Intro and Deep Dive on Nitric Oxide Production and Vasodilation

Douglas Kalman: So, Joey, if you don't mind, while we're talking about pre-workout products, and we just think of the theme to start with.

Nitric oxide production, vasodilation, why is vasodilation or any of that important for somebody that wants to get the benefit of a pre-workout. What's the benefit of enhancing vasodilation through nutrition?

Joey Savage: So, when it comes to vasodilation, it's usually not the first thing that you think of when you think of a pre-workout. Like, the first thing you're really going think about is whether this is a caffeinated drink something that's going to motivate me to go to the gym and get off the couch, but then there's secondary characteristics of a pre-workout that start coming into play, and the most common one probably is the vasodilation concept.

It's usually done through taking ingredients or using ingredients in a pre-workout that increase the molecule nitric oxide which has an impact on blood vessel walls, causing them to dilate, which does a whole host of different things. It enhances nutrient delivery if there's anything co-administered with it, so those will get delivered to muscles a lot more efficiently.

It also enhances oxygen delivery, which is the whole point of oxidative respiration that's going on at the cellular level. So, what this is doing is it's fueling all these different metabolic processes to happen at a much more enhanced rate. But then there's the cosmetic reason for increasing nitric oxide and causing this vasodilation, because it puts more blood in the muscles. It may seem like it's a temporary or transient effect, but putting more blood in the muscles just causes that little bit of extra swelling. People like how they look in the mirror, but it also enhances the mechanical micro-tearing process of what's needed in the physical stimuli for increasing protein synthesis in that post-workout window.

So, enhancing blood flow does aesthetically good things, it does mechanically good things in helping the body start to stress itself out so it can adapt later on, and then, there's also that nutrient-oxygen delivery angle to it, where it helps your muscles perform better.

Kalman: With that, I know that some of the research with nitric oxide modulating ingredients—not pharmaceutical, nutritional—have actually shown that when you enhance NO₂ bursts and enhance nitric oxide, that you actually make cellular respiration more efficient.

So, the body is more efficient at using the energy for what it's doing, and more efficient at getting you to your goal… so now they're able to do more reps with less work, or more load with less work. They realize their strength is going up, or their energy levels are going up, because they're also getting greater oxygenation. Like you said, deeper delivery to the tissue, right?

Savage: More endurance with less fatigue.

Kalman: Right, right, which I think everybody wants more endurance and less fatigue.

So, Katie, turning to that, more endurance and less fatigue. Pre-workout, and Joey mentioned this, pre-workout supplements often contain an essential ingredient: caffeine. What can we do to differentiate caffeine’s effects vs nitric oxide promoting type of effects for pre-workouts.

Katie Emerson: Well, I think they go great together, right? Like, they're doing different things, different mechanisms. As Joey said, those nitric oxide boosters, they're meant to increase that blood flow, the nitric oxide production, the muscle pump, while the caffeine, that's really stimulating our central nervous system. There's a ton of research on caffeine and performance, and we're getting increases in alertness.

There's reduced perception of fatigue and reduced perception of pain, which I think is one of the coolest things, especially looking at a performance outcome measure.

There's a mental aspect to it, but there's also a physical [aspect]. Can you push yourself one step further to true failure? I always have caffeine before my workout. It's not necessarily giving me energy because that's not the mechanism of caffeine; it's blocking adenosine… but it also increases your adrenaline that's going to help stimulate my sympathetic nervous system, that fight or flight.

Yes, I'm going to get an increased heart rate and blood pressure, but I kind of like that. I kind of like feeling a little bit amped up and jittery. It helps to improve my physical performance.

Kalman: Well, I think there's a difference between feeling amped up and then somebody having jitteriness from, let's say, having a Vente Starbucks, right, which is a 20-ounce Starbucks…If you get a 20-ounce coffee, I'm using them as an example, public data saays that's over 500 milligrams of caffeine. According to the FDA, anything above 400 milligrams [creates the] potential for the jitteriness that kind of makes you feel uneasy, vs what I think you're talking about, the amped up feeling like: Let's go!

Emerson: I'm glad you pointed that out because there is a distinct differentiation between 100 to 200 milligrams vs that 400 to 500 milligrams. I don't want to feel like my heart is pumping out of my chest and I'm going to fall over. I know some people crave that, but no thank you. I'll take the increased motivation from that increased dopamine activity that you get with caffeine.

Kalman: More is not always better.

Emerson: Totally agree.

Kalman: So, Joey, let's continue on that theme, but now let's talk a little bit about common ingredients…that are nutritionally either through the diet, through foods, or through supplements—because supplements are a subset of foods under regulation—that are known to promote nitric oxide burst or nitric oxide metabolism?

