability of producing nitric oxide. So, what you're saying is that is impacting
both the nitric oxide production from the upper airways and the nitric oxide
production in the, in the blood vessels,

Dr. Nathan Bryan  41:43

that's right, because of the enzyme, because of the loss of function of the enzyme, so
that we know typically declines with age, but we now know that that doesn't
have to be the case, right? We can shift that curve to the left and rapidly
accelerate it, we see it in young kids that have ED, and 25 years old ED,
hypertension, diabetes, their body can't make nitric oxide. And then you've got
perhaps people like me and you. I'll speak for me personally, because I know
I'm 51 but I've got the vascular age of a 36 year old, so I've, I prevented, at
least delayed this, this age-related loss of nitric oxide production because of
what I do, what I eat, I think more importantly, what I don't do, I don't be
exposed to fluoride, I don't use antiseptic mouthwash, and I don't take an
acids, so now my body's primed to make nitric oxide, so when I do nasal
breathing exercise, or I take my supplement, I'm giving my body nitric oxide on
a daily basis, okay,

Patrick McKeown  42:42

I was writing The Oxygen Advantage, I think it was back in 2015 and I talked
about nitric oxide, and I can remember as well writing about beets, what I
actually included as well, just going a little bit off topic, and coming back
to erectile dysfunction, Viagra, as a drug, was initially proposed for
cardiovascular health, and when they administered it to the subjects, they
found it obviously had other uses, but that was all based on nitric oxide as
well, wasn't it?

Dr. Nathan Bryan  43:11

Well, not necessarily, no, not so the PD five inhibitors, the Viagra, the Cialis,
little betrays of the world, those are downstream of nitric oxide, so they're
called phosphodiesterase inhibitors. So, you know, we talked about nitric oxide
being that first domino. Nitric oxide leads to an increase in cyclic GMP, and
every cell in the body has what's called a phosphodiesterase enzyme, so it
degrades cyclic GMP. So, if you give a phosphodysterase inhibitor, you prevent
the breakdown of cyclic GMP, but in patients who can't make nitric oxide,
there's no increase in cyclic GMP, so the PD five inhibitors don't work. In
fact, they can't work. So, and we know that today that Viagra was approved in
1998 by the FDA in the US, and today we know that 50% of the men that are given
these PD five inhibitors do not, do not respond with better erections, and it's
because their body's not making enough nitric oxide to lead to the accumulation
of this second messenger, and so they're non-responsive, but no, the PD five
inhibitors have nothing to do with nitric oxide production, they potentiate
nitric oxide based signaling, but they do not affect nitric oxide production,
and that's why people don't respond to them. So, what we focused on is going,
you know, one step higher. Let's restore the production of nitric oxide, and
then now in patients who take PD five inhibitors, they can reduce the dose,
making them much more safe, or they can eliminate the need for them altogether,
because we're, we're restoring the body's natural physiology.

Patrick McKeown  44:45

Okay, so the production of nitric oxide, how to do that, or increase their
production.

Dr. Nathan Bryan  44:54

Well, I think you have to stop doing the things that inhibit it, so get rid of
fluoride in your toothpaste, so. Stop using mouthwash, and if you're on an
acid, you have to get off of antacids.

Patrick McKeown  45:04

Yep,

Dr. Nathan Bryan  45:05

And then once you stop doing the things that disrupt it, the other big thing is
sugar. Sugar leads to, you know, sugar is sticky, it sticks to proteins and
causes the enzyme to become dysfunctional. So, you got alcohol,

Dr. Nathan Bryan  45:18

including alcohol, and so you have to eliminate sugar, go to a low glycemic index,
eliminate sugar from your supplements, from your diet, and then once you
eliminate those things, then you can do nasal breathing, you can do moderate
physical exercise, 20 to 30 minutes of sunlight, you know, there's certain
wavelengths of lights and frequency that can release nitric oxide or stimulate
nitric oxide release from from metals and make that a label source of nitric
oxide, and then you know when all else fails, we've developed technology that
does it for you. So if your body can't make it, then then we we have product
technology that provides it for you.

Patrick McKeown  45:57

I think the supplement is very interesting. I bought them when I was in Austin. I
don't typically talk about supplements. In actual fact, this is the first
podcast I have spoken about supplements, and this one here is your supplement,
and it was more so on the base that I understood about nitric oxide, the role
it plays, and I just felt that, yeah, this could be very, very interesting, and
I, I've never actually seen nitric oxide as a supplement in the health food
store. Maybe I just was looking in the wrong place. Now I'm in Ireland. It
seems that nitric oxide has been kind of overlooked still, even in terms of
people going into a health food store having various issues. Like, I'll give
you a comparison: so many people my age, including friends, have high blood
pressure. No doctor has talked to them about nitric oxide, you know. They've
talked about taking different drugs, Ramaparel, and different drugs to help
lower high blood pressure, but nitric oxide is overlooked. But yet, nitric
oxide seems to be the most obvious one. Is there any side effects, by the way,
from taking a supplement of nitric oxide?

