Scivation NOxidant Ingredients & Servings:
Supplement Facts:
Serving Size: 3 Capsules
Servings Per Container: 30
Amount Per Serving:
Gamma-Tocopherol: 500mg
Selenium (.2%): 100mg
(yielding 200mcg Selenium)
Alpha Lipoic Acid: 100mg
Grape Seed Extract: 200mg
Green Tea Extract (50%): 300mg
Quercetin: 200mg
Apple Polyphenols (60%): 300mg
Zinc Aspartate (20%): 50mg
(standardized to 10mg zinc)
Copper Gluconate (20%): 500mcg
(yielding 100mcg copper)
Manganese Chelae (20%): 1mg
(yielding .2mg Manganese)
Vitamin C: 250mg
Other Ingredients:
Dicalcium phosphate, gelatin and silicon dioxide.
Directions: As a dietary supplement, take 3 capsules daily. On training days, take one serving post-workout and on non-training days take one serving before breakfast.
Known for its ability to cause mind blowing pumps, crazy vascularity, and increased muscle gains, NO, or Nitric Oxide, is one of the hottest supplements on the market. However, few realize the negative side-effects associated with NO supplements: free radical induced DNA damage, arteriosclerosis, inflammatory response, neurological damage...
Yeah, I know - that's not what the label says, is it?
The fact is, Nitric Oxide, when combined with various metabolic by-products, such as superoxide, form very nasty radicals called Reactive Nitrogen Species, or RNS. Lipid peroxidation from Reactive Nitrogen Species in brain and body tissues has been shown to promote atherosclerosis. Damage to the integrity of our DNA by RNS leads to a whole host of problems, to the actual aging process itself! Finally, it has been hypothesized that the actions of RNS in penile tissue can eventually lead to problems. Despite Nitric Oxide being an essential molecule for erection, its harmful metabolites can induce problems.
The irony only thickens when we see that oxidative/nitrosative damage caused by elevated NO levels is actually catabolic. Increased messenger signaling from NO would be expected to lead to increased muscle gains if it wasn't for the damaging effects of Reactive Nitrogen Species. This probably explains some of the non-response to NO supplements and the failure of studies to show an increase in lean mass or strength gains.
So how do we get the positive benefits of increased NO levels without hindering our gains or jeopardizing our overall health? In collaboration with its esteemed advisors and industry peers, Scivation introduces NOxidantâ„¢, which may very well be the missing piece in your Nitric Oxide puzzle. In this article, we will break out some of the nitty-gritty science on the formation of Nitric Oxide, Increasing Nitric Oxide in Muscle Tissue via Supplementation with NO Precursors (L-Arginine, Arginine Alpha-Ketoglutarate (AKG), Ornithine AKG, Di-Arginine Malate, Citrulline Malate), Nitric Oxide as a Free Radical, Preventing DNA Damage from RNS (Reactive Nitrogen Species) and ROS (Reactive Oxygen Species), Other Possible Substances to Use in Conjunction with Hemodilators, and then we break it all down and provide a full proof plan to maximizing your Nitric Oxide! Read on.....
Introduction to Smooth Muscle Contraction and Relaxation
The contractile activity of all kinds of muscle, including skeletal muscle, and for our purposes the smooth muscle that lines the walls of blood vessels, is regulated primarily by the reversible phosphorylation (addition of phosphate, PO4) of myosin. Myosin of smooth muscle consists of two heavy chains (Molecular weight 200,000 each) that are coiled to form a filament. Each heavy chain is associated with two pairs of light chains (MW 20,000 and 16,000) that serve as substrates for calcium dependent protein kinases in the contraction process. Recall that a kinase is an enzyme capable of phosphorylating its substrate. Together with actin (MW 43,000) they participate in a sequence of events that lead to muscle contraction and relaxation.
Cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and especially cyclic guanosine monophosphate (cGMP) play significant roles in muscle relaxation and contraction. cAMP is the mediator associated with the smooth muscle relaxation caused by beta adrenergic agonists such as clenbuterol and albuterol. Smooth muscles line the bronchial passages as well as blood vessels. cAMP activates the kinases that phosphorylate myosin light chain kinase (MLCK), rendering it inactive, and unable to sustain contraction of myosin.
