#254: Mackay Rippey - Toxins and Nitric Oxxide's Role in Pain and Inflammation
Only golden calling only juice. It's time for live aradio. Join US every Thursday. I tunes for the latest episode of Lime Ninja Radio. Hello I'm your show producer brains behind Lime Ninja Radio Aurora and this is episode number two hundred fifty four with your host and official nitric oxide expert an earn expert. If you get asked to talk about it right one would think so I think so too McKay rupee. And that's why you still the intro for is Sawai. I stole the intro. Don't be fooled. I am here live in the studio and today we're going to be learning three things. Yes what I'm going going to be. Presenting is a talk. I gave in Denver about nitric oxide and toxicity and how the toxicity oxidative damage our ability to produce nitric oxide which eventually leads to heart attacks and death now. We all know that lyme disease Aziz has a component where it can damage your heart lime card itis right and I believe this is the pathway through which it's doing that damage but the other thing that's happening and talk about in this talk is there's significant. DNA damage going on as well and nitric oxide can also damage Mitochondria Eddie congre it's at the centerpiece of the inflammation that happens with lime disease and particularly something called Nas uncoupling so Nassir simply employees. Nos Nitric Oxide synthase and their various synthase is located in different parts of the body when this enzyme becomes uncoupled doesn't do its job or maybe people would say it does it's secondary Ab- then it starts creating much much much much can say much much more time. It seemed more times I think inflammation mation just it goes off the rails and our sickest patients out there definitely have nas uncoupling going on now. There's genetic factors that can play into NAS uncoupling as well but we won't dive too deep into that so that's why I wanted to bring this to. It really is Geeky. It's really technical. It's really awesome. If you grasp even a little bit you'll begin to understand. Why one of the things you need to do? The heel is to get your nitric oxide synthesis back on track and there are a couple strategies are quite a few strategies do that. The talk was too long so I didn't go into into all the different supplements that have formulated for this. But if you have any questions send us an email or just google nitric oxide supplements out. There they're really some good ones Berkeley life in particular is an easy way to get started the human N.. And Neo forty is also a good one and then if you do have a genetic nutrition practitioner who worked with Bob Miller and his system. We have three specialty supplements designed just for that system all right. That was a long introduction. Wasn't isn't it. Yes for those listening. Still listening or having scared off Lauren. I want to give a big shoutout tell you longtime longtime lime Ninjas. You're the reason we have more than half a million downloads Aurora. I really appreciate you tuning in and we also like to welcome all the new listeners listeners. Out there welcome to lime into radio you are now officially a lime Ninja and as you know lime disease is an international problem. Each agree of listeners. sner join you from all over the world and this past week. We've had listeners tune in from Berlin Germany to Burwood Australia. That's so cool you'll have to and we're not GONNA do an intro about me. You kind of know who I am. I'm an acupuncturist. I work with Bob Miller on his research staff. Jeff become an expert in nitric oxide. You say a little bit more about yourself a little bit more. Oh good do I introduce myself to know more about me. Listen to the talk. It's in the first few minutes so you won't be scared off yet no really. It's good I go slowly I explain it all. There's also a youtube video video of this. That has the slides as well and we'll put that in the show notes. If you're listening in the car you want to say you know what I need to see again with. The slides will have that on lime Ninja radio DOT COM. And I think that's enough so let's get started without further ado and any other cliches cliches. Let's get started with my nitric oxide presentation. Hello this is a presentation I gave in Denver. Bob Miller's Tuck Society Conference in in September two thousand nineteen for those of you. Who Don't know me yet? My Name's McKay ripping. My training is as of five ELM acupunctures. I've been in practice for thirty years ears and live on a small farm in central New York. My journey down the nitric oxide rabbit hole began to an F. years ago when I had a reactivation of lyme disease and that left me unable to lift my right arm for three months it was a miserable experience however I am grateful that gave me a lot of time to really dig into the power purpose and pathology of nitric oxide but before we jump in I need you to do one thing for me okay. And that is. Don't drink the KOOL aid so I'm him by that. I want this presentation to be like a wine tasting except you're going to be sampling information instead of wine. I want. She does sniff what I'm teaching swirling around the glass. Hold it up to light. Take a SIP. You know do that. Funny thing. That wine tasters do with their cheeks and and then spit it out. If what I'm teaching is good and I believe this information is very very good. You'll want more. You will understand your most difficult go patients in a whole new way and you'll have new tools in your clinical toolbox to help them and that reminds me conflicts of interest or no joke. I make a small all bit of money on the supplements recommend. And that's that so. Are you ready to jump in awesome. Let's go oh toxins. Create all kinds of health problems but we're going to focus on cardiovascular disease. Why because it's a huge problem and you're