What on Earth is Nitric Oxide Doing Here?

The year 1952 was a bad one for Londoners. The city was frequently shrouded in smog – something between a smoke and a fog – causing traffic chaos and considerable physical distress, particularly amongst the more elderly members of the population. Smog forms when the moisture in a fog, for which London had long been famous, condenses around tiny particles from industrial emissions. Then sulphur dioxide, coming from the burning of coal rich in sulphur in open fires, dissolves in the moisture to give the acrid taste so characteristic of smog. The authorities took rapid action to reduce the amount of smoke and sulphur dioxide released into the air in urban areas. London's smog episodes were quickly eradicated.

London was by no means the only city with smog problems. For some years similar measures had been taken in Los Angeles to reduce smoke and particulate emissions, but the chronic smog problem had failed to ease. It transpired, much to the surprise of the local residents, that the Los Angeles smog had a different cause. Car exhaust fumes, in which the air above Los Angeles abounded, contained not only carbon dioxide and water but also traces of two oxides of nitrogen (nitric oxide, NO, and nitrogen dioxide, NO2) as well as volatile organic compounds. To complicate matters further, the strong Californian sunlight provided suitable energy for a complex series of reactions involving NO which gave a 'photochemical smog'. This was just as distressing as London's industrial smog. Exposure caused eye and bronchial irritation in humans, it blanched the leaves of trees and it accelerated the corrosion of rubber. This is the context in which, before 1987, NO was usually mentioned.

NO is a simple gas and each molecule contains one atom of nitrogen and one atom of oxygen. It just gets mentioned in a school chemistry syllabus. Its most well-known property is that when it is released into the atmosphere it reacts with oxygen to form a brown gas, nitrogen dioxide NO2. This means that if NO forms in the atmosphere the result is a mixture of NO and NO2. Formation of NO does occur naturally, but only in the extreme conditions of a lightning strike. For convenience the mixture of NO and NO2 is known as NOx, pronounced to rhyme with 'socks'. Areas with high NOx concentrations (and hence photochemical smog) sometimes appear on weather charts to warn people to keep away if they can.

Without NOx photochemical smog does not form and so cars in Los Angeles, and elsewhere, are now fitted with catalytic converters to destroy the NOx before it enters the atmosphere. This process is described in more detail later (Chapter 7). With increasing understanding of air pollution NO and NO2 were seen as major villains in the saga and great efforts were made to banish them. However, in 1987 scientists were astonished to learn of another side of NO's complex character: human life depends upon it.

Vessels that carry blood around the body can enlarge, or dilate, and this fixes the amount of blood that is delivered to specific tissues or organs. To see how this happens we have to look at the structure of a blood vessel. The hole in the middle, down which the blood flows, is called the lumen. On the inside of the lumen is a single layer of cells known as the endothelium (endothelial cells) and the wall of the vessel consists largely of smooth muscle (Figure 1.1). It is called smooth because of its appearance under the microscope. When the muscles of the artery wall relax the lumen enlarges and more blood flows through the vessel, provided the heart is pumping properly. If the muscles contract the lumen decreases in size. Then, either less blood flows along the vessel or the heart has to work harder to maintain the flow of the same amount of blood. This is why 'hardening' of the arteries, which prevents muscle relaxation, puts strain on the heart.

It had been known for many years that certain substances, such as acetylcholine, bring about vascular muscle relaxation and some of these substances are released into the bloodstream when relaxation is required. During the late 1970s this matter was under investigation by one of the world's leading muscle physiologists, Robert Furchgott (Figure 1.2), working at the Downstate Medical Center in New York City. He wanted to know how and why substances like acetylcholine affected muscles in this way and he was working with small segments of artery taken from a rabbit. He and his student (John Zawadzki) encountered the most trying of situations in scientific research; their results were not reproducible. In one set of experiments acetylcholine was an active muscle relaxant but in another set of apparently identical experiments it had hardly any relaxing effect at all. The most natural thing to do when this happens is to give up and go fishing, but Furchgott and Zawadzki were made of sterner stuff and they eventually concluded that the result they obtained depended on whether or not the endothelium was intact. It is extremely easy to damage the endothelium when the experiment is being set up.

If the endothelium was undamaged acetylcholine worked fine; remove the endothelium by rubbing, either intentional or accidental, and acetylcholine had no effect at all. Furchgott concluded, quite rightly it is now clear, that acetylcholine was not acting directly on the muscle cells but on the endothelial cells which, in turn, produced another chemical species that diffused into the surrounding muscle and began the process of relaxation. Such a substance is called a messenger molecule as it tells the muscles what to do. Furchgott named this particular messenger molecule the 'endothelium-derived relaxing factor'. It was seen as important enough to warrant a set of initials (but not an acronym): EDRF. The chemical identity of the EDRF was a matter of intense study by many scientists during the 1980s. It was assumed to be a complex organic molecule, like most messenger molecules in the body, but it stubbornly resisted identification. You can see the magnitude of the challenge. The EDRF is produced, along with hundreds of other chemicals, by endothelial cells in quantities around a thousand millionth of a gram, well below the limits of detection by normal chemical means.

The problem was solved by an inspired guess and, although the first person to make the suggestion in print was Furchgott himself, the same idea...