Episode 93 - Nitric Oxide

Speaker 1: 00:00 This is Dr Chad Edwards and you’re listening to podcast number 93 of against the grain on Nitric Oxide.

Speaker 2: 00:05 This is Diana Edwards and I’m here with Dr Chad Edwards and we’re continuing the discussion of cardiovascular disease. Now. In our last podcast, we actually discussed endothelial function and its relationship to cardiovascular disease. Now, if you haven’t heard that one yet, you may actually want to go back and listen to it first so that you have a much better foundation for what we’re talking about today for episode 93.

Speaker 1: 00:33 So we have a couple of visitors in the recording studio with us today. We have doofy and Gizi, the two dogs, and we’re also known as Lucy 1 and Lucy 2 no joke. That’s really what their names are, Lucy and Lucy. Um, and so if you hear any extra noises or barking or sniffing or grunting or anything like that… You never know. Um, okay. So today we’re, we’re tagging on with the endothelial function discussion that we talked about last week. And this is one of my favorite topics. I mean, I love this topic because there’s a lot of cool things that you can do here that can really change cardiovascular disease and a lot of things that we can evaluate that are not evaluated by traditional medicine, which opens the door wide for revolution health patients, uh, and you know, what we do in our clinic from a functional medicine perspective, we are driving down to what is causing the problem for hypertension, cardiovascular disease, atherosclerosis, all kinds of things.

Speaker 1: 01:40 Uh, and, and we can do something about this. So the endothelium, as we talked about, just to recap a little bit, the endothelium, uh, the, um, the lining of the artery is called the endothelium and it maintains vascular health. And it does that by the endothelium, does that by a balance between five different things, a dilation and constriction, growth, inhibition and promotion, antithrombotic and prothrombotic effects, anti-inflammatory and pro inflammatory effects and antioxidant and pro and, and pro antioxidant bad pro oxidants. There we go. That’s a hard one. I wasn’t getting my merge quickstep and pro oxidant effects. So the endothelium has to balance all of those. And you know, you have to be able to have some vasoconstriction, but you also have to have vasodilation. You need the right amount at the right time. The problem is standard American diet, Standard American, a sedentary lifestyle, uh, the, the toxins to which we’re exposed, all kinds of things tend to tip the scale more toward cardiovascular disease and we want to tip it the other way.

Speaker 1: 02:48 So nitric oxide is one of the most essential components to promote, uh, the, uh, called the left side of the teeter totter, which the dilation and the growth inhibition in a thrombotic antioxidant and inflammatory effects, um, and the other things are counterbalanced by a number of things that we may talk about and some other podcasts. So nitric oxide is one of the most important molecules for overall endothelial health and function. So it’s pretty cool stuff and that’s, and that’s great. And now we kind of understand some of the things that is responsible for, but what exactly is nitric oxide itself? So nitric oxide is a colorless, odorless gas, and it has a very, very short half life. It’s only like a, you know, a couple of seconds and there are some things that you can do to prolong the life span of nitric oxide, but it is simply a gas, uh, composed of a nitrogen and an oxygen, so it’s not nitric oxide which is into, oh, and it’s not nitrous that you use, like in your car to, you know, make it go faster and all those things.

Speaker 1: 03:55 What do I get at the dentist that’s nitric oxide. I’m sorry, nitrous nitrous oxide, one x and us. Sounds like a relationship problem. Too many eggs in us. Uh, so, uh, no, that’s nitrous oxide into. Oh, and wait a minute. Yeah. So regardless in, oh, is nitric oxide and it’s a gas composed of those two things made in your body short half life. And it helps balance, um, the, uh, the effects. So, uh, the nitric oxide is actually produced by the endothelial cell and there are three different enzymes that make it and it’s called nitric oxide synthase. And there’s an NOS 1, 2, and 3. NOS3 is also called endothelial nitric oxide, or eNOS. And the nitric nitric oxide does is it actually binds to soluble Guanylyl cyclase or SGC.

Speaker 1: 04:55 So I’m getting biochemical geeked out, just bear with me for a second. I won’t get too deep here and Diana will always bring me back if needed. Um, but so it binds to that stuff, um, which is an enzyme. And the purpose of that is to increase a chemical called Cyclic GMP. Now most people don’t care about that. Um, but if you have erectile dysfunction and you have endothelial dysfunction, then you should care about it because the phosphodiesterase enzymes work on some of this stuff. So, you know, like your viagras and things like that, they work on this stuff. So Cyclic gmp then acts on cyclic amp. Cyclic amp is what actually does a lot of the effect, especially with relaxation and a dilation. So when you want an erection, you want to be able to have dilation of those blood vessels. Um, and that is, you know, the effect of nitric oxide is that it affects cyclic gmp, cyclic amp.

Speaker 1: 05:53 And the, uh, the Phosphodiesterase enzyme is the enzyme that breaks down or deactivates cyclic amp and the phosphodiesterase inhibitors like Viagra and Levitra and Cialis and all those things are called phosphodiesterase inhibitors or PDE-5 inhibitors. And so they, they block the breaking down of cyclic amp, which means cyclic amp is there an active longer. And what that means is that you have more vasodilation. Yeah. And so if you have erections and, and endothelial dysfunction, then the phosphodiesterase inhibitors can help with that and help with some vasodilation. And also if you go to the emergency room and you have chest pain, uh, then one of the first things that we’re going to do is, or if you call the EMTs or whatever, therefore, one of the first things they’re going to do is they’re going to give you Nitroglycerin, you know, scored three times, squirt under your tongue, or put a little tablet under your tongue and let it sit there.

Speaker 1: 06:55 That stuff works to increase nitric oxide. So the reason that they say don’t take Viagra if you’re using these other drugs is because it will result in so much vasodilation that you lose all of your blood pressure and pass out and you know all those so you can have a profound hypotension. So you have to be very careful in using those things in combination. Trying to make sense. Absolutely. So now that we kind of understand what nitric oxide itself is a, what exactly does that have to do with the endothelial function itself? Yeah. So as we talked about, endothelial function is extremely important for cardiovascular health and nitric oxide is one of the most important things that maintain into theoretical function and endothelial dysfunction where the endothelium is not functioning appropriately, uh, is, is often due to a loss of the relaxing, relaxing factors like nitric oxide.

Speaker 1: 07:54 Nitric oxide is one of the primary ones, um, and slash, or an increase in the things on the other side of that teeter totter. So, you know, you got relaxing factors and constriction factors. And so here nitric oxide is one of the major relaxing factors. And the increasing factors would be things like endothelial angiotensin two aldosterone, uh, those kinds of chemicals that are beyond the, beyond the podcast for today. So nitric oxide loss, uh, not having enough as generally due to one of five or six things, so decreased endothelial nitric oxide synthase activity or enormous or decreased cofactors for nitric oxide synthase or attenuated nitric oxide release, meaning that you can’t, um, there’s something preventing you from releasing nitric oxide or decreased nitric oxide bioavailability Bay bio availability, or increased nitric oxide degradation as a whole lot of words. You did it. Well, I don’t know.

Speaker 1: 08:53 Let us know what you think. Give us your comments. Um, so the nitric oxide again, has a very short half life. So there are some chemicals in your body that serve as reservoirs for nitric oxide. And, and to be clear, this stuff when it’s made, it’s like instantaneous flash paper basically. That’s kind of what it is. It’s, you got the signal, you make it, and it’s gone. I mean it’s, it’s really, really fast. It’s very short. It’s amazing. It has any kind of impact at all. Right? But so that just kind of underscores the importance of, of all these systems and making sure that biochemically, those things are firing on all eight cylinders, um, but you do have chemicals that will serve as nitric oxide reservoirs and there thiol type chemicals and most people aren’t going to care about that. But things that we often recommend at revolution health, they’re going to be things like a inositol assisting, which we use for a number of things.