seeing the facts of it in your office every day? According to the American Heart Association every forty seconds in American of heart attack as of two thousand in sixteen twenty eight point two million. US adults were diagnosed with heart. Disease the hard toxins is a really depressing. Six hundred sixty the eight page read. It thoroughly examines many sources of toxicity. And how those toxins affect the heart. This truly is the age of chemistry and this age has a dark side. We could spend the rest of this weekend going over the toxins in this book. But I've chosen to focus on one and that is bis- FINOL A. or B. P. A.. A two thousand three. CDC Studies showed that ninety three percent of people had BPA in their urine. And that makes me wonder about the other seven percent if they don't have some sort of detox vary in addition to its well known endocrine disrupting effects the CDC links BPA to all kinds of health issues and you can see that as found in lots of everyday items. It's no wonder we're all have. BPA In our systems. This two thousand fourteen study from the Journal of the Federation of American Societies for experimental biology. She showed that. BPA caused hypertension. Here are some of the highlights from the study. There's higher urinary. BPA concentrations are associated associated with arterial hypertension in humans. And they wanted to know why that happened so they designed to study they put. BPA In the drinking water of eight week old mice for thirty days. The mice developed a dosage dependent high blood pressure and that's a strong indication that there is a cause and effect relationship ship. The reason they develop hypertension and the mice is they had a one point seven. Fold increase in arterial. Ngo tencent to a two point five fold increase in calcium calmodulin dependent protein. Kinase two Alpha and eight point seven fold increase in endothelial nitric oxide synthase now that huge. BPA increases the expression of endothelial. Nitric Oxide synthase. Thanks are enormous. The reason why that's used is as up till recently emails was believed to be expressed at a fairly constant physiological level and didn't very very much we now know that just isn't true. They also found significant emails dependent superoxide and PEROXY nitrite accumulation. And so. That's how also huge and you might get tired me saying huge during this presentation but it's immensely important. What that showing is? Is that the nitric oxide. Three the in the endothelial nitric oxide is being over expressed first and that it is being uncoupled and instead of producing nitric oxide is producing the oxidant. superoxide peroxy nitrite so any light bulbs Czarnikow for you like. They did for me when I first read about this paper. Yes no it's okay. If the aren't we're going to unpack the the details of what is happening in the study. And you'll see later that not only does blood pressure rise because of a lack of nitric oxide but the stage is also set for significant can't inflammation and even tissue destruction by activation of the innate immune system so the study concludes our data suggests chests that BPA regulates blood pressure by inducing NGO tencent to and calmodulin kindness to Alpha uncoupling of endothelial. Nitric Oxide Ed clearly. EPA is a huge problem. But I don't WanNa get stuck on. BPA instead of focusing solely slowly on the toxin itself we're going to focus on something which I think is far more important and far more universal. We're going to focus on how nitric oxide and in its synthesis get disrupted and I believe nitric oxide is disrupted in many of your sickest patients there is no way to cover everything. Nitric Oxide dozen ninety minutes and do it any kind of justice so this during this presentation just going to be focusing on the downstream cardiovascular damage Mitch from nitric oxide this regulation but we could just easily talk about Alzheimer's or lime disease or autism autumn unity. LS So forth and so on insomnia depression. The list literally is endless. Nitric oxide is involved in a vast sporadically of physiological. Something symptoms so this is a two thousand seven seven study from physiological reviews. It's a fabulous paper nitric oxide. superbeets ain't proxy nitrate. It's open access. I highly recommend that a two track this one down so the name superoxide implies that superoxide should be a powerful oxidant superoxide however more generally behaves Habes as a mild reduction under physiological conditions rather than a super oxidizing agent. This is because superoxide exists naturally as a small Anti Ryan which is more likely to surrender its electron than to accept a second electron from another biological molecule. However superoxide is a strong oxidant? When it's made to a protein that way will directly oxidized positively charged chemical Mortiz such as iron sulfur centers enters and? I'M GONNA be dig into this more because I think this is super significant. I WanNa know exactly what. Proteins are getting charged up by superoxide and who they're chasing after. So the destruction of iron sulfur centers might occur. Andrea has been well described in superoxide dismutase knockout doc out mice so to review superoxide when it's paired with a protein has a particular appetite promote a cadre this is why superoxide dismutase and genetic variants in the production of that enzyme or such a big deal although nitric oxide is often described as a highly talk sick and reactive molecule it's not in fact inhaling low concentrations of gaseous nitric oxide is approved by the FDA for treatment of persistent instant pulmonary hypertension in newborns. In addition nitric oxide can be produced for eighty years by neurons in the human brain without overed toxicity. Paradoxically the production of the same. All you'll can become highly damaging to the same neurons