Dr. Nathan Bryan  46:59

No, not when taken as directed. I mean, there's dose dictates toxicity. The only
signs of toxicity are taken too much. You would have an unsafe drop in blood
pressure, called hypotension, or you develop a condition called met
hemoglobinemia, where oxy too much nitric oxide can oxidize the iron of
hemoglobin and reduce the oxygen carrying capacity of the red cell. But you
don't see that. We've never seen it.

Patrick McKeown  47:21

It had to be really high doses,

Dr. Nathan Bryan  47:23

would have to be really, really high doses. Yeah, but I, you know, again, we talked
about it. Nitro, 50% of the people that are prescribed anti-hypertensive
medication, whether it's Samlodipine, you know, ACE inhibitors, centipril,
ARBs, things like that don't respond with better blood pressure. 50% of the
medication used to treat people with high blood pressure don't work, and the
reason for that is because it's not addressing nitric oxide, and I believe 90,
probably 95% of the hypertensive cases is due to a loss of nitric oxide because
of the physics problem, right? Same amount of volume of blood going through
smaller pipes, pressure goes up. If we can provide nitric oxide, dilate the
blood vessels, we fix the physics of hypertension, and it's so very simple. The
supplement does that, and so you know our whole thought process, dating back 20
years ago, was look, if your body can't make nitric oxide, then we got to do it
for you. So that law isn't just really the what we call a solid dose form of
nitric oxide gas. When you put it in your mouth, it dissolves over five
minutes, and it's releasing 20 to 30 parts per million, the same amount they
give to premature babies with pulmonary hypertension. So we try to train
people, put the lozenge in your mouth and deep breathe, because number one,
it's going to provide a source of nitric oxide. Number two, we're restoring the
ecology and the diversity of the oral microbiome, because it's an orally
disintegrating tablet. And then number three, we've, we understand the enzymology
and the biochemistry, where we actually fix the enzyme in the upper airways and
in the endothelium. So now that laws in just improving your body's natural
ability to make it on its own, so put the laws in your mouth, do nasal
breathing. It takes five to six minutes to completely dissolve, and again, it's
stacked the hack. You're delivering nitric oxide airway, we're improving tissue
oxygenation, blood oxygen saturation. We can mobilize stem cells, we can
normalize blood pressure, prove oxygen saturation. We did this during Covid. We
had a drug trial, a phase three trial during Covid with the nitric oxide, and
we made people better and kept them out of the hospital.

Patrick McKeown  49:29

Yeah,
it's pretty amazing. I think there was one published paper, a review article on
nitric oxide. Could nitric oxide help to mitigate the effects of Covid 19? And
they did include in the article the importance of nasal breathing and
increasing the production of nitric oxide, but other than that, I really feel I
couldn't find all that much.

Dr. Nathan Bryan  49:50

You made a comment that you didn't see nitric oxide based products as we're
increasing awareness, which hopefully this podcast can do. There's hundreds of.
So called nitric oxide products in health food stores in pharmacies, but the
problem is 99% of them don't provide any nitric oxide benefit, because they're
giving these patients the precursors or substrates and hoping their body can
convert it, but again, if the enzyme is dysfunctional, then these arginine,
citrulline-based products can't work, if you don't have the right oral
bacteria, the nitrate, the beetroot-based products can't work. If you're taking
an acid, they can't work. And so, what we do is completely different. Is your
body can't do it, then we provide it for you. And I, in fact, I, I coined a new
term called Nitraceuticals. So, Nutraceuticals are like dietary supplements.
I'm not a nutraceutical, because most nutraceuticals don't work. They don't do
anything. So, what we do is called nitraceuticals, which is a term that I
trademark, because in that word is nitric, nitric oxide. We can provide nitric
oxide that we can detect, we can quantify, and verify that these products are
generating nitric oxide gas.

Patrick McKeown  51:00

Oh, I think it's been a wonderful conversation, and just tying everything in
together. Okay, so we started off with this at the very beginning about the
importance of nasal breathing, not just during rest but also during physical
exercise. You spoke about doing your press ups and your squats, very
impressive, which are mouth closed, and also during sleep, and other aspects in
terms of, does the speed at which you breathe also influence, is it the
production of nitric oxide, or is it just because you're breathing slower that
you're going to capture more of the gas? Can you speed up the generation of the
gas inside the nose?

