Science: Nitric oxide crops up everywhere

By ALISON ABBOTT ONE OF the simplest of molecules may play important roles throughout the body. It may also be an important new target for the development of drugs. In the past two years, researchers have made the surprising discovery that cells can use the reactive molecule, nitric oxide (NO), as a chemical messenger which allows a signal to one type of cell to induce a response in another (Trends in Pharmacological Sciences, vol 10, p 427). The mechanism is simple. The cell that receives the signal – from a hormone, for example – responds by synthesising nitric oxide, which then diffuses between that cell and the true target cell, where it acts. Scientists first identified nitric oxide as a messenger, or biological mediator, only two years ago. They discovered it in two different systems. In 1987, Salvador Moncada and his colleagues at the Wellcome Institute in Beckenham, Kent, found that a much-studied substance in the body, called endothelium-derived relaxing factor (EDRF) was nitric oxide (Nature, vol 327, p 524). EDRF had been the focus of much interest because it seems to influence blood pressure and the clotting of blood. It is released from the endothelium, the sheet of cells which line the smooth muscle that forms blood vessels. Many biological signals, such as neurotransmitters, control the tone of blood vessels but not all act directly on the vessel walls. Moncado and his colleagues found, for example, that some trigger the endothelial cells to release nitric oxide, which can then diffuse across the small gap between endothelium and blood vessel wall and cause the muscle to relax, dilating the vessel. They also found that nitric oxide inhibits the clumping of platelets, a primary event in the development of a clot. Also in 1987, John Gibbs and his colleagues at the University of Utah reported that macrophages, a kind of immune cell, release nitric oxide when they are activated by bacteria (Science, vol 235, p 473). The molecule also diffuses short distances to tumour cells and is capable of killing them. Gibbs also discovered that cells produced nitric oxide from the amino acid arginine, and this has been confirmed by other researchers. Most believe that the rise in levels of intracellular calcium which is a common response of cells to activating signal, switches on the enzyme, nitric oxide synthase, which makes the molecule. These major discoveries have prompted biologists to look for nitric oxide in other cells. John Garthwaite of the University of Liverpool has shown that the brain makes nitric oxide when at least two types of receptor for glutamate are excited. Glutamate is an amino acid neurotransmitter that excites nerve cells. Researchers believe that one of these receptor types, the NMDA receptor, is involved in the processes of learning and memory. The receptor is also involved in causing the irreversible brain damage that occurs after a stroke. Garthwaite found that the nitric oxide diffuses out of the receptor-bearing cell to different types of cell close by. It somehow modifies their activity. S. H. Ferreira in Brazil has shown that nitric oxide regulates peripheral nerves involved in suppressing pain. Cells known as neutrophils, the immune system’s first line of defence against acute infection, also generate nitric oxide. The mediator here may have a dual role in killing bacteria and in regulating the blood flow at the site of infection. How can such a small and simple molecule have such a diversity of effects? And why should some cells see nitric oxide and respond appropriately, while others see nitric oxide and die? One answer could be that more than a threshold concentration of nitric oxide kills. Cells that make nitric oxide may protect themselves from a build-up of nitric oxide by also producing substances, so far unidentified, which promote its degradation. Now researchers have found that it is possible to manipulate pharmacologically the production of nitric oxide in humans (1989, The Lancet, ii, p 997). Joe Collier and Patrick Vallance from St George’s Hospital Medical School collaborated with Moncada to show that an inhibitor of nitric oxide synthase, L-NMMA, reduces the blood flow through the forearm of healthy volunteers. Moreover, the drug glyceryl trinitrate (GTN), commonly used in treating angina, had the opposite effect. Doctors know the body converts GTN to nitric oxide. Thus we already have a drug which exploits nitric oxide. Because of the molecule’s diverse action,
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