within a few minutes during pathological challenges. such as stroke broke. And so how is this possible. The answer lies in our old friend. PEROXY nitrate the reaction of nitric oxide with superoxide to form the much more powerful oxidant. Peroxy nitrite is a key element in resolving the contrasting roles of nitric oxide in physiology. Oh Gee and pathology. A number of pathological conditions are associated with a simultaneous generation of nitric oxide and superoxide nitric nitric oxide sources are restricted to the activity of the various nitric oxide synthesis whereas superoxide arises from multiple sources including including electronic from the Mitochondria and ADP oxidise Xanthi knocks. Today's and the uncoupling of nitric oxide synthesis. By the way I think that part of the paper the review needs to be updated. I'd like to add that side. Chrome pugh four fifty can reduce nitrite to nitric oxide aside and so can other enzymes in the body under high pox or acidic environment so there are situations where nitric oxide can be formed outside of the nitric oxide synthesis. Think that's important to point out so products like Berkeley Life. Professional whether providing nitrate that eventually gets converted to nitrate Ken up your nitric oxide levels. Okay the next part of the paper is a bit long but it's really the heart of the presentation. Jn Yes I meant that Pun so sit up take a few deep breaths and get some oxygen into your brain. It's that important. In nineteen ninety. The first paper suggesting testing that peroxy nitrate could be a biological oxidant were published before then most scientists did not believe that the body could produce something as toxic as PEROXY Roxie nitrite in fact some of the original ideals of nitric oxide and proxy nitrite came from the research into air pollution at the time. Much of the literature suggested that nitric oxide was simply a scavenger of superoxide and thus acting as an antioxidant however however Josef Beckmann and his group at the University of Alabama Birmingham showed proxy nitrate exists in Vibo and produces far more hydroxyl so radicals than the widely accepted Fenton reaction in addition peroxy nitrate produces nitrogen dioxide which can lead to the novel oxidation products that were previously only suspected to occur after exposure to cigarette smoke or to air pollution. So essentially if your body's producing Roxy Ni- I trade. It's as bad as if you were smoking or out. And the smog of a big city. And that's crazy. It's just mind blows my mind. Minded proxy nitrate can generate the same toxins. That are in cigarette smoke. You know just let that sink. In for a moment separately neither superoxide nor nitric. Oxide is particularly toxic in Vivo. Because they're efficient means to minimize their accumulation superoxide is rapidly removed by high concentrations of scavenging enzymes called superoxide dismutase and their distinct ice. Oh enzymes located in the mighty cadre the site of Plaza Awesome an extra cellular compartments nitric. Oxide is rapidly removed by. It's free diffusion through tissues and into red blood cells where it is rapidly rapidly converted to nitrate by reaction with oxy hemoglobin. This limits the biological half of nitric oxide in Vivo to about a second where as concentrations of nitric oxide can preserve persist in vitro for an hour. So that's the paper saying in a nice scientific way All you in vitro studies that show nitric oxide existing for long periods of time urge or just plain wrong when both superoxide and nitric oxide are synthesized within a few cell diameters of each other. They will combine spontaneously heinous lead to form peroxy nitrite by diffusion limited reaction that means what that means chemicals every time nitric oxide and superoxide collide. They form peroxy nitrite. The incredible speed of proxy nitrate formation is an important part of its effect and no enzyme is required to format. That fact will be obvious to the biochemist listening to this. Because of the nature of diffused limited reaction actually the definition one of diffusion limited reactions and enzyme cannot possibly catalyze a reaction as fast as nitric oxide and superoxide reset react all by themselves in fact nitric. Oxide is the only known biological molecule that reacts faster with superoxide and has produced in high enough concentrations to out compete and dodging US levels of superoxide. dismutase so what that means under normal conditions if it's a choice between nitric oxide and forming with superoxide and making proxy nitrate or superoxide getting cleansed from the body by superoxide superoxide dismutase. The nitric oxide is going to win out every single time and make peroxy nitrite. That's huge so if you have lots nitric oxide being produced anywhere near the source of superoxide and sometimes that's happening in the same cell all the superoxide dismutase in the world's not how can stop the formation of Peroxy Nitrite consequently the kinetics and the thermodynamics of the reaction of superoxide with nitric talk side make the formation of proxy nitrate inevitable in Vivo. It's not a question of if you're making proxy nitrate but how much watch so. Let's look into that. This is what you would expect as the equation of nitric oxide plus superoxide to make proxy nitrite so as a example ten right hand. Gloves plus ten left-hand clubs equal ten pairs of gloves right. It should be that simple. However right we're dealing with biochemistry here? Nothing's ever simple however because all the biological reactions proxy night triggers downstream. Can you get this a tenfold increase in nitric oxide and superoxide gives a hundred fold and crease and peroxy nitrite. So when the immune system is activated nitric oxide and superoxide levels can increase by a thousand fold that gives rise to a million enfold increase