After 130 years, the molecular mechanism of action of nitroglycerin is revealed

Nitroglycerin, which was originally synthesized by Ascanio Sobrero, was used by Alfred Nobel to manufacture dynamite. It was in Nobel's dynamite factories in the late 1860s that the antianginal effect of nitroglycerin was discovered. Two interesting observations were made. First, factory workers on Monday mornings often complained of headaches that disappeared over the weekends. Second, factory workers suffering from angina pectoris or heart failure often experienced relief from chest pain during the work week, but which recurred on weekends. Both effects were attributed to the vasodilator action of nitroglycerