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Interest in nitric oxide has exploded in recent years due to the recognition that the gas plays an important role in many physiological processes, and that manipulating the nitric oxide signalling pathway can have major medical benefits. But, only 30 years ago, the idea that a gas could have biological functions would have seemed far-fetched.

In 1980, Robert Furchgott reported that acetylcholine could contract or relax the smooth muscle surrounding blood vessels, but that this relaxation only occurred if the endothelium — the lining of the blood vessel — was intact (see Nature 288, 373–376; 1980). The implication was that a signal molecule was being released by endothelial cells and acting on the muscle cells, and Furchgott called the postulated molecule endothelium-derived relaxing factor - EDRF.

The link with nitric oxide was not immediately obvious. EDRF was highly labile, and candidate molecules, such as prostacyclin and other prostanoids, were soon ruled out. But in the 1970s Ferid Murad had discovered that the gas could activate guanylate cyclase, the enzyme that mediates the production of the signalling molecule cyclic GMP.

Murad also showed that nitroglycerin and other vasodilating drugs released nitric oxide. But the physiological relevance of this discovery remained unknown. The various links in the story were only pulled together at a conference in 1986 when Furchgott and Louis Ignarro, who had been working independently of each other, hypothesized that EDRF and nitric oxide were identical.