in proxy nitrite. Not One hundred. Fold not a thousandfold not a hundred thousand fold a million fold increase and that's just bigger than us. It's a game changing biological shift. So is it any wonder why some of your patients are struggling. Cling is it any wonder they're inflamed. Is it any wonder they cannot handle anything anything that might cause even even the slightest bit of inflammation. I had a patient once who couldn't eat without having a massive inflammatory storm so now I understand what you're going through a whole lot more you know we've talked about and the'll nitric oxide but we really haven't gone over. What what the endothelium is and what it's doing so here is a diagram of a blood vessel in the middle those little peach peach colored things? Those are red blood cells. And then you'll see a layer the endothelium and then on either side either above or or below those bigger cells. Those are the smooth muscle cells. So the endothelium serves as a barrier and a sensing mechanism. And that's really enough enough to know for this This lecture this video that we're putting together. There's so much more that the feelings doing but that's its job it's to to create a barrier and to sense what's going on inside the blood vessel and to communicate that to the entire system we've talked about what nitric oxide is doing but what we really important to understand is how far are these. Chemicals can diffuse outside the source cell whether generated so what you see here is nitric. Oxide can diffuse. WHO's really freely throughout cells and it lets? It bounces something it's reacting with mostly a team so if it goes into the bloodstream. It's GonNa react react with the platelets there and react with whom hemoglobin and to form nitrate and that gives gives a half life of about one second so it can easily diffuse through several cell diameters no problem all right. Next let's look at superoxide and there you can see. superoxide doesn't travel so much and that's really due to the fact that there's so much superoxide dismutase around right there SURPRI dismutase inside the Mitochondria inside the cell and even outside in the extra cellular space. So there's lots of superoxide around to mop up super oxide however we just as we mentioned before if nitric oxide gets there before the superoxide there at the same time the superoxide will react with the nitric oxide to form proxy nitrite. And that's what we'll look at next peroxy nitrate. I try even though it gets form so incredibly quickly by the chemical reaction it can diffuse quite a bit. And that's because it react selectively. It isn't even though it's a radical and a strong oxidant. It doesn't just react with everything around it so it can bounce around from cell all to sell for a while before it finds a site that wants to react with and last. I think it's really important to have a look at the other other really well known radical the hydroxyl radical. And here. You can see how tiny its diffusion radiuses and that's simply because it is so so so very reactive that it doesn't travel anywhere. The ability of the hydroxyl radical travel is about the diameter of a small protein protein. And that's ten thousand times less than proximate travels so they're just radically different even though we call them free radicals and talk about oxidative the date of stress in this kind of general blanket terms. I think it's really really important to begin. Distinguishing the difference between these radicals and what they're doing. What their potential art they are? Not the same. You can't not treat them the same. They're radically different. Based on how quickly they're formed a and then how quickly quickly or how far they can diffuse be and then see what they're reacting with so hydroxyl radical just react with everything oxidises anything in its path. It's so reactive. They cannot travel at all. So the contrast between PEROXY nitrate and hydroxyl radical is dramatic the hydroxyl radical is formed by by a rather slow chemical process via the reaction of bears iron with hydrogen peroxide. But react so quickly with everything around it that it can only diffuse about the diameter of a small protein and contrast roxy nitrate is formed very very quickly each time superoxide and nitric oxide Clyde. However it reacts more slowly and more selectively throughout the cell that makes the biological and pathological implications of Brock's nitrate four far far more interesting because it can have a more subtle and more specific action in and around the cell so one of those is reactions have discovered recently and it was interesting to hear Dr Joseph McCulloch bring up the same fact here? We're kind of on the same page. As far as nitric oxide excite goes and that is when you combine peroxy nitrite and carbon dioxide and there's plenty carbon dioxide in the cells rate had just part of the oxidative process within the Mitochondria. You get a curious molecule called the carbonate radical and it's particularly particularly damaging to DNA so peroxy nitrite forms another radical. That goes out and KLOPPERS. DNA is isn't that interesting. This two thousand one study from the Journal of Biological Chemistry shows that the carbonate radical is particularly good at oxidizing acquainting proteins in DNA. Man peroxy nitrate is the give that keeps on giving just crazy isn't it and have you noticed something something here. All these radicals are so much different from each other and they behave in so much different ways we need to stop thinking of them simply as oxidants partisan partisan vague term like oxidative stress. They each have unique personalities a hydroxyl radical does not behave anything superoxide superoxide behave nothing like nitric oxide and nothing can keep superoxide and nitric oxide apart from each other and proxy nitrate has its own