The activity of cGMP in smooth muscle relaxation is affected by a number of exogenous and endogenous agents. It's thought that vasodilators such as nitroglycerine undergo transformation in vascular smooth muscle cells to form nitric oxide (NO). We all recall the scene in the film "The Exorcist" where Max von Sydow puts a nitroglycerin tablet under his tongue to stave of an attack of angina, a medical condition involving contraction of the coronary blood vessels. The nitroglycerine is metabolized to NO, which relaxes these vessels, restoring blood flow to the heart NO relaxes smooth muscles by activating guanylate cyclase to increase intracellular concentrations of cGMP. cGMP in turn activates kinases that phosphorylate MLCK, rendering it inactive and leading to smooth muscle relaxation. Note the parallelism between cAMP and cGMP action.
Figure 1. Mechanism of action of nitrovasodilators and NO. Nitric oxide (NO) formed in smooth muscle from nitrovasodilators or from endothelial cells activates guanylate cyclase (GC*). GC* activates cGMP-dependent protein kinases that phosphorylate myosin light chain kinase, causing its inactivation and subsequent muscle relaxation.
While we don't normally sense NO regulating the expansion and contraction of cardiac vessels, we are all quite familiar with one NO dependent process: Penile Erection. During sexual arousal, neurons enervating the penis release NO, as do the endothelial cells lining the penile vasculature. The blood vessels within the penis relax, via the cGMP-mediated process described above, allowing penile tissue to fill with blood.
Bodybuilders are familiar with another NO mediated phenomenon: the pump. In order to ensure adequate blood flow and oxygenation to exercising muscle, NO, along with other vasodilatory compounds are released from muscle cells and the nerves that stimulate them during contraction (1,2).
Formation of NO
Figure 2. Arginine is converted to Nitric Oxide (NO) and Citrulline by NO synthase
NO is a short-lived free radical gas widely distributed in the body. As described above, it plays an important physiological role by its effect through cGMP on the smooth muscle vasculature. It is synthesized in the vascular endothelial cells from the amino acid L-arginine by the enzyme NO synthase.
After production in the endothelial cells it diffuses into the surrounding smooth muscle cells where, as described above, it activates guanylate cyclase, which leads to an increase in cGMP, followed by smooth muscle relaxation. We mentioned that exercising muscle releases NO, contributing to relaxation of blood vessels in the muscle so as to allow for increased blood flow, oxygenation, and nutrient supply to working muscle.
Increasing NO in Muscle Tissue via Supplementation with NO Precursors
Achieving a maximal pump while performing resistance exercise is a sought after goal among bodybuilders. Aside from the pleasant sensation, it is a sign to us that we are maximizing blood flow to muscle, ensuring adequate oxygen supply and nutrient delivery. As an aside, one of insulin's anabolic effects is related to its ability to induce muscular vasodilation, which in turn increases nutrient delivery to working muscle (3). This provides part of the rationale for ingesting carbohydrates and amino acids before a workout rather than after a workout (4).
Applying the above logic, and the fact that NO is derived from the amino acid arginine, a number of supplement companies have developed "hemodilators" based around various forms of arginine. These forms include L-arginine itself, arginine alpha-ketoglutarate, citrulline-an arginine precursor, di-arginine malate, and ornithine alpha-ketoglutarate (AKG).
Arginine alpha-ketoglutarate (AKG) reportedly is better absorbed than arginine, and has a more sustained effect on NO production. Ornithine AKG provides arginine for NO synthesis, and has been shown to increase insulin and growth hormone production (6). Insulin we recall is also a vasodilator as well as an anabolic hormone. AKG itself has been used extensively for nutritional support in various illnesses and in the post surgery setting.
Di-arginine malate consists of 2 arginine molecules bonded to a malic acid molecule. Many anecdotal reports by users claim a more sustained effect from di-arginine than from other NO precursors, although there are no experimental data to support these claims.
Citrulline is converted to arginine in the body, so serves as a precursor to NO. There are many other ergogenic benefits of citrulline (and the malate in the NO precursor Di-arginine malate), so adding these extra ingredients can increase the ergogenic potential of the various hemodilators.
As there have been no head to head comparisons of the different hemodilators on the market that have been published in the scientific literature, one ought to experiment to find the product that works best for any given individual.