Savage: Usually when it comes to boosting nitric oxide, there's what I would call “the classical set” of amino acids that are involved and arginine is seemingly one of the most direct ways of producing nitric oxide, even though it comes with a caveat. There's an enzyme called arginase that kind of breaks it down pretty rapidly in the gut. So, the bioavailability of arginine has been questioned in recent years, so a lot of people shifted to using its downstream metabolite, L-citrulline. And L-citrulline is not subject to arginase metabolism. It's also a downstream metabolite of arginine, so it will pass into the blood and get recirculated through the nitric oxide cycle into becoming arginine and producing more nitric oxide. Those are the top two candidates in that category.

After that would be consuming nitrates of any form. And that could be vegetable nitrates that come from beets, or spinach, or any of those, and then there are also different nitrate salts, like amino acid nitrates. In some cases, you could get arginine or citrulline nitrate, where you're getting the benefits of those amino acids bonded to these different nitrate salts, even though it takes them a little bit longer to produce nitric oxide.

So, the thing about nitrates is you have to in a sense consume them twice, because they're a strange molecule that hasan interesting relationship with the body. You consume it, it goes into the small intestine, it gets recirculated back into the tissues of the mouth, where it gets secreted, where the oral microbiota will reduce that nitrate into nitrite, it gets swallowed again, and then converted into nitric oxide. All that transit takes an hour on the short side of all that happening to convert a form of nitrate into nitric oxide.

It's common that you will see these in combination with amino acids, because the amino acids will provide the first round of nitric oxide production, followed by the nitrates after that, so you get a longer duration of nitric oxide production when you combine them. But there are other things that are proximal to this. There are different plant polyphenols that can potentiate nitric oxide production through increasing the genomic expression of certain nitric oxide synthase enzymes, which are the enzymes responsible for taking those amino acids, like arginine, and then turning those into nitric oxide.

There are other things you can use, like the amino acid glutathione which also helps conserve nitric oxide by forming another downstream metabolite called S-nitrosoglutathione, so it's like a stored form of nitric oxide perpetuating the production even further.

Then there are other simple things, like…tea polyphenols, there's cocoa polyphenols, there's citrus polyphenols, all those things have different roles in producing nitric oxide, or helping assist the production of it.

Kalman: With that, I'm going to pivot to the registered dietitian that's part of this crew today, the other one, besides myself, and that's you, Katie. From a food perspective, I heard Joey mention beets, or beetroot,spinach or any of the dark green leafy vegetables really, turnip greens, and a few [other] things.

If somebody was looking to make sure that part of their diet, meaning what they're eating…in food form, of some of the ingredients that are known to have a positive impact on nitric oxide metabolism. How much are we talking, do you need, like, a pound of spinach a day? Is it 250 milligrams of a beetroot?

Emerson: Yeah, it's the dose, right? That dose is in the poison and the dose is in the benefit, right? We talk about beets all day and how good they are for you, for vasodilation and other various health properties, but if you don't have the right amount, you're not getting the so-called benefit that's been clinically validated. So, like, beets are the perfect example.

If you get a beetroot concentrate, you're talking about a 70 mL dose. But then there's beet juice, and I think that one's like 500 mL. But then there's beet powder, and that one's like 3 to 5 or 3 to 6 grams. And then if from the natural source, oh my gosh, that's completely different. I don't know how many beets you can eat. I eat maybe one. But I think I actually learned from you in one of your classes as an undergrad. We were talking about mushrooms, and you're like, “Do you have any idea how many mushrooms you would have to consume to get the beneficial properties that we are talking about that you could get from a supplemented form?”

And I was like, “Oh yeah, that's a good point.” Of course, we want to slowly incorporate all of these foods into the diet if we can, but when you're talking about a performance benefit, supplementation seems to be a little bit more direct and easier to get at the dose that you're looking for.

Kalman: What are some of the considerations that both of you would use in formulating any ingredient that would target NO?

Savage: I like to consider things from that little bit more of a holistic approach. If I can touch on multiple parts of the nitric oxide pathway, like, that classical system, then I'll use all the different amino acids that are in that category, even more obscure things like ornithine. Some people use agmatine. Even though ornithine's got more of a direct role in the nitric oxide pathway, it, along with agmatine, has a different, more interesting role in the urea cycle and the detoxification of that metabolic waste product from muscle. So that alone can start bridging into another realm of enhancing endurance and decreasing fatigue by detoxification of ammonia. But supporting those main points of the nitric oxide cycle is my first stop.