own Bikila like it's exponential multiplying effect and its ability to generate a whole host of other oxidants including our new friend the carbonate radical which has its own idiosyncratically of gobbling up wanting in DNA. So back to the two thousand seven paper from physiological article reviews they say once Affleck's of nitric oxide and superoxide is produced simultaneously in close proximity. The generation of proxy nitrate is considerably enhanced proxy nitrite dependent. cyto-toxicity is then mediated by myriad of effects including Lipid PROC sedation protein attrition and oxidation DNA oxidative damage and activation of Matrix. Mattel proteinase is is and the inactivation of various enzymes. Mida conrail enzymes are particularly vulnerable to attacks by Peroxy nitrite it and this leads to reduced. ATP Formation Might Andrea swelling and weakening of the outer mitochondrial membrane so so this allows for the flux of several pro APEP todic molecules including site chrome C and a pup. twos Shari a pop. toasties inducing factor actor in addition to its damaging effects on mighty Qendra peroxy nitrate can afflict mild to severe oxidative injury to DNA a resulting in DNA strand breakage. That's bad news this in turn activates. The nuclear repair enzyme. Par activate debated park consumes N. A. D. and you don't have time to go to any D. but it's all over the Internet and it's the kind of the the the supplement of choice these days NICOTINAMIDE riboside and so forth and so on but any deeds usually important so anyway back to to the paper. Mild damage of DNA activates the DNA repair machinery and normal cell functions. So there's only a little bit of proxy nitrate the body can handle it however once more proxy nitrate is produced and moderate oxidative in nitrous attentive. Say again oxidative and Nitro cives stress. It's induced DNA. Damage occur. The cell may be retired broken apart recycled by the pop toasties process and and if even more proxy nitrates produce and massive damage occurs the orderly process of a pop does fails to keep up. And you get necrosis instead instead of a pop toes. Is that bad news. This last scenario park over activated. That's DNA repair enzyme. So let's overactive. Aided massive amounts of any deer consumed and cellular ATP Production Collapses and is released into the extra cellular matrix tricks. So that's what that chart they're showing. It's the whole proxy Nitrite Dom damage to the mighty cadre. And what can occur with that so want Cell death by necrosis kicks in. It can be very difficult to stop. Septic shock is the classic example but I think many arsenic is patients are flirting on the edge of an a pop towse's slash necrosis crisis. So I'M GONNA go out on a limb here with this hypothesis of mind. I believe we have to go beyond the good and bad paradigm of the Reebok System. Simply antioxidants are good Free radicals or bad. Why does the body make proxy nitrate? It's a good question right. Is it a mistake. I don't thanks so so. Proxy Nitrate is by phasing physiological amounts. Mediate a tose a pop. towse's is an an immensely immensely important process. The orderly retirement of cells recycles proteins and Lipids and prevents runaway inflammation and on the other hand. Large amounts of peroxy nitrate is part of the innate immune system and mediate cell death by necrosis which targets both pathogens and host cells. So it can take four to seven days for the daft immune system to react to a novel pathogen. And if you didn't have a robust the native Younes response you would just die. So you proxy nitrate is an important molecule. The problem is proxy nitrate production action can spiral out of control mostly because of the exhaustion of anti oxidant enzymes but genetics can also play a huge role in that as well so so once that starts it can be super hard to stop then. Snack section is based on two papers two thousand nineteen article from nitric talk side and this two thousand thirteen article from the American Journal of Heart and circulatory physiology. So we're going to talk about the nitric oxide synthesis the enzymes and they all share these common traits. So this covers all three versions of the enzymes. We've all heard a ton about uncoupling. Uncoupling is a technical chemical. Turn all you need to know. Is that uncoupling beans. The enzyme is producing superoxide. Not Nitric Oxide. So the first way that this happens is l.. arginine is not available now. There's some among discussion about whether or not this can happen. And in fact I'm here to tell you it can so what happens is there can be plenty of Arjun in the blood supply so the tests come out normal there can even be enough arginine within the cell but it's being yeah sucked away. The gradient isn't close enough to the nitric oxide synthase and this team this red hime oxidized him. That does the work in the enzyme isn't stable enough and it falls apart so when the art gene isn't isn't available right there right on time what happens is the oxygen and the domain create a superoxide radical instead. Now what is going on there is in the literature. Refer to as the arginine paradox. However I just like to call it the Argentine in steel and the primary culp Brit in the Argentine? Steel is. RJ's now how Argentina's produced a lot when the immune system is tilted toward the teach to or macrophage to immune response so when the immune system gets pulled rise to that that's essentially the healing phase. That's a little oversimplified but basically the healing phase of the immune system on a larger level the liberal urea pathway can consume a ton of arginine. And this can affect the nitric metric oxide. synthase three the field NAS. It's not simply something. That's going on with the induced loss and the immune cells all right. So that's the first method of uncoupling top about