When we created Testosterone, one of our goals was to act as a sort of watchdog for the sports supplement industry. So far, we've done a pretty good job. We've exposed frauds, cut through the hype, and provided readers with the info they need to make smart supplement choices.

Now we'd like to take our role one step further. From now on, we'll be regularly reviewing supplements from various companies. If we feel they're worth buying, we'll let you know. If they stink, we'll tell you that too.

But can we review supplements in an unbiased manner given T-mag's relationship with Biotest? You bet we can! Of course, with all the new people just discovering T-mag, we'd also like to use this series to spotlight some of our own products as well, but ideally we'd get an outsider to write those reports. Unbiased, fair reviews: that's what this new series is all about!

This installment takes a look at a new category of supplements loosely coined "hemodilators,"among them being products that stimulate NO (nitrous oxide) production. The ads for these products are at times compelling and at times ludicrous (some ads even claiming that NO can actually improve the appearance of your face!). Given the broad spectrum of claims, we felt it was time to shine some light on this product.

It struck me by surprise when I saw the first ad for a new supplement touting "perpetual pumps and super-anabolic action." This new wonder-supp did all that groovy stuff by stimulating nitric oxide (NO) secretion in the body. Not only that, but it was invented by the creator of creatine*. Wait a minute, God created a new NO-stimulating supplement? How did that one slip past me? I mean, since creatine is a naturally occurring substance found in the body and food, this must be the case. Who else could have created it but good old Yahweh? This stuff had to work miracles. I was going to be so "pumped-up" that I would look like a tick about to pop.

Then it dawned on me. This was a supplement ad. Most supplement ads are for suckers and ill-informed idiots, Brad. Aw shucks, they almost had me there with their divine intervention approach. That’s A-1 marketing if I’ve ever seen it.

However, I was reminded that a lot of people don’t realize this indisputable fact of supplement industry degeneracy. So I decided to look into what these NO-stimulating supplements were all about and if any performance enhancing effects could be obtained by using them.

*Editor’s note—While Brad made a good joke about the "inventor of creatine" (Ed Byrd, the business man behind NO2 claims to have invented creatine in his ads), we thought a few of you would like to know the real story of how creatine was introduced to the United States. Long used by track and field athletes in the U.K., creatine had gone largely unnoticed in the US until a Bill Phillips lieutenant by the name of James Bradshaw happened to be rummaging through a box of supposedly worthless supplements that Bill kept in his office. Bradshaw, the captain of many of MET-Rx’s most successful ad campaigns, found a bottle of creatine, tried it, and was impressed by the results. He told Bill about it and soon after, Bill decided to market the product through his new company, EAS. The founding fathers of EAS included of course Bill, an adequate biochemist by the name of Anthony Almada, and a businessman named Ed Byrd. While Byrd was indeed part of the team that introduced creatine to the United States, his involvement was incidental at best.

Put A Little Smog in Your Heart

When first understanding NO, it’s important to differentiate between how NO exists in the environment and how it exists endogenously. In the environment, NO is formed via engine combustion at high temperature and pressure. This in turn floats into the atmosphere where it’s converted by sunlight and photochemical processes to nitrogen oxide. NO is a precursor to ozone pollution or smog, and appears as a red-brown gas that just happens to be poisonous.

Now, before you go sucking on a tailpipe to increase NO levels, it’s important to differentiate between NO as it exists in the environment and how it exists within the body. Endogenous NO is a free radical gas produced by a variety of cells. It’s synthesized from arginine by undergoing a complex reaction and is finally catalyzed by nitric oxide synthase. NO is a relaxing factor, and its primary function is causing vasodilation by relaxing vascular endothelium. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. NO is also involved in a number of other physiologic processes including metabolism, muscular activity, and hormone function.

Alpha-Ketoglutarates

The common active ingredient in the majority of these nitric oxide increasing supplements is arginine alpha-ketoglutarate (AKG). I’m sure some of you have heard of ornithine alpha-ketoglutarate (OKG) as it’s been touted as an anabolic supplement for some time now. What you may also know, if you ever wasted money on the product, is that it’s not in the least bit anabolic. You can pretty much clump ornithine and alpha-ketoglutarate together, as they’re both precursors to glutamine and arginine within the body. There are actually a number of alpha-ketoglutarates that form intermediary roles in the production of numerous amino acids in the body. These are primarily amino acids belonging to the glutamate family, or those that are disposed through the conversion of glutamate (1).

The most widely studied of these glutamates is ornithine alpha-ketoglutarate, which has been shown to help promote protein metabolism, immune response, and cell proliferation via nutritional supplementation for disease state or injured patients (2,3,4). Read those last five words of that sentence again please. Applying knowledge gained from a disease state individual and correlating it to a healthy individual is risky practice. If that were the case, we’d all be destroying our kidneys with all the protein we’re eating based on research done in subjects with renal failure. Just because something helps to achieve near normal or normal physiologic conditions in a disease state doesn’t mean it’ll create supra-physiologic conditions in a normal individual. Besides, we all know how potent an anabolic agent that glutamine and arginine can be, right Testeteers? (In case you didn’t catch it, that last sentence was dripping with sarcasm.)