Nitric Oxide as a Free Radical
Recall above that we described NO as a free radical gas. Nitric oxide is an uncharged molecule composed of seven electrons from nitrogen and eight electrons from oxygen. This combination results in the presence of an unpaired electron making NO by definition a radical. The majority of biological molecules contain bonds filled with two electrons. The unpaired electron in NO makes the molecule highly reactive with other molecules that have unpaired electrons in their outer orbital. They are typically other free radicals or transition metals, such as heme iron.
NO acting by itself has a number of damaging effects in body tissue, but the direct toxicity of nitric oxide is modest. This is primarily because the radical is highly reactive and in the body is quickly transformed into other reactive nitrogen species (RNS), primarily nitrate (NO3-), and nitrite, (NO2-). The toxicity of NO increases greatly upon reaction with superoxide radical (O2-) to form the highly reactive peroxynitrite anion (ONOO-)
By itself, NO can damage DNA resulting in mutations (7). Reaction of NO with oxyhemoglobin yields methemoglobin, an inactive oxygen transporter, which decreases the oxygen-carrying capacity of hemoglobin. NO modulates platelet function by inhibiting platelet aggregation and adhesion. This may increase the bleeding time and the risk of problems. NO can accelerate lipid peroxidation in the presence of reactive oxygen species (oxygen based free radicals, ROS) resulting in the formation of atherosclerotic plaques. Recent research has shown that the central nervous system may be particularly sensitive to reactive oxygen and nitrogen species induced damage because the brain is deficient in oxidative defense mechanisms (8).
So we see a potentially serious downside to supplementation with hemodilators: the formation of a number of long lived RNS. Moreover, as stressed in (1) even without the use of hemodilators contracting muscle produces both ROS and RNS.
Preventing damage from RNS and ROS
What can be done to help prevent the damaging effects of ROS and RNS? The answer is fairly simple, as stressed in (7): the use of an array of antioxidants is currently the best way to prevent free radical damage. The authors in (7) limit their antioxidant selection to the mainstream antioxidant vitamins. We know of a number of other excellent antioxidants however, such as alpha lipoic acid (ALA), plant polyphenols and flavonoids, Gamma-Tocopherol, and antioxidant minerals. NO is so short lived that it would have little time to be scavenged by these agents, so we would still get our desired pump. Here is a breakdown of each of these antioxidants:
Gamma-Tocopherol, a form of Vitamin e normally obtained through food but severely lacking in the Western diet, has been generating a lot of excitement and controversy lately. Studies show that it is much more effective than Alpha-Tocopherol (the form used in most supplements) in deactivating and preventing the formation of Reactive Nitrogen Species. This is due to G-Tocopherol's ability to be nitrated at the 5th position, which is impossible with A-Tocopherol. G-Tocopherol has also been shown to be two times more powerful than A-Tocopherol at preventing lipid peroxidation in liposomes. G-Tocopherol also decreases inflammation-induced cell damage and loss of Vitamin C, which is especially important post-workout.
Ascorbate (or Vitamin C) is one of the most common and powerful anti-oxidants in the body. Even with the ready availability of Ascorbate supplements, the typical bodybuilder's diet is still severely lacking this important nutrient. Combined with Gamma-Tocopherol, Ascorbate is one of the most powerful weapons we have to fight RNS.
Plant polyphenols and flavonoids, especially those contained in Green Tea, Grape Seed, and Apple Extract, are very potent anti-oxidants, which work by increasing the activity of the anti-oxidant enzyme, Glutathione Peroxidase, especially in the liver and intestines. Glutathione is extremely important to healthy functioning, and protects DNA from damage, as well as preventing inflammatory responses and more. Polyphenols and flavonoids work synergistically with Ascorbate.
Alpha Lipoic Acid and its main metabolite - Dihydrolipoic Acid, is known as the Universal Anti-Oxidant. It has the ability to protect against both Reactive Oxygen and Nitrogen Species, especially in brain tissue, which helps prevent an age-related decline in mental abilities and neuronal damage.
Zinc, Copper, and Manganese are essential components of the enzyme Superoxide Dismutase, or SOD. SOD de-activates the free radical superoxide, preventing its reaction with NO. Manganese-SOD is most active in the mitochondria, and Zinc/Copper-SOD is most active in the cytosol. A precise ratio of these three minerals assures adequate levels of Superoxide Dismutase are available to combat the formation of RNS.
Selenium, a metal, works hand in hand with Vitamin E, and is also essential for the formation of Glutathione Peroxidase.