Speaker 1: 09:42 Uh, they, they’re antioxidants, they help the liver support, detoxification, those kinds of things. So we often recommend to that as well as glutathione, which those two things are thiol with aisles are like a, it’s a sulfur centered kind of molecule smell good. Yeah. They smelled like rotten eggs. If, you know, when somebody comes in for glutathione to be clear, you’re not going to smell, leave smelling like rotten egg. It’s if, when we’re doing something, if we get it on her hands, it smells like rotten eggs. It’s, it’s, it’s pretty cool. And we all know and you know, the other thing is if you go to, if you. These are like all emergency room stories today, uh, so if you overdose on Tylenol, that tylenol causes damage by a oxidative damage and your liver, and so we will give in a subtle assisting in the emergency room, uh, either oral or ivy because that helps to regenerate glutathione, which is the master antioxidant and prevents the oxidative damage that tylenol would cause.

Speaker 1: 10:45 So those are some things that serve as a reservoir and can prolong the activity of nitric oxide. Take it from where it’s a half life of a couple of seconds up to even minutes up to like 10 minutes or so. So that stuff can really make a big difference. And if you’re deficient in glutathione deficient and inositol assisting, then you may have a higher risk for cardiovascular disease, albumins another one that kind of holds onto nitric oxide and can be beneficial. Beautiful. So we now know how the relationship is between that and the endothelial function. How exactly does it work in that relationship? Yeah. So, uh, the, the effects of nitric oxide are going to be things like vasodilation against, on the lefthand side of that teeter totter. So vasodilation causing your blood vessels to open up a, it’s anti atherosclerotic, that’s a big word.

Speaker 1: 11:38 So your cardiovascular disease, you have atherosclerosis or plaques in your arteries and there are a number of biochemical mechanisms by which this stuff is. This nitric oxide stuff is anti atherosclerotic, so very important, very cool stuff. Want to make sure that you have good levels of nitric oxide. In fact, this stuff was the subject of a Nobel prize. I think it was 1998. Um, uh, what was his name? A narrow, forget his first name, one the nitric oxide or won the Nobel prize for, for some of the stuff related to nitric oxide. Nitric oxide is also anti-platelet. So, you know, we take aspirin, you know, especially around cardiovascular disease, we think aspirin has been official. You get these platelet plugs and so you, you don’t want too much platelet stuff. Nitric oxide can help with that anti growth. And when you look at how atherosclerosis works and uh, the blood vessel with, with dilation and what we call hypertrophy or getting thicker causes the Lumen to kind of shrink.

Speaker 1: 12:37 So growth in that regard as bad. So nitric oxide is anti growth and then finally nitric oxide is an antioxidant and it works specifically with Super Oxide Nin. It works out with some other things, but it also decreases oxidized ldl. And if you listen to our last podcast, we talked about how ldl in its native form is not atherogenic, but when it’s oxidized or damaged in some other way, it is identified as abnormal. Your body then mounts an inflammatory immune response and goes in and tries to clear that stuff. And so nitric oxide decreases oxidized Ldl, which is very, very cool. So it’s got a lot of mechanisms that are working against cardiovascular disease. Nitric oxide is good stuff.

Speaker 2: 13:24 All so now you have had this huge platform on this amazing nitric oxide and and told us all these great things. It’s got a short, short half life. So we want to make sure that we have enough of it. So how can we make it? How can we make sure we have enough?

Speaker 1: 13:38 Yeah, there’s actually two different pathways. The pathways through which we make nitric oxide. The first one is the L-arginine pathway and there are a lot of workout supplements and things like that that have L-arginine in it, and I actually used to prescribe a lot of L-Argentine thinking that that was going to and help enhance nitric oxide because because of this mechanism right here, now there’s some, there’s some parallels in that theory, but basically lr. Janine is a precursor to nitric oxide and the endothelial nitric oxide synthase. The nos works on L-arginine to make nitric oxide. So the theory is that you don’t in most in many reactions in chemistry, biochemistry, and the human body. A testosterone is a good example. When we give testosterone, the higher your testosterone, the more you’re going to convert it over to estrogen, so the more you increase the substrate, the more you increase your, the the final outcome, and so it drives the reaction to the right.