now. There's a second uncoupling that happens and this involves B H Four. You're molecule and you'll see there to recycling circles Next to the beach four to the right of it and in between between there's excuse me the three and a score bait so as be h for donates an electron to this process it becomes a radical called three as long as it is reduced back to be h four. There's not a problem a score bait which is bioactive a form of vitamin C.. Enables this to happen now. This is the very very very important role a beach for nitric oxide production so as we talked about earlier up to the top left in the reductive domain the NASD PH donates electrons. Now this electron in terms terms of chemistry biochemistry moves down to the opposite side slowly. And if it doesn't happen fast enough the hime doesn't stay stable and spits out the superoxide so be h four. Is there to temporary. Lend temporarily lend an electron so as long as a beach. Four is there the hime is stable enough long enough to oxidise the arginine to citrulline. And then what happens if there if the beach. Four after donates electron isn't able to recycling. It's stuck it's B h three then. The arginine doesn't matter how much they're the Arginine can't get oxidized. It can't get transferred there to the site of the enzyme that makes us. This all happened fast enough because the hime is so unstable and it's para state in his oxidized state that it spits out a superoxide so so just like Jane this case though it the Argentinians right there but the Hemas so unstable it can't reach out and grab the Janie. That's what's the beach. Four NAS uncoupling so to recap. We've got the Argentine steel when there's no arginine available well then we have beach for deficiency. So sometimes there's just not enough beach for being made by the body was certain deficiencies or pathway deficiencies. There and this this case the nitric oxide synthase home audemer isn't going to be formed or stay. Formed long enough to make enough nitric oxide. So in these cases we can see very low level production of nitric oxide. The other thing that happens is there's a lack of reduction capacity inside ride the cell essentially the cell can't keep up with all the oxidative stress and the nitric oxide synthase starts to fall apart and produce superoxide instead right. So that's the uncoupling and we know now because of what we've been looking at the when you've got the superoxide being produced next next to nitric oxide magic one cycle the enzymes producing superoxide and they kind of recovers a bit and the producers nitric oxide. They're going to combine immediately right and form as a proxy nitrate. That's bad bad news. All right so we're entering the homestretch. You've done a great job CBS. So far hang in there. We're going to bring this all home. You know when I first Dr Bob Miller and invited me to present it as conference he said. Can you do this hour. Our said no problem then I started doing some more research. I called the Bagga said Bob. I think I need another half hour. Let us look at this mouse l.. Study it blew my mind. The two thousand nine Japanese study published in the circulation journal. And it's open access so take your time. This is well worth reading. This is where he got the concept of team nitric oxide. This study shows that nitric oxide citzen faces work in tandem and will compensate for each other. All right here is a graph showing basically how many of the mice died so the the red steps at the bottom is is the is the worst case and other cases are Not Quite as bad as you can see so what they did. was there trying to find a model a mouse model to mimic doc. Human heart disease particularly heart attacks so they started out by taking out the nitric. Oxide faces genetically knocking out and then they started with endothelium so they started knocking out one enzyme at a time thinking. Okay which one of these most important so they started with us and when they knocked that at one nitric oxide enzyme. They weren't getting the model they were looking for. So they started deleting two enzymes at a time when the various combinations nations and that was a little more what they were looking for but it wasn't until they took out all three nitric oxide enzymes that the mice started did having heart attacks in the same way that human beings do what they learn from. This is that the NAS enzymes work together as a team and compensate eight breach other so this is huge. You can't pigeonhole one NAS enzyme as only having one effect. Don't make that mistake somehow. There's crosstalk going on between the enzymes and they worked together to maintain nitric oxide levels. So if you have a patient with heart disease and you're looking at genetic snips you can't just assume because they don't have Inau snips right NAS three snips that they're okay. You also have to look at the other NAS enzymes times as well so what you see here is cross section of the mouse hearts on the left is the wild type. You can see how nice and clear it is. And there's the cross section of the coronary artery. It's beautifully open on the right hand side. What you see is a heart from a mouse that had all three nitric oxide? Synthase aces knocked out. That's the Tripoli knocked out NAS mouse and the blue and the top part in the heart that's all narcotic tissue from the heart attack and down below what you'll see. It's the same type of coronary artery. But you can see see the blues fibrosis of the body's trying to repair damage being done. And then you can see all the narrowing going there right. That artery is really blocked up and that's because of tissue growth after all the damage being done all right so let's this is. A graphical will abstract of what the study found so basically a defective nitric oxide. synthase system activates the Renan NGO tencent system him and if you