Pharmacologist Robert Furchgott, at the State University of New York in Brooklyn, was investigating how acetylcholine causes the smooth muscles lining blood vessels to relax, thus allowing more blood to flow to certain organs. Acetylcholine appeared to stimulate the IP3 signal transduction pathway to produce an influx of Ca2+, which led to an increase in the level of another second messenger, cyclic GMP (cGMP). This nucleotide bound to a protein kinase, which then stimulated a kinase cascade leading to muscle relaxation. So far, the pathway seemed straightforward.
But while this pathway seemed to work in intact animals, it did not work on isolated strips of artery tissue. When Furchgott switched to tubular sections of artery, however, signal transduction did occur. There turned out to be a crucial difference between these two tissue preparations: In the strips, the delicate inner layer of cells that lines blood vessels had been lost. Furchgott hypothesized that this layer, the endothelium, was making something that diffused into the muscle cells and was needed for their response to acetylcholine. The substance was not easy to isolate. It seemed to break down quickly, with a half-life (the time in which half of it disappeared) of 5 seconds in living tissues. It turned out to be a gas, nitric oxide (NO), that had been thought of only as a toxic air pollutant!
In the body, NO is made from arginine by an enzyme, NO synthase. This enzyme is activated by Ca2+, which enters the endothelial cells through a channel opened by PIP2, which is released after acetylcholine binds to its receptor. The NO formed is chemically very unstable, and although it diffuses readily, it does not get far. Conveniently, the endothelial cells are close to the smooth muscle cells, where NO acts as a second messenger. In smooth muscle, NO activates an enzyme called guanylyl cyclase, catalyzing the formation of cGMP, which in turn relaxes the muscle cells (Figure 15.13).
The spectacular discovery of NO as a second messenger explained the action of nitroglycerin, a drug that has been used for over a century to treat angina, the chest pain caused by insufficient blood flow to the heart. Nitroglycerin releases NO, which results in relaxation of the blood vessels and increased blood flow. Penile erection is also caused by the dilation of blood vessels in that organ, and the new drugs that promote erection are NO synthesis activators.
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