Office for Science and SocietyIt’s a Gas!There were no Guinness Records back in 1772, but if there were, Joseph Priestley would certainly have been awarded one for discovering eight new gases in a single year. That is a record that will never be broken! Priestley, though, didn’t call them gases. To him they were different “airs,” with the most famous one being “dephlogisticated air” which we know today as oxygen. The others were silicon tetrafluoride, sulfur dioxide, nitrous oxide, hydrogen chloride, ammonia, nitrogen dioxide and nitric oxide, although of course he did not know their molecular formulas since the concept of molecules would not be introduced by Dalton and Avogadro for another three decades. Nitric oxide, or NO, that Priestley prepared by adding nitric acid to copper was to him “nitrous air.” To us today, it is an amazing molecule that on one hand is a pollutant, and on the other a biochemical that in 1998 garnered the Nobel Prize in Physiology or Medicine for Robert Furchgott, Louis Ignarro and Ferid Murad, the three researchers who discovered its function in the body. The pollutant role traces to nitric oxide being produced whenever oxygen and nitrogen are heated together to a high temperature, as happens in a car engine. Once released into the air, it becomes involved in the formation of acid rain and depletion of the ozone layer, so it certainly qualifies as a pollutant. But nitric oxide is also produced in the endothelium, the layer of cells that line blood vessels from where it diffuses to the smooth muscle cells that surround the blood vessels, signalling them to relax. This causes a dilation of the blood vessels and results in improved blood flow. That comes in handy when the heart is starved of oxygen as in angina, when blood pressure is elevated or when blood has to be delivered to produce an erection. A discovery worthy of a Nobel Prize! The awarding of the highest honour in science commonly stimulates more research in the field that was recognized, in this case, the role of nitric oxide in the body. It turns out that beyond signaling smooth muscle tissue to relax, nitric oxide is also produced by white blood cells to kill bacteria and fight tumours. But it is the ability of nitric oxide to act as a signaling substance that creates the most interest. Chemical messengers in the form of hormones and neurotransmitters had long been known, but a gas as a signaling molecule was a novelty. Nitric oxide isn’t a hormone, and doesn’t really qualify as a neurotransmitter because it isn’t stored in a nerve cell waiting to be released when the nerve cell “fires.” It is just generated by cells and diffuses out as needed. But how? There are three ways in which nitric oxide can be produced. One source is the amino acid arginine that is found in many proteins in the diet but can also be synthesized in the body from another amino acid, citrulline, also found in the diet or made in the body from glutamine, yet another amino acid. An enzyme, nitric oxide synthase, converts arginine to nitric oxide. A second source of nitric oxide is nitrate that occurs naturally in leafy green and root vegetables. Bacteria in the saliva convert nitrate to nitrite that then enters the circulatory system where it is reduced to nitric oxide as needed. Drugs such as nitroglycerin and isosorbide dinitrate used for the treatment of angina constitute a third source of nitric oxide. Although nitroglycerin was introduced by English physician William Murrell in 1878, its mode of action was not known until 1977 when Dr. Ferid Murad, one of the Nobel recipients, discovered that nitroglycerin releases nitric oxide that then causes arteries to dilate. This is all interesting information to be sure, but of what practical use is it? Once the role of nitric oxide in the body was recognized, it didn’t take long for supplement manufacturers to capitalize on the discovery and roll out a variety of nitric-oxide-stimulating dietary supplements. These targeted athletes seeking to increase muscle performance, men with erectile difficulties, and people desiring to reduce the risk of cardiovascular disease. Two of the Nobel prize winners, Drs. Louis Ignarro and Ferid Murad jumped on the bandwagon with different companies promoting arginine supplements based on personal anecdotes and animal studies. That, I think has unfortunately tarnished their reputation. Another company, United Therapeutics Corporation, hyped the “HeartBar,” claiming that its arginine content both prevented and treated cardiovascular disease. The company was taken to task for deceptive advertising by the Federal Trade commission and the product soon disappeared. Most nitric-oxide-boosting supplements available today contain arginine or its precursor, citrulline. Some are sources of nitrate, generally from beet root, while others contain sodium nitrite. All these can be a source of nitric oxide, but the relevant question is whether there is any evidence of a practical benefit. Unfortunately, not much. Arginine is very quickly broken down, before it has a chance to make it to tissues where it can release nitric oxide. Citrulline is more effective because it does make it into blood vessel walls where it converts to arginine that then releases nitric oxide, which in turn lowers blood pressure by dilating blood vessels. The effect, though, is small and citrulline is not the way to go for people who have high blood pressure. As far as erectile dysfunction goes, nitric oxide causes the muscles in the penis to relax allowing for an infusion of blood needed to produce an erection. Studies have shown that citrulline can have an effect in men with mild erectile dysfunction, but nowhere near the benefit produced by sildenafil (Viagra). Nitric oxide does not actually cause blood vessel dilation directly, but rather stimulates the production of a molecule, cyclic guanosine monophosphate, that does the job. Sildenafil interferes with the enzyme that normally degrades this molecule, therefore prolonging the nitric oxide effect. In theory, nitric oxide mediated increase in blood flow should help with athletic performance. Enhanced vasodilation should deliver more oxygen and nutrients to working muscle tissue that in turn should result in greater endurance, faster recovery and less muscle soreness. There have been dozens of trials that have investigated these potential effects using L-arginine, L-citrulline and nitrates as well as combinations of these. The amino acids ranged from 3 to 12 grams per day, while the nitrate dose was in the range of 800 milligrams. Results are in general disappointing. While most found no significant difference between supplement and placebo, some showed less muscle soreness and more repetitions of exercises such as squats, chin ups and bench presses before exhaustion. Basically, the evidence for benefit from nitric oxide boosters is less than overwhelming. Finally, not every effect of nitric oxide is positive. In case of a severe bacterial infection, white blood cells release a large amount of nitric oxide to dilate blood vessels so that more immune cells can get to the site of infection. This can result in a dramatic drop in blood pressure leading to shock. An interesting footnote to the nitric oxide story takes us back to Alfred Nobel who made a fortune with the invention of dynamite. Nitroglycerin is a powerful explosive but is a notoriously unstable liquid. Nobel discovered a way of harnessing its energy by mixing it with kieselguhr, a type of clay. The product, dynamite, is not sensitive to shock and only explodes when ignited. Nobel was concerned about his invention being used for evil and established the Nobel Prizes to foster science that benefits humanity. As chance would have it, late in his life Nobel developed angina and was prescribed nitroglycerin. Having worked with the chemical for years he knew that it can cause severe headaches. He decided not to take it. Interestingly enough, it was the triggering of headaches that had stimulated Dr. Murrell's use of nitroglycerin for angina. He believed the throbbing headaches were caused by the dilation of blood vessels in the brain and he surmised that the chemical could have the same effect on constricted coronary arteries. He was right. @JoeSchwarcz
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