Dr. Nathan Bryan  51:35

Well, I think you can, but again, there's some chemistry that's occurring because
nitric oxide can react with oxygen, and without getting too technical, this is
a second order reaction with oxygen, and so you have to have a normal, and
that's why it's so important to regulate the oxygen delivery and the flow rate
in inhaled nitric oxide therapy, because you don't want to facilitate the
dioxygen reaction and form what we call nitrogen dioxide, which is a toxic
pulmonary toxicant. So, I think in normal breathing we're activating these
mechanoreceptors on the epithelial cells, producing nitric oxide, and just
during normal breathing. And I don't think it affects, because typically we
have much higher concentration of oxygen than we have nitric oxide, because nitric
oxide is so potent, you don't need a lot, and so the simple kinetics of this
physical chemistry that occurs with oxygen and nitric oxide, oxygen is so far
in excess that unless you typically don't get it with normal breathing
patterns, but I think normal slow breathing during sleep is effective, I think.
If you're doing rapid breathing during high intensity interval training, you
know the data show that you can produce nitric oxide in the nasal cavity. It's
vasoactive, it's dilating blood vessels systemically. So, there doesn't seem to
be a limitation in that regard.

Patrick McKeown  52:55

Swift is a researcher back in 1988 and he found when people continuously switched
from mouth to nasal breathing, if they continuously breathe it through their
nose, the PO two in the blood increased by nearly 10% Now that's the partial
pressure of oxygen, as you know, which in turn would influence the SAO two.
It's possibly nitric oxide that's that mechanism. Is it because of the
redistribution of blood throughout the lungs, the dilation of the airways, and
also the dilation of the blood vessels.

Dr. Nathan Bryan  53:25

No, I think it's all of that, you know. In 2015 it was published that nitric oxide
is the cardiopulmonary cycles, a three gas system, so you need nitric oxide
bound to hemoglobin for oxygen to come off hemoglobin. So, without nitric oxide
being bound to that beta cysteine residue on hemoglobin, you don't get oxygen
uptake, and you don't get oxygen delivery. So, when we increase nitric oxide
production, we're improving tissue oxygenation, and we're improving oxygen
offload of hemoglobin when it goes from the arteries to the veins. So, we're
improving blood oxygen saturation, we're improving oxygen delivery to
individual cells of the body, and we're more efficiently taking up co,
preventing lactic acid production, and we're exhaling co in the exhaled breath,
but that entire cycle cannot work without nitric oxide.

Patrick McKeown  54:13

That's amazing, because if we look at the oxygen dissociation curve, and we think of
oxygen being carried bound by hemoglobin, I've never seen nitric oxide being
mentioned. We talk about carbon dioxide, we talk about resultant drop to blood
pH, we talk about temperature to three dysphosphoglycerate, no nitric oxide. So
night, so he, so basically for the late population, I won't know, I won't keep
you long, nitric oxide is going from the nose into the lungs, passing into the
blood, so in the blood is it's bound with hemoglobin and hemoglobin, then it's
nitric oxide that is influencing the release of oxygen from the hemoglobin to
the tissues.

Dr. Nathan Bryan  54:54

Absolutely
amazing conformational change, right? We call that the Bohr effect and. Nitric
oxide is part of the bore effect. In fact, I think it's more important than the
drop in pH and the two three DPG, because none of that works. Those are
consequences of lack of nitric oxide production that explain the more effect.
So that's why this is such a foundational molecule, because everything you know
kind of propagates from that.

Patrick McKeown  55:19

Wow, Nathan, it was a fascinating conversation. So, wrapping it up very, very
quickly, we were talking about the importance of nasal breathing. It's very
important that your body is able to produce nitric oxide. Your supplements, can
they be bought in Europe? By the way, nitric oxide,

Dr. Nathan Bryan  55:38

you can. We ship to Europe. We're working on a UK and EU distributor now, to where
they can be, you know, because of the import taxes and the cost of shipping,
we're trying to make this more cost effective, but yeah, the supplements can be
found at n1 oh one.com that's the letter N, number one, letter O number

Patrick McKeown  55:55

one, okay, we'll put it into the links as well, then don't do the things that harm
the production of nitric oxide, such as fluoride and mouthwash. I'm assuming
eat good foods, do regular exercise, nasal breathing. It's all there. Listen,
it was a pleasure. Thank you so much. I think it was brilliant. I could talk
for another hour, conscious of time. So, your website again for people, if they
want to dive a little bit more,

Dr. Nathan Bryan  56:17

in 101.com for the product technology, but I encourage people to subscribe to my
YouTube channel, Dr. Nathan S. Bryan Nitric Oxide, for education awareness
information around nitric oxide. I just published a new book, I'll shamelessly
plug my book, it's called The Secret of Nitric Oxide: Bring the Science to
Life. We talk about nasal breathing, we talk about this cardiopulmonary cycle,
but you can get that on Amazon Barnes and Noble, or go to Nathan's book.com and
it'll redirect you.

Patrick McKeown  56:45

Right, pleasure. Well, enjoy the rest of the day in sunny Florida. And thank you very
much.

56:50

All
the best. Bye.