On top of that, supplement companies pushing this junk are even trying to screw over the consumer with ridiculously low doses of the active ingredient. To achieve beneficial results in individuals who have undergone traumatic injury or suffering from a chronic illness, a much higher dose of OKG must be used to achieve a beneficial effect. In a study done on burn patients, 20 grams/day was employed to achieve a beneficial effect on repair and immune function, while most supplements have a dose of 4-6 grams/daily (4). What’s even worse is that this worthless supplement, with instructions to take a worthless amount, is being sold as much as $80 to over a $100 per bottle–a bottle that only lasts a few weeks. Can you detect a very profitable scam going on? You don’t have to be watching CSI to figure that one out.

The L-arginine nitric oxide stimulating pathway has been widely studied in rat and other animal models. AKG plays an intermediary role in this pathway, which ultimately leads to the production of NO. However, just because it plays an intermediary role in this pathway does not imply that taking exogenous AKG will stimulate greater NO production. What’s even worse is that there’s virtually no data supporting the use of AKG in humans as a nitric oxide stimulator or as being anabolic in nature. All the claims touted by the companies producing AKG are supported by research done in rats.

Since no research exists for the use of AKG in stimulating NO production in humans, let’s examine what increased NO may do in creating an anabolic environment in the body and whether or not increasing NO is even a good idea in theory.

NO and Glucose Uptake

AKG has not been shown to increase glucose uptake or overall glucose utilization in humans. Only two studies to date have looked at increased NO in humans and its effect on glucose uptake by skeletal muscle. NO has been shown to increase glucose uptake in basal leg muscle, but this was achieved by infusion of the nitric oxide donor sodium nitroprusside, not AKG (5). L-arginine, another precursor to NO in the body, has been shown to initiate vasodilation, but had no impact on insulin-mediated glucose uptake (6). So, depending on the stimulating agent used, the ability of increased NO to stimulate glucose uptake is still unclear at this point. And, this increased glucose uptake effect is non-existent for AKG.

NO as a Vasodilator

NO has been shown to clearly increase blood flow at both resting and exercise conditions. In fact, endurance training has been shown to increase NO-dependent vasodilation in exercising muscle, mainly by increasing the amount of total NO produced (7). As such, doing cardio (especially higher intensity) will initiate an increased NO response within exercising muscle.

Is supplementing with an NO stimulator for it’s vasodilatory effect during or immediately after exercise even necessary if you’re doing regular cardio like every good meathead should? This remains to be examined, but could explain why Cy Willson has trouble getting a boner without going for a good walk.

NO and Muscle Contraction

Nitric oxide has been shown to have diverse effects on muscle contraction depending on experimental conditions within rat and other mammalian models. It’s been shown to inhibit both smooth and skeletal muscle contraction (8,9). This in turn limits total and also sub maximal force production, which is primarily achieved by modulating excitation-contraction coupling (10). NO has also been shown to inhibit calcium channel opening which limits the amount of force produced by muscle fibers (10).

Funny enough, NO has conversely been shown to help regulate optimal velocity and power output (11). In fact, if sufficient NO doesn’t exist, then your muscles may not be able to achieve maximal shortening velocity, which decreases the overall power your muscles are able to exert. Some reports have shown that NO can preserve contractile function, but this effect is lost during higher intensity exercise, thus making NO increasing supplements worthless for anyone lifting heavy weights (12,13).

NO and Muscle Metabolism

NO has been shown to inhibit mitochondrial respiration by competing with molecular O₂ for the active sites on oxidative enzymes and also as an inhibitory modulator of oxidative phosphorylation under normal physiologic conditions (14,15). Not only that, but NO inhibits phosphocreatine breakdown by creatine kinase (16). Exogenous NO has been shown to down-regulate creatine kinase activity in striated muscle (16,17). This effect results in a decline in intramuscular ATP levels and thus depressed contractile function (17).

Endogenous NO and the Possible Dangers of Excess NO

NO production and distribution has been shown to be greatly up-regulated during muscular activity. NO release is increased 50-200% during periods of repetitive isometric contraction in rat muscle (18). That’s right, 50-200%! This would lead to three very important questions. First, whether increasing NO levels via a supplement would even be necessary before training? Secondly, would your body even be able to use the increased NO from some form of NO-stimulating supplement? And finally, with the negative effects regarding increased NO on muscle metabolism and function previously mentioned, would achieving higher levels be detrimental to performance? This hasn’t yet been examined in humans and is at best, guesswork at this point.