Speaker 1: 14:40 That is what we call it with with nitric oxide. That’s not the case. You can take all the L-arginine in the world you want, and there is a ceiling effect. In fact, nitric oxide synthase enzyme has what’s called a Michaelis-Menten constant or a km, and in biochemistry terms, that means above that level, it doesn’t make any difference how much you give it. It’s not going to choose. Exactly. Uh, and so that’s Kinda how this enzyme works. Plus there are like 10 different cofactors for a nitric oxide synthase that if those are not all optimized or if there’s any piece of that missing that the cause is what’s called uncoupled and it doesn’t work anyway. So giving L-arginine can actually cause a problem in some of those patients, especially if they’re nitric oxide synthase, is uncoupled, so not [inaudible] may be beneficial, but it may be detrimental because of this mechanism and it’s what we call the L-Arginine paradox because giving it can actually cause more of a problem even though that’s what exactly.

Speaker 1: 15:50 So it’s a good idea if you’re going to take an L-arginine, that you have that, um, L-arginine level measured, which we do with all of our patients at revolution health. Um, so then there’s also, there’s a, an enzyme called arginase that actually breaks down L-Arginine, and that’s important for a bunch of reactions that we may end up having podcasts about some of this stuff later. Um, so probably not that big a deal for, for um, for our listeners today, but there is a chemical called ADMA or asymmetric dimethylarginine, which is a big chemical term. We measure that on most of our patients. And the cool thing is, is that that chemical is a, is a competitive inhibitor of the enzyme, so it makes the enzyme think that it’s L-arginine, but it’s not. So the more of this ADMA you have, the less l-arginine can plug in there and it doesn’t make nitric oxide when the ADMA goes through there.

Speaker 1: 16:46 So it is an excellent, uh, call it a biochemical surrogate for nitric oxide. The higher your ADMA, the less your nitric oxide. So it’s a really good test to be able to kind of determine where are you in that pathway. And there are multiple things that will influence. Well, there you go. There’s a dog bark. Yeah, that’s probably because of the other. Lucy was getting on her nerves tiring to biochemistry, right? Yup, exactly. So the ADMA piece is very important and can explain a lot of things, um, you know, with a vascular health and nitric oxide and those kinds of things, but after the age of 30 to 35 years, so you know, people that are in their forties, they’re probably making most of their nitric oxide from a different pathway. It’s called the nitrate pathway, then through the yell, arginine pathway. And there’s a lot of, a lot of things that will influence that pathway as well. You have to make sure that you’ve got lots of good green leafy veggies and you got good nitrate intake and the standard American diet, you know, the burger king, Mcdonald’s Diet does not have a lot of those things. So you got to make sure that you’re getting good intake of, of those things as well. So, um, yeah, it’s two different pathways.

Speaker 2: 18:02 Well, at this point. So, um, you were talking about the average age of about 40 over 30, 35 years of age and they’re switching those pathways. Does that mean that the Lr Janine is done, so even taking the Lr Janine supplementation, is that going to open that pathway backup or are they just purely nitrate?

Speaker 1: 18:20 No, it looks like we suspect that they’re pretty much going to be more nitrate dependent. Uh, you still want to measure, um, if, if, if I get a patient and I measured that lower their L-arginine and they’re deficient, then we still might supplement with L-arginine, but we have to understand that there’s a ceiling effect on that and that can go through a different pathway that causes problems. So you have to be careful with that.

Speaker 2: 18:45 Good. Of course in certain situations we are still going to want to increase our nitric oxide. So how exactly do we go about that when it is appropriate?

