This section explains what nitric oxide is, it explains the main functions nitric oxide has in our bodies, and it also gives an overview of nitric oxide in recent history. In addition, this section explains why nitric oxide is such a critical element needed for a man to get an erection, and it explain the details behind this process.
Nitric oxide is a simple molecule consisting of one atom of nitrogen and one atom of oxygen. Little attention was given to this molecule until the 1970’s, when it was discovered that nitric oxide had blood vessel dilation properties.
All blood vessels are lined by endothelial cells. These cells act as selective filters that regulate the passage of gases, fluids and various molecules across their membranes. They are also instrumental in the production of the signalling molecule and free radical called nitric oxide. In the endothelial cells, a family of enzymes called nitric oxide synthase create nitric oxide from an amino acid called l-arginine, and oxygen. The mechanism behind this is for nitric oxide synthase to take a nitrogen atom from l-arginine, combine it with an atom of oxygen from molecular oxygen, and nitric oxide is created.
When nitric oxide is formed in the endothelium in blood vessels in the penis, it diffuses into the vascular smooth muscle cells of the penis where it binds to and activates an enzyme called guanylyl cyclase. This enzyme converts a molecule called guanosine triphosphate to another molecule called cyclic guanosine monophosphate (cGMP).
This serves as a messenger for many important cellular functions, including smooth muscle relaxation. When cGMP instructs the smooth muscles to relax, a surge of blood flow is allowed to freely pass into these smooth muscles, and the build-up of an erection starts. To learn more about the process behind penile erection on Truelibido, please go here.
This smooth muscle relaxation is paramount for a penile erection to take place, as the penis needs to be filled with blood in order for an erection to happen. No blood flow to the penis means no erection. The smooth muscles are ordinarily in a state of contraction, which means that they clench together and do not allow blood to flow to the penis, other than for regular maintenance purposes. On the other hand, when these smooth muscle relax, blood is allowed to flow into and engorge the penis.
The process is as follows: The nitrate is altered in the mouth and the digestive tract by bacteria that are normally present on the back of the tongue. These specialized bacteria use the nitrate to help them make energy in the form of adenosine triphosphate (ATP). In return, the bacteria utilize their own nitrate reducing enzyme called nitrate reductase to generate nitrite. Once in the stomach, gastric acids act on nitrites and convert them to nitrogen dioxide, dinitrogen trioxide and nitric oxide. The entire reduction process of nitrate into nitrite and then into nitric oxide occurs without the intervention of nitric oxide synthase.
In the late 1970s, researchers who were investigating the dilation mechanisms of the anti-angina drug nitroglycerine made a very interesting discovery. When nitroglycerine was administered to angina patients, it turned out to react with other chemicals in the body and subsequently convert into nitric oxide. And it was discovered that it was in fact this nitric oxide that produced the potent vasodilation effects of the blood vessels that benefited angina patients.
This finding initiated a whole new raft of research into nitric oxide. A rather profound breakthrough came in the late 1980s, when it was discovered that this nitric oxide acted as a neurotransmitter to erectile tissue. This lead to the development of the erectile dysfunction drug Viagra in 1989, although it was not approved for use to treat erectile dysfunction by the FDA in the U.S. until 1998. In 1998, three scientists received the Nobel Prize in Physiology for their discoveries of “nitric oxide as a signalling molecule in the cardiovascular system.” Nitric oxide was also named the molecule of the year in 1992.
Nitric oxide is what is called a free radical because it contains a single unpaired electron in its molecule. Hence it is very reactive, and has a half-life of only a few seconds. It is therefore not normally present in the body as nitric oxide, but reacts with other molecules to form more stable components such as nitrate. When nitric oxide is synthesized in the body, it has an almost immediate effect because of this very reactive property. At the same time, unless there is an adequate and persistent release of nitric oxide, the impact on blood vessels will wane quickly.