remember back to the beginning we were talking about the EPA study BPA also activated the Renan Ngo tencent system so a lack of nitric oxide or a Tux. ity Has the same effect that to me is mind blowing so we know with this first bucks here the bachelor dysfunction that that's going to happen without up nitric oxide right. That's a given these other things. Though I've found were super fascinating donating and the next is when we don't have enough nitric oxide. There's not enough of hormone called ADIPONECTIN. ADIPONECTIN connecting is produced by our fat cells and there is a fat layer around the blood vessels probably as an energy source but it also oh produces nitric oxide. There is endothelial. Nitric oxide in these fat cells as well and obviously these fat cells are sending out hormones Food and talking to the rest of the system here. So when there's not enough Adiponectin we know this is greatly involved with Metabolic Syndrome so not only getting metabolic syndrome because the activation of the round Andrew tencent system but you have low adiponectin and that's contributing gene to it as well so it's no wonder that your patients are obese struggling with blood sugar struggling with hypertension all those metabolic syndrome Symptoms that we see day in and day out the next thing that they saw with the triple knockout mice is there's higher levels of LDL right. That's comes as no surprise. But also with this charge you get the idea that simply a strategy of luring. LDL is not a good idea. So if you're stuck still still stuck on the cholesterol paradigm heart disease. It's time to move away from that. And last this was super crazy fascinating without nitric oxide controlling and down regulating mass cells. The vessels began to invade the heart. And they lead to coronary spasms. And that was one of the triggers for the spontaneous myocardial infarction. So it's just crazy. How much patrick outside plays into all these systems right when you take away? Nitric oxide is like taking away gears on a mountain bike and eventually the body gets to a condition. Where just can't compensate all right? So let's go a little bit deeper into the pathways that get disarray with nitric oxide synthase dysfunction. So we're going to put this all together. Okay here we go so this time only going out a little bit on a limb all all. This information has come from the studies. We've looked at but I put it together in a slightly different way and included couple different things and I think it's going to really make this bring this all together for you and help you make sense of it. We're going to build a chart so first thing and this is Scott Zero what I want to say controversy to it at the bottom. We've got NAS three and Theo Nas makes nitric oxide right. No that's right. We don't have to argue about that. All and above it we know that nitric oxide down regulates mast cells and down regulates knocks one and knocks to if not the other Knox's as well in and the Knox enzyme is the NASD Ph oxidise and any oxidation. It's only job is to make superoxide and and is triggered as an immune response K.. So that's our starting foundation here. Now we learn from our first study that BPA INCREASES NGO tents attention to and not mentioned in that study but from other studies and your tencent to boost the knox enzyme so that creates more superoxide. So we've got a major source of superoxide here. We also know that nitric oxide is being made so when you put superoxide and nitric oxide together you get peroxy nitrite. The dreaded Ono chemical it's chemical Shorthand his own. Oh and that hat. PEROXY NITRITE CAUSES DOWN regulate speech for right. It causes problems with beach four. The forecast oxidized to be h two or three. Put them both in there because if the eight fours oxidise all the way down one more step after the BA three becomes beach too and has to go somewhere else to get a refurbished so to speak to be reduced back to be h four and this all leads to the NAS uncoupling remembered that. Study those charge that I showed you about Nas uncoupling so onc- uncoupling is happening. That leads to more superoxide and a reduction in nitric oxide so once the nitric oxide synthesis are uncoupled. What you're going to see is more superoxide and less nitric oxide bad news for your coronary system? Now if there's not enough nitric oxide what happens eventually. Is that the mast ask cells and the Knox enzymes are no longer regulated particularly when the Knox enzymes get going like crazy. They start start. Something called the NAACP. This is Bob Miller's term and we need an ADP for all kinds of reactions in the body and a DP h donates electron in so many different pathways. It's critically important. So it's getting burned up by the NASD PH oxidise the Knox enzymes. Then you don't have enough and ADP H to go around. In fact what Bob Miller talks about is is that an ADP H.. One of the emergency pathways. For making any DP. H is the body will take trip the fan to create an ADP H.. And when that happens then you start getting wired and tired right okay. And when mass cells aren't regulated recuperated you get excess histamine dump you get Maso activation and interestingly enough histamine up regulates NAS three so here you have uncoupling happening of the KNAUSS. You have an increase in the NAS right and we showed here that the BPA increases NAS is eight point seven percent. Now you've got. I'm sorry not eight point seven percent. Eight point seven fold. You've got histamine increasing us so some of that is producing some nitric oxide. But but it's income uncoupled as well right so it's also producing lots of superoxide so this is just a peroxy nitrate machine going on there and we know that the proxy nitrate also when it meets up with the carbon dioxide makes a car boxer radical that leads to DNA damage and and wants