It was the well-known effect of nitroglycerin on intense chest pains that first put investigators on the trail of nitric oxide as a messenger molecule. Nitroglycerin works in remarkably small doses to dilate the blood vessels and relieve chest pain. Pharmacologists already knew that nitric oxide was the active ingredient formed by the body from nitroglycerin. But what became clear only in the late 1980s was that nitric oxide was the very substance being sought independently in cardiovascular research as a “relaxing factor” that works in tandem with the neurotransmitter ACh in the lining of blood vessels. It soon emerged that nitric oxide does not bring about this effect alone; rather it stimulates the production of a second messenger, cyclic GMP (cyclic guanosine monophosphate).

As for its origin, nitric oxide is formed by the action of an enzyme from the amino acid arginine; another acid, citrulline, is given off as a by-product. One of the reasons nitric oxide has been so difficult to find in the body is that it is so shortlived (its half-life is five seconds). But the citrulline that is produced at the same time does remain in the system and it can be measured, providing a clue to the evanescent presence of nitric oxide.

At this point in the inquiry, brain researchers began to take an active interest. Solomon Snyder, director of the neuroscience department at Johns Hopkins Medical School, was intrigued by the actions of nitric oxide, and especially by their extraordinary rapidity. He felt sure a system as remarkable as that of nitric oxide could not have developed only for use in blood vessels—it must also be at work somewhere in the brain.

Snyder's research team used as their starting point the established fact that when the neurotransmitter glutamate binds to receptor sites, the calcium channels open and a great amount of cyclic GMP is produced. Once the investigators knew what to look for, they could follow two lines of evidence simultaneously: levels of citrulline and levels of cyclic GMP, both of which indicate the action of nitric oxide.

Sure enough, stimulating the glutamate receptors in the cerebellum tripled the levels of citrulline and increased the levels of GMP almost tenfold. (Conversely, when the cells were treated with a drug that inhibits the nitric oxide-forming enzyme, no cyclic GMP was produced, even when the glutamate receptors



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