Nitric oxide has a multitude of functions in the body, and adequate levels of this messenger molecule are crucial for several bodily functions to operate optimally. Other than being paramount to proper erectile functioning, some of the most important roles of nitric oxide are:
- It is a key signalling molecule throughout the body. Produced by the endothelial cells lining the arteries, it penetrates the underlying smooth muscles and acts as a potent vasodilator that relaxes the arteries. Therefore, nitric oxide plays a critical role in blood pressure and overall circulation, as well as in increasing nutrient and oxygen delivery to every system, organ, and tissue in the body.
- Nitric oxide acts as a neurotransmitter in the brain and is especially important in regards to learning and memory tasks that take place specifically in the hypothalamus. Nitric oxide is synthesized in the brain upon demand and can be used in cognitive tasks immediately after being formed.
- Nitric oxide improves brain functioning and reduces cognitive decline. This is because it enhances blood flow to the brain and also because it functions as a secondary neurotransmitter between nerve cells.
- Nitric oxide is important to the immune system as white blood cells use nitric oxide to fight off bacteria, parasites and viruses. Nitric oxide produced by white blood cells is toxic to these entities and therefore plays an important role in their destruction.
- Nitric oxide plays an important role in bone formation and remodeling of old and damaged bones, as nitric oxide is utilized by cells called osteoblasts which are responsible for the maintenance and growth of bones.
- During physical exercise, additional nitric oxide is produced by the endothelial cells in order to dilate the arteries. This enables blood flow to be increased and hence the muscles and other tissues can be supplied with adequate amounts of oxygen and nutrients.
- A wide range of cellular activity is regulated by nitric oxide including cell division, cell survival and cell movement.
- Nitric oxide facilitates sleep and particularly REM sleep, and it also improves sleep recovery. Sleep apnea syndrome is correlated with decreased levels of nitric oxide.
Beavo JA, Hansen RS, Harrison SA, Hurwitz RL, Martins TJ, Mumby MC. Identification and properties of cyclic nucleotide phosphodiesterases. Molecular and Cellular Endocrinology. Volume 28, Issue 3, November–December 1982.
Bescós R, Sureda A, Tur JA, Pons A. The effect of nitric-oxide-related supplements on human performance. Sports Med. 2012 Feb 1;42(2):99-117. DOI: 10.2165/11596860-000000000-00000.
Braith RW, Conti CR, Nichols WW, Choi CY, Khuddus MA, Beck DT, Casey DP. Enhanced external counterpulsation improves peripheral artery flow-mediated dilation in patients with chronic angina: a randomized sham-controlled study. Circulation. 2010 Oct 19;122(16):1612-20. DOI: 10.1161/CIRCULATIONAHA.109.923482.
Bogdan C. Nitric oxide and the immune response. Nature Immunology 2, 907 – 916 (2001) DOI: 10.1038/ni1001-907.
Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, Snyder SH. Nitric oxide: a physiologic mediator of penile erection. Science. 1992 Jul 17;257(5068):401-3.
Burnett AL. The role of nitric oxide in erectile dysfunction: implications for medical therapy. J Clin Hypertens (Greenwich). (2006).
Chen J, Wollman Y, Chernichovsky T, Iaina A, Sofer M, Matzkin H. Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind, randomized, placebo-controlled study. BJU Int. 1999 Feb;83(3):269-73.
Damoulis PD, Hauschka PV. Nitric oxide acts in conjunction with pro-inflammatory cytokines to promote cell death in osteoblasts. J Bone Miner Res. 1997;12:412–23.
Eiserich JP, Patel RP, O’Donnell VB. Pathophysiology of nitric oxide and related species: free radical reactions and modification of biomolecules . Mol Aspects Med. (1998).
Feil R, Kleppisch T. NO/cGMP-dependent modulation of synaptic transmission . Handb Exp Pharmacol. (2008).
Furchgott RF, Jothianandan D. Endothelium-dependent and -independent vasodilation involving cyclic GMP: relaxation induced by nitric oxide, carbon monoxide and light. Blood Vessels. 1991;28(1-3):52-61.