Then there are the nitrates I was talking about. That would be another way of increasing nitric oxide, which is a different way behind that. And then the supporting ingredients, looking at, you know, grape or blueberry or any of the darker berry polyphenols, or even pine-barked polyphenols to enhance nitric oxide production by playing with the expression of those different nitric oxide specific genes. Recently, I've even come across a specific strain of probiotic that is capable of increasing nitric oxide by secreting different peptides, and then having a synergistic effect with the nitrates, because it's got an active nitrate reductase enzyme.

And all those things flow through the gut anyway, so there's definitely some new potential that's kind of being established on including probiotics into this mix a little bit, too.

Kalman: Probiotics are fascinating in and of themselves, especially the more we learn about [them] and how they affect neurotransmitter production in the GI system, and how not only the microbiome, but specific strains influence GABA production, serotonin production, and a whole host of other things.

We know that we're talking about pre-workout, so from a supplement perspective, that's being used by people that are already going to the gym, and they're using it primarily to improve their exercise performance, and maybe also to have an impact on physical appearance.

What are some of the other benefits that may occur whole-body wise from having a healthier NO₂ metabolism.

Savage: So, this is all about cardiovascular health. Like, the ability for your body to produce nitric oxide is tied to so many different things. One is just the concept of vasoplasticity to begin with. So, this has everything to do with normalizing blood pressure so you don't have high blood pressure. It can segue into sexual performance, because if you do have the high blood pressure tendencies, then you're not going to be able to perform in the bedroom, and it's also about overall cardiovascular health because the more of that vasoplasticity you have, the less likely you're going to be to have any adverse events, like stroke or possibly even a heart attack because your body's able to rebound a lot more efficiently.

And then there's even more on top of that whole thing, as far as whole body metabolism, the more nitric oxide that you've got going around, it's also been tied to having increased insulin sensitivity and the ability to metabolize glucose a lot more efficiently. And that could just be by virtue of the plumbing and the pipes are wider going to the peripheral tissues where glucose needs to be metabolized instead of stored.

You don't even really have to be exercising to really benefit from the effects of nitric oxide.

Kalman: No, you definitely don't. Katie, what can you add to that?

Emerson: I tend to think of nitric oxide as a vessel for delivery, right? So you're going to widen those blood vessels, relax the smooth muscle cells, and so it's going to increase that blood flow. Like you were saying, Joey, pairing it with various things is going to have different outcomes, so depending on what your trajectory is, if you're taking a vasodilator with anything else, let's just say protein, right, it's going to [increase] your amino acids for that recovery basis after your exercise. Let's say collagen, bovine collagen, you want to target those skin cells and hair cells.

I think of vasodilation as a way of transporting all of these individual nutrients to the target location more efficiently. So, you can change that outcome based on what you're pairing it with.

Savage: We're talking about blood vessels here which aren't necessarily restricted to muscles because your blood vessels go everywhere, they go all the way to the surface of the skin, so I like your point about collagen…Vasodilation's going to have a role in all these different organ systems just outside of the muscles as well.

Kalman: So, how would somebody translate this to a structure function type of claim?

Emerson: There's a bunch, right? Like, “supports nitric oxide production,” “boosts blood flow,” “helps recovery.”

Kalman: “Improved circulation” was the first thing I was thinking of.

Emerson: I always get a little weary when we start to throw in words like, “improves inflammation,” or talking about cardiovascular health, obviously, avoiding disease claims and not mentioning high blood pressure, things like that: just sticking to the soft language of the claim of what the science is supporting of, but I like the circulation angle. That kind of skirts around the disease, the cardiovascular disease, but still shows the benefits of what it's doing on the blood vessels.

Savage: I think it's interesting when you talk about structure function claims, because they're always a toned-back version of kind of what you really see in the data. You could have a natural product that may have a mechanism of action that is in line with what a pharmaceutical is, but when it comes to our industry, you really can't say that on a label. So, you know, mechanistically, if I have, say, a peptide that inhibits angiotensin-converting enzyme ACE, you can't say that on the front of the label, but what you can do is pare it back to where you can say “supports healthy blood pressure,” and that's the walk back that happens on every product.

Now, if you were to put that on the front of your pre-workout, it's not a sexy claim, not by any means. But, if you can take that to “supports optimal blood flow” or “healthy blood flow,” then that's a little bit better. We're moving in the right direction there. But when it comes to, substantiated structural function claims, it's never going to be as flashy or as cool as…It's annoying because there's a lot of companies out there who will just put whatever they want on a label and just put a funny FDA disclaimer asterisk on everything even though it's something that they probably can't say.