Quercetin has been demonstrated to reduce Nitrite (a Nitrogen Free Radical) back to Nitric Oxide, thereby enhancing the lasting effects of NO supplements.
The more harmful long-lived RNS and ROS would, however, be neutralized to a large extent by these potent antioxidants. And as mentioned, it would be prudent to employ these antioxidants even if one were not using a hemodilator since working muscle itself generates RNS and ROS.
Other Possible Supplements to Use in Conjunction with Hemodilators
Even though the pump feels great, the true reason for increasing blood flow to muscle is to supply oxygen and nutrients, and remove waste products. The only one of the three we have any real control over is nutrient delivery. In (4) Tipton et.al. showed that carb/protein intake before a workout improved protein synthesis compared to an identical post workout meal. It makes sense then to have a carbohydrate/whey shake before a workout, along with your favorite hemodilator. An alternative would be carbohydrates and BCAAs rich in leucine. Leucine has been shown to act in a way similar to anabolic hormones, activating the same pathways as IGF-1 and insulin to promote protein synthesis. NOxidant by Scivation would go well with a hemodilator as it contains all the BCAAs and is particularly rich in leucine. Moreover, it contains citrulline, which itself is a hemodilator. As for countering the damaging effects of ROS and RNS , here again Scivation is at the forefront with NOxidantâ„¢, a blend of all the major antioxidants that have been proven effective at quenching reactive species of molecules.
Putting it all Together
Now that we have the reasoning and the science behind what can be done to maximize Nitric Oxide, let's go over a plan to help maximize your program!
Pre Workout
Consume the following 15-30 minutes pre workout:
* 3-5 grams Di-arginine Malate such as Primaforce Nitrocharge or Arginine AKG
* 20-30 grams whey protein isolate such as PrimaForce Substance WPI
* 25-35 grams dextrose or a piece of fruit
Immediately Pre and During Workout
* Scivation NOxidant mixed in water or a carbohydrate beverage (dose NOxidant per label directions)
Post Workout
* 3-5 grams Di-arginine Malate such as Primaforce Nitrocharge or Arginine AKG
* 20-30 grams whey protein isolate such as Primaforce Substance WPI
* 25-35 grams dextrose or a piece of fruit
* 3 Capsules NOxidant
This plan will help you safely maximize your Nitric Oxide levels. What are you waiting for? Go get your pump on!
REFERENCES:
1. Patwell DM, McArdle A, Morgan JE, Patridge TA, Jackson MJ. Release of reactive oxygen and nitrogen species from contracting skeletal muscle cells. Free Radic Biol Med. 2004 Oct 1;37(7):1064-72.
2. Dinenno FA, Joyner MJ. Blunted sympathetic vasoconstriction in contracting skeletal muscle of healthy humans: is nitric oxide obligatory? J Physiol. 2003 Nov 15;553(Pt 1):281-92.
3. de Jongh RT, Clark AD, IJzerman RG, Serne EH, de Vries G, Stehouwer CD. Physiological hyperinsulinaemia increases intramuscular microvascular reactive hyperaemia and vasomotion in healthy volunteers Diabetologia. 2004 Jun;47(6):978-86.
4. Tipton KD, Rasmussen BB, Miller SL, Wolf SE, Owens-Stovall SK, Petrini BE, Wolfe RR. Timing of amino acid-carbohydrate ingestion alters anabolic response of muscle to resistance exercise. Am J Physiol Endocrinol Metab. 2001 Aug;281(2):E197-206.
5. Huynh NT, Tayek JA. Oral arginine reduces systemic...: its potential role in nitric oxide generation. J Am Coll Nutr. 2002 Oct;21(5):422-7
6. Schneid C, De Bandt JP, Cynober L, Torres E, Reach G, Darquy S. In vivo induction of insulin secretion by ornithine alpha-ketoglutarate: involvement of nitric oxide and glutamine. Metabolism. 2003 Mar;52(3):344-50.
7. Ray G, Husain SA Oxidants, antioxidants and carcinogenesis. Indian J Exp Biol. 2002 Nov;40(11):1213-32
8. Gupta YK, Gupta M, Kohli K. Neuroprotective role of melatonin in oxidative stress vulnerable brain. Indian J Physiol Pharmacol. 2003 Oct;47(4):373-86