Gielen S, Sandri M, Erbs S, Adams V. Exercise-induced modulation of endothelial nitric oxide production. Curr Pharm Biotechnol. 2011 Sep;12(9):1375-84.
Greene RW. Role for neuronal nitric oxide synthase in sleep homeostasis and arousal. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):19982-3. DOI: 10.1073/pnas.1319863110.
Guix FX, Uribesalgo I, Coma M, Muñoz FJ. The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol. 2005 Jun;76(2):126-52.
Hakim TS, Sugimori K, Camporesi EM, Anderson G. Half-life of nitric oxide in aqueous solutions with and without haemoglobin. Physiol Meas. 1996 Nov;17(4):267-77.
Gusarov I, Gautier L, Smolentseva O, Shamovsky I, Eremina S, Mironov A, Nudler E. Bacterial Nitric Oxide Extends the Lifespan of C. elegans. 14 February 2013, Cell DOI: 10.1016/j.cell.2012.12.043.
Lewis SJ, Bhopatkar MY, Walton TM, Bates JN. Role of voltage-sensitive calcium-channels in nitric oxide-mediated vasodilation in spontaneously hypertensive rats. Eur J Pharmacol. 2005 Dec 28;528(1-3):144-9.
Lowenstein CJ, Glatt CS, Bredt DS, Snyder SH. Cloned and expressed macrophage nitric oxide synthase contrasts with the brain enzyme. Proc Natl Acad Sci USA. 1992;89:6711–5.
Moncada S, Higgs A. The L-arginine nitric oxide pathway. N Engl J Med. 1993;329:2002–12.
Musicki B, Kramer MF, Becker RE, Burnett AL. Inactivation of phosphorylated endothelial nitric oxide synthase (Ser-1177) by O-GlcNAc in diabetes-associated erectile dysfunction. Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11870-5.
Niedbala W, Cai B, and Liew FY. Role of nitric oxide in the regulation of T cell functions. Annals of the Rheumatic Diseases. 65. (2006).
Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–6.
Presley TD, Morgan AR, Bechtold E, Clodfelter W, Dove RW, Jennings JM, Kraft RA, King SB, Laurienti PJ, Rejeski WJ, Burdette JH, Kim-Shapiro DB, Miller GD. Acute effect of a high nitrate diet on brain perfusion in older adults. Nitric Oxide. 2011 Jan 1;24(1):34-42. DOI: 10.1016/j.niox.2010.10.002.
Ralston SH, Grabowski PS. Mechanisms of cytokine induced bone resorption: role of nitric oxide, cyclic guanosine monophosphate and prostaglandins. Bone. 1996;19:29–33. 10.1016/8756-3282(96)00101-9.
Robinson LJ, Weremowicz S, Morton CC, Michel T. Isolation and chromosomal localization of the human endothelial nitric oxide synthase (nos3) gene. Genomics. 1994;19:350–7. 10.1006/geno.1994.1068.
Sullivan ME, Thompson CS, Dashwood MR, Khan MA, Jeremy JY, Morgan RJ, Mikhailidis DP. Nitric oxide and penile erection: is erectile dysfunction another manifestation of vascular disease? Cardiovasc Res. 1999 Aug 15;43(3):658-65.
Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000;289:1504–8. 10.1126/science.289.5484.1504.
Tsukii K, Shima N, Mochizuki S, Yamaguchi K, Kinosaki M, Yano K, Shibata O, Udagawa N, Yasuda H, Suda T, Higashio K. Osteoclast differentiation factor mediates an essential signal for bone resorption induced by 1 alpha,25-dihydroxyvitamin D3, prostaglandin E2, or parathyroid hormone in the microenvironment of bone. Biochem Biophys Res Comm. 1998;246:337–41.
Vig M, Srivastava S, Kandpal U, Sade H, Lewis V, Sarin A, George A, Bal V, Durdik JM, Rath S. Inducible nitric oxide synthase in T cells regulates T cell death and immune memory. Journal of Clinical Investigation. 113.12 (2004): 1734-42.