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L-Arginine/L-Citrulline Cream
To understand the potential health benefits of L-Arginine/L-Citrulline Topical Cream, we must first become acquainted with nitric oxide, a biologically active substance that is produced from L-arginine in the body. Nitric oxide (NO for short; not to be confused with nitrous oxide [N2O], also known as laughing gas) is a cellular signaling molecule that has multiple biological functions. Chief among the beneficial effects of NO in the body is its role in improving blood flow. Other biological activities include muscle relaxation, modulation of immune responses, reduced inflammation, increased kidney function, enhanced sexual performance (notably with respect to penile erections) and stimulated hormone secretion. NO also has favorable effects on nervous system and brain function. In short, NO is a remarkably versatile, multifunctional biological molecule. Scientific studies of the biological effects of NO are relatively recent, with the discovery of what was originally called “endothelium-derived relaxing factor” dating back to 1978. Since then, research into the biological effects of NO has exploded. NO was named “Molecule of the Year” by Science magazine in 1992, and the three co-discoverers of the biological functions of NO – Robert Furchgott, Louis Ignarro and Ferid Murad, were awarded a Nobel Prize in Medicine in 1998. So, what do the amino acids L-arginine and L-citrulline have to do with the production of NO in the body? NO is produced by the actions of a group of enzymes known as nitric oxide synthases. L-Arginine contains two terminal amino (NH2) groups as part of its chemical structure.Nitric oxide synthase catalyzes the removal of the nitrogen atom from one of these amino groups, yielding NO plus L-citrulline as the products of the deamination of arginine. It is worth noting that there are several different types of nitric oxide synthases with different physiological roles. Briefly, they are a) neuronal nitric acid synthase (nNOS or NOS1), which generates NO in cells and tissues of the central and peripheral nervous systems; b) inducible nitric acid synthase (iNOS or NOS2), present in the immune and cardiovascular systems; and c) endothelial (formerly called constitutive) nitric acid synthase (eNOS or cNOS or NOS3), present mainly in blood vessels. If nitric oxide synthase enzymes convert L-arginine into L-citrulline (and NO), why add L-citrulline to L-Arginine/L-Citrulline Topical Cream in the first place? Because L-citrulline can itself generate L-arginine. The primary biochemical pathway for producing L-arginine in the body occurs through the action of two cellular enzymes, argininosuccinate synthetase and argininosuccinate lyase. By supplying both L-arginine and L-citrulline in the same product, L-Arginine/L-Citrulline Topical Cream provides both supplemental L-arginine and the means for its production in the body. As just one example of the potential benefits of combined L-arginine/L-citrulline supplementation, Toshio Hayashi and colleagues reported in the prestigious Proceedings of the National Academy of Sciences (volume 102, pages 13681-13686, 2005) that supplementation with the two amino acids retarded the progression of atherosclerosis in a rabbit model of the disease. They found that the L-arginine/L-citrulline combination was superior to either amino acid alone with respect to raising eNOS levels and decreasing vascular damage (as measured by such parameters as blood flow changes, aortic vascular relaxation responses and histological evaluations of atherosclerotic injury). L-Arginine/L-Citrulline Topical Cream will probably have the greatest potential health benefits with respect to dermatological applications. Dr. Richard Weller (currently at the University of Edinburgh in the United Kingdom) and his colleagues and collaborators have been the lead researchers in studying the beneficial effects of NO in the skin. Among their findings: NO can be produced on the surface of the skin by the reduction of nitrates present in sweat, with bacteria normally present on the skin first enzymatically converting nitrates to nitrites. (The bacterial enzyme involved is nitro reductase, not nitric oxide synthase. Production of NO from nitrite then occurs chemically via the slight acidity of the skin surface). It was speculated that a key benefit of this route to NO formation is in protecting against topical fungal infections (Journal of Investigative Dermatology 107:327-31, 1996). Weller and colleagues then showed that a topical cream containing acidified nitrite was clinically effective in treating tinea pedis, commonly known as athlete’s foot (Journal of the American Academy of Dermatology 38:559-63, 1998). In an extension of this research, Weller and others found that acidified nitrite cream also could inhibit pathogenic skin bacteria such as Staphylococcus aureus (Journal of Applied Microbiology 90:648-52, 2001). In the most recent research findings involving normal and diabetic mouse models, Weller and M. J. Finnen showed that acidified nitrite cream had clinical effectiveness in promoting wound healing (Nitric Oxide 15:395-9, 2006). In separate research, Weller and colleagues from the University of Pittsburgh found that NO could protect keratinocytes (skin cells) from apoptosis (programmed cell death) caused by UV radiation (American Journal of Physiology - Cell Physiology 284:C1140-8, 2003). All of these findings raise the intriguing possibility that if L-Arginine/L-Citrulline Topical Cream can raise NO levels at the skin surface (by the actions of skin cell nitric oxide synthases and/or by the combined bacterial enzymatic and chemical processes described above), this product has potential a) for controlling annoying superficial fungal infections such as athlete’s foot, jock itch, etc.; b) for controlling topical infections caused by pathogenic bacteria; c) for promoting wound healing; and d) for protecting the skin against environmental damage such as that caused by UV radiation. Although L-Arginine/L-Citrulline Topical Cream may have more limited application in systemic cardiovascular, neurological and immune system effects of increased NO production, a number of these biological activities are worth noting. With respect to cardiovascular health benefits, probably the best-known property of NO is signaling the smooth muscle surrounding the endothelial walls of blood vessels to relax or dilate, which increases blood flow. In fact, this is the same mechanism by which nitroglycerin acts in preventing or treating cardiovascular problems. (And to think that I once believed that nitroglycerin actually worked by “dynamiting” blood clots – silly me!). Speaking of which, NO also can inhibit platelet aggregation, thus helping to prevent blood clots from occurring. One cautionary note: There is recent clinical evidence that L-arginine supplementation should not be used in conjunction with standard therapies administered after acute myocardial infarctions (Journal of the American Medical Association 295:58-64, 2006). NO plays an important physiological role in neurotransmission. Whereas chemical neurotransmitters such as acetylcholine and serotonin mainly act between the synapses of neurons, NO can, by diffusion, transmit chemical information to multiple numbers of surrounding nerve cells. It is believed that NO is involved in the brain’s memory and learning processes. The relationship between NO levels in various neuropsychiatric disorders is somewhat complex. It has been noted that while NO possesses neuroprotective effects and acts as a neurotransmitter at low or moderate levels, excessive NO levels can cause oxidative stress because NO can act as a free radical. This in turn can result in such neurotoxic effects as impaired nerve cell function and cell death (Cerebellum 3:141-51, 2004). With regard to autism, at least two relatively recent studies (In Vivo 18:377-90, 2004; Biological Psychiatry 55:434-7, 2004) have reported higher NO levels in autistic patients relative to controls, so supplemental L-arginine and L-citrulline may not benefit these individuals. On the other hand, these studies provide further support for the role of oxidative stress in autism, suggesting that antioxidant supplements may be therapeutically beneficial for these individuals. With respect to immune system effects, macrophages can produce NO in response to systemic bacterial and fungal infections, and this eventually leads to the death of the invading pathogens. NO also can stimulate host defenses against cancer cells. However, just as excessive NO can be detrimental to neuronal cells, certain bacterial infections can lead to NO overproduction by macrophages, with symptoms of septic shock as a consequence. Another example of the two sides of NO can be seen with the inflammatory skin disease, psoriasis. While increased NO can decrease infections in psoriatic skin lesions, it also can increase inflammation in those lesions. L-Arginine and L-citrulline do have biological functions separate from their roles in NO production. In addition to being a precursor of NO, L-arginine is a substrate for the production of physiological substances such as urea and ornithine, as well as being incorporated into numerous proteins. Physiological activities in which L-arginine is involved separate from NO include wound healing, cell division, waste (ammonia) removal, hormone production, and immune responses. Although L-citrulline is not incorporated into proteins during conventional protein synthesis, several important proteins, notably myelin basic protein (which covers nerve tissue in the brain and central nervous system) and some histones (proteins associated with DNA) do contain L-citrulline. The L-citrulline in these proteins probably arises from certain enzymes (deiminases) that can convert L-arginine into L-citrulline. L-Arginine/L-Citrulline Topical Cream may have utility in alleviating erectile dysfunction. NO is known to play a rather complex yet important role in producing and maintaining penile erections. Suffice to say that the downstream effects of NO involve vascular smooth muscle relaxation and increased blood flow in the penile tissues. Since oral prescription drugs such as sildenafil (Viagra®) also lead to penile erections via vasodilation of the penile tissues, it is speculated that local topical application of L-Arginine/L-Citrulline Topical Cream may have the potential to do the same. Any volunteers? Ingredients: Deionized Water, Caprylic/Capric Triglyceride, L-Arginine, L-Citrulline, Simugel 600, Citric Acid, Carbomer, Stearic Acid, Sodium Hydroxymethylglycinate, Potassium Sorbate. 2 ounces For external use only.
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