I’d also theorize that chronically elevating NO levels, like many of these supplements claim to do, could have potentially dangerous effects by interfering with natural clotting mechanisms and heighten the risk for internal bleeding and insufficient healing of certain tissues. This is, as mentioned at the start of the article, due to NO’s natural role as a disruptor of the platelet plug and thus clot formation within vascular tissue.

Conclusion

An understanding of NO and it’s role in skeletal muscle is relatively new in animal models and in its infancy in human research. Exercise alone can go a long way in increasing NO bioavailability, including increased nitric oxide synthase enzyme expression and activity (19). This may be another mechanism to explain why regular exercise has been shown to have a protective effect against many cardiovascualar diseases and why exercise is so important for individuals already in a cardiovascular disease state. However, chronically elevating NO levels in normal healthy individuals could be dangerous and detrimental to performance in and out of the gym. Maybe supplement companies should focus on finding a way to inhibit NO instead of stimulate it.

Oh wait, they have! Some supplement companies producing NO-stimulators have added L-nitroarginine to their mix of potential NO-stimulating agents. L-nitroarginine is a nitric oxide synthase inhibitor, used to decrease overall NO concentration in a variety of tissue types (20,21). So these companies are selling something that inhibits NO secretion and don’t even realize it! The funny thing is, who is really the fool here? Is it the supplement company, excuse me, worthless pill selling company, or the thousands of people buying this stuff?

References

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2. Donati L, et al "Nutritional and clinical efficacy of ornithine alpha-ketoglutarate in severe burn patients." Clin Nutr. 1999 Oct;18(5):307-11.

3. Jeevanandam M, et al "Substrate fuel kinetics in enterally fed trauma patients supplemented with ornithine alpha ketoglutarate." Clin Nutr. 1999 Aug;18(4):209-17.

4. Jeevanandam M, et al "Immune modulation with OKG supplementation in burn injury." Nutrition. 1999 Nov-Dec;15(11-12):952-3.

5. Durham WJ, et al. "Exogenous nitric oxide increases basal leg glucose uptake in humans." Metabolism 2003 Jun; 52(6): 662-5

6. Meneilly GS, et al. "Contrasting effects of L-arginine on insulin-mediated blood flow and glucose disposal in the elderly." Metabolism 2001 Feb; 50(2):194-9.

7. Delp MD. "Effects of exercise training on endothelium-dependent peripheral vascular responsiveness." Med Sci Sports Exer 1995 Aug; 27(8): 1152-7.

4. Ballon TW, et al "Nitric oxide release is present from incubated skeletal muscle preparations." J Appl Physiol 1994 Dec; 77(6): 2519-21.

8. Moncada S, et al "The L-arginine-nitric-oxide pathway." New Engl J Med 1993 Dec; 329(27): 2002-12.

9. Kobzik L, et al "Nitric oxide in skeletal muscle." Nature 1994 Dec; 372(6506): 546-8.

10. Cattarall WA "Excitation-contraction coupling in vertebrate skeletal muscle: a tale of two calcium channels." Cell 1991; 64: 871-74.

11. Morrison RJ, et al "Nitric oxide effects on shortening velocity and power production in the rat diaphragm." Comp Biochem Physiol A Mol Integr Physiol 1998 Jan; 119(1):203-9.

12. Murrant CL, et al "Effect of nitroprusside and endothelium-derived products on slow-twitch skeletal muscle function in vitro." Can J Physiol Pharmacol 1994 Sep;72(9):1089-93.

13. Murrant CL, et al "Endothelial cell products alter mammalian skeletal muscle function in vitro. Can J Physiol Pharmacol 1995 Jun;73(6):736-41.

14. Cleeter MW, et al "Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, by nitric oxide. Implications for neurodegenerative diseases." FEBS Lett. 1994 May 23;345(1):50-4.

15. Brown GC, et al "Nitric oxide regulates mitochondrial respiration and cell functions by inhibiting cytochrome oxidase." FEBS Lett. 1995 Aug 7;369(2-3):136-9.

16. Wolosker H, et al "Inhibition of creatine kinase by S-nitrosoglutathione."
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17. Gross WL, et al "Nitric oxide inhibits creatine kinase and regulates rat heart contractile reserve." Proc Natl Acad Sci U S A. 1996 May 28;93(11):5604-9.

18. Balon TW, et al "Nitric oxide release is present from incubated skeletal muscle preparations." J Appl Physiol. 1994 Dec;77 (6):2519-21.

19. Kingwell BA "Nitric oxide-mediated metabolic regulation during exercise: effects of training in health and cardiovascular disease." FASEB J. 2000 Sep;14(12):1685-96.

20. Gauthier C, et al "The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle." J Clin Invest. 1998 Oct 1;102(7):1377-84.

21. Mukhtarov MR, et al "Effect of nitric oxide and NO synthase inhibition on nonquantal acetylcholine release in the rat diaphragm." Eur J Neurosci. 2000 Mar;12(3):980-6.