Molecule of the Month: How to lie back and still rise to the occasion: Nitric oxide is an environmental pollutant. But in our bodies, says John Emsley, it relaxes muscles and causes erections

John Emsley
Monday 18 January 1993 00:02

IN SPRING a young man's fancy turns to thoughts of love - and they turn to nitric oxide, without which he will never rise to the occasion. This simple molecule is used by our body to relax muscles (it will relieve an attack of angina), to kill foreign cells and to reinforce memory. And, curiously, our young man relies on its relaxing quality to secure an erection.

Until 1987, however, nitric oxide was regarded only as a environmental pollutant from vehicle exhausts, and a forerunner of acid rain. That it was part of our metabolism was unsuspected.

It consists of a nitrogen atom bonded to an oxygen atom, and its chemical formula is NO. The American Science magazine has just voted it Molecule of the Year, and showered it with puns: NO sex; NO wonder; NO way. In 1991, a team headed by Professor K E Andersson of Lund University Hospital, Sweden, showed that NO activates an erection. Sexy thoughts send a signal to release NO to the nerves of the corpus cavernosum, the spongy muscle in the penis. This relaxes the muscle and lets blood enter the tissues, which swell.

When NO is released by cells on the inside of blood vessels, nearby muscle cells relax and blood pressure is lowered. In 1987, Dr Salvador Moncada and colleagues at the Wellcome Research Laboratories at Beckenham, Kent, were the first to realise that blood vessels could make NO; and a year later they discovered that it came from the common amino acid arginine. They could then explain how a group of drugs, such as amyl nitrite and nitroglycerine, could stop a painful attack of angina.

It is too dangerous to treat people directly with NO, so drugs that release it slowly are given instead. The effect on blood pressure of breathing amyl nitrite vapour was noted as long ago as 1867, and Sir Arthur Conan Doyle endowed Sherlock Holmes with that knowledge in The Case of the Resident Patient. During the First World War, doctors noticed that ammunition workers packing shells with nitroglycerine had very low blood pressures, and this led to this compound's use as a vasodilator.

In NO's second role - the killing of unwanted cells - macrophages seek out invading bacteria or cancer cells and give them a fatal dose of NO. Sometimes, however, too much NO may be formed: a leading cause of death in intensive care is septic shock; and as the body generates NO to fight infection, it may also lower the blood pressure to dangerous levels (inhibitors that block the NO-forming enzymes can restore the pressure within minutes).

It is still not clear how a drug such as nitroglycerine produces NO in the body, but research on this may offer a new range of NO-releasing drugs. Professor Lyn Williams of Durham University believes that cysteine, a sulphur-containing amino acid, is involved when nitroglycerine is used. 'By understanding the underlying chemistry, we hope to design compounds that are more effective in dealing with circulatory ailments than current treatments such as nitroglycerine, which only works for a short time,' he says.

At St Andrews University, Dr Tony Butler and Dr Eric Flitney are researching NO's ability to prevent blood clots, and are already testing a new NO-releasing drug.

Nitric oxide is easy to make in the laboratory: you simply add copper turnings to concentrated nitric acid, and collect the colourless gas over water (it nearly killed Sir Humphry Davy when he tried breathing it in 1800).

Scientists are intrigued by its metabolic role as a free radical; that is, it has an odd electron. Although such molecules generally survive for only a fraction of a second, NO is stable. It is highly reactive, however, and with oxygen it forms brown fumes of nitrogen dioxide (NO2 ).

NO also acts as a messenger. Because the molecule is small, it can diffuse into and out of cells easily, and is quickly mopped up by oxygen. It may even be the looked-for 'retrograde messenger' that is the basis of memory.

When a receptor cell in our brain has been stimulated, it can recognise the same stimulation again because the sending cell generates a chemical messenger that the receptor cell will pick up. If it is strongly stimulated, the receptor sends back an NO molecule to tell the sender that the message has been received, and programmes it to send an even stronger signal next time.

Nitric oxide was first identified in the brain by Professor John Garthwaite and colleagues at Liverpool University, and at the same time, Dr Moncada's group discovered that the brain makes NO in the way that blood vessels do. These findings were confirmed when Dr Solomon Snyder at Johns Hopkins University in the US, cloned the NO- producing enzyme, NO-synthase, and found it was abundant in the brain.

NO has been protecting our food for more than 100 years. Meat producers use sodium nitrite to inhibit dangerous bacteria from growing on cured ham and in tins of corned beef.

Now, we know that this simple salt acts as a source of NO. And when we have eaten our corned beef sandwiches, NO may be there to help them on their way: it triggers the wave-like contractions of the gut that move food through our stomach and intestines.

The author is science writer in residence in the department of chemistry, Imperial College, London.

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