the DNA damage happens we get the park activation more. Na De Depletion so we got the NASD still going on any deed depletion which is is also a form of the NFC steal this leads to necrosis and necrosis. Those of you who know is a massive massive inflammatory flammable Mary trigger so when the body senses proteins. That shouldn't be in the extra cellular space. It gets very excited and pays attention. And sends ends the Innate Immune System to go take care of business and that causes a massive inflammatory cascade and against septic shock is the classic example Sampler that where it spins out of control. But in this case what we're talking about is damage done to the heart disease. You can see here that between the Histamine and the inflammation nations damage done that there. Are you GE- Problems. So my bet is that you have many patients coming into your office. Where their heart's coronary? Mary arteries look something like our poor mice. Here let's review this toxicity. Nas coupling proxy nitrate DNA damage mastel dysfunction the steel and cardiovascular disease. That's essentially what I've shown you right. That's if we could sum up this video in one slide. That would be it but it was important to take you on a journey to get here. They're all related. Can you see that now. The toxicity causes Nelson coupling nothing. Coupling Calls Proxy Fight Trade that causes DNA damage. The proxy nitrate also lends lends itself to mast cell dysfunction of the lack of nitric oxide included in that It also leads the NAACP because the Knox enzymes going nuts and that's going to reduce the efficiency of the nitric oxide synthase as well. 'cause there's not an donate the electron and all this bundled up is creating cardiovascular disease in your patients now the other thing is I'd like liked to say that NAS uncoupling is such a misunderstood term and it doesn't really have the emotional impact so I would like to call this whole all thing. The nitric oxide steel so not only is proxy nitrite being formed but it stealing nitric oxide. So you've got at this explosion of inflammatory process. You don't have enough nitric oxide. Everything just goes haywire This was really cool. Why thank you here? I have a fan club in the family. You're very welcome. Father Club indeed What really blew my mind? was that whole nitric oxide in Peroxy acce- nitrate coupling uncoupling uncoupling. And how much the inflammation increase like. You're saying it was like a million fold old increases like well. Let's back up there. What's important knows once peroxy nitrite starts getting formed and the body and basically anytime you're immune system kicks in? That's going to start or when the cells are under oxidative stress then or nitrous eight of stress. It's any and let's say any type of stress when the seals are under stress PEROXY nitrates starting at formed and because the way peroxy nitrite interacts with other compounds in the cell in and around the cell. What happens is instead of just increasing what you would think like on a Linear it it gets Algorithm Iq the inflammation just really gets ramped up at the body does not have the resources to combat back down again. That's when you you're stuck in bed and every joint hurts and just won't stop. He can't get it to stop right and that's why that's why they do you prescribe hormones. Steroids right thank you prednisone. And things like that prednisone shuts all those pathways off as the problem is if you've got a chronic infection or any type of infection also shuts down your immune system caused this is a function of your immune system that said if things are really stuck assure those apprentice oh might be advantageous. I'm not you know they're also urban waste. Do I start with urban pathways personnel. The natural stuffer but sometimes things are so bad. Then you just need to back it up with some sort of antibiotic or Erbil antibiotic the Prentice Omer talking about. But that. That's the important part to nose wants. This inflammatory cascade gets cranked up before your body's ability to cool it off on this Chinese there's too much heat it just goes off the rails and it's really really really difficult to shut down as I say really enough really difficult to shut down so that's the answer to question. It is the answer to my and I think it's so much suffering that's going on it's like the damage is done so you can. You can have the same symptoms that you had because of this inflammation when you were infected. Even after the infection's gone because because inflammatory cascade has not been shut down yet and damage right so so a dying cell. That's not retired properly. That goes into nick grosses instead of a pop doses is going to start off as much inflammatory signaling as an infection will bill so you can you can get this cycle of damage and inflammation ages. Won't let up whether or not the bugs still present whether it's hiding behind a biofilm film gone inactive and that's why there's so much suffering out there right so you can keep throwing antibiotics at it. And that's not gonNA help you need to cool these systems down you need. Could you nitric oxide back online and back on track K.. GonNa give a kindergartner summary of that okay. Okay if if you don't get your inflammation in your body under control you're gonNA keep suffering. I think that's a good way to some yes. I think that's a little more well said and actually really it's much more difficult to synthesize that down to one sentence so I'm going to say that's not kindergarten that's like PhD level simple. The simpler simpler the better. All right if you like what we're doing here at Lime Ninja radio hit the subscribe button at the bottom of the episode. And even more importantly scroll all the the way down to the bottom and leave us a review. 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