Speaker 1: 18:54 Yeah. So I mean, and really for most Americans in and for most of our patients a revolution, we do want to increase nitric oxide. That’s a, I can’t find a time where we’re going to have too much of that. Even though you want balance that. The reality is is that we, we need good nitric oxide. So the first thing, measure your L-arginine, and if it’s deficient than take Lr, also consider supplementation of L-citrulline and other methyl Argentines. Uh, but again, you gotta be careful with that pathway, but that’s, we keep that in mind. Number two, make sure that you’ve got good amounts of dietary nitrates, so nitrates are going to be in your green leafy vegetables. They’re going to have more of your nitrates beet root powder, excellent choice for this pathway and making nitric oxide. This is enhanced with vitamin C and polyphenol.

Speaker 1: 19:47 So polyphenols are going to be your vegetables and things like that. We have a supplement at revolution health. You can certainly get it online as well, called Neo40. This stuff was formulated, if I understand correctly by Nathan Brian, Dr Brian, and he has written several books on nitric oxide and its effect on the human body. And there are studies on this stuff. And in fact, one study showed that, uh, taking Neo40 lowered blood pressure, 10 points a systolic blood pressure, 10 points inhibited platelet aggregation by 20 points and had some flow media dilation. I think by 30 percent as well and that effect we’re seeing within an hour, so very quickly we had some good benefit, uh, in, in, uh, in those systems. And additionally, it also lowers your CIMT which is the carotid intimal medial thickness score, which also goes along with some cardiovascular disease risk things.

Speaker 1: 20:46 So we suspect that this is because of the overall vascular health being improved by increasing nitric oxide. Now the next thing that you can do is increase enough activity that enzyme that makes nitric oxide. Uh, and there are a few ways to do that. I’m going to use a bunch of big words because I don’t know how else to do it. I’m a Tetra Hydro Biopterin or bh four. It’s kind of a full eight, a derivative, a chemical that is involved in methylation and things and that helps that enzyme to work gludethyon. We talked about that as a reservoir or allowing the nitric oxide to kind of bind to it and being a reservoir for it. A fad, Flavin Adenine Dinucleotide, I think I’m saying that right. And, and cal module and as well as Co substrates such as NADH. Now we also have a supplement at revolution called Benagene, which helps the NADH/NAD+ ratio and as shown to be beneficial for a lot of things.

Speaker 1: 21:42 And we’ll definitely need to have a podcast about that one. Um, and uh, so I’ve benagene, the chemical name is oxaloacetic acid, which is part of the, um, uh, the krebs cycle and that, um, we suspect is going to have some increase on the, uh, the activity as well. You can prolong the activity of nitric oxide. And again, we talked about glutathione and inositol assisting and then there are some other things that you can do to help increase nitric oxide. There are some medications that you can take. I’m not a big fan of statins, but they do have their place in some patients and that can increase nitric oxide. A aspirin has been shown to do that. Ace inhibitors like Lisinopril, which is not my favorite one, but things like bananas approval, um, you know, those kinds of things, uh, arbs or angiotensi receptor blockers, your direct renin inhibitors like a spironolactone and I think indapamide is the other one, a calcium channel blockers are the dihydropyridine calcium channel blockers, and for women, estrogen can help increase nitric oxide.

Speaker 1: 22:43 So there’s a whole litany of things that you can do at revolution. We want to make sure that we evaluate those pathways so that we understand what needs to be worked on, what’s already doing well. And we fixed the ones that are wrong. Perfect. At Neo40 I’m thinking it’s the new Viagra that. Yeah, and we’re going to talk more about that kind of stuff in one of our future podcasts. A little teaser. There you go. We’ve got a big. If you’re Viagra isn’t working, we’ll explain why. Exactly. Alrighty. Thanks guys. Be sure to go on to itunes and give us some, uh, some ratings. Let your friends know about the podcast and it’s not good. Let us know. Uh, otherwise, other than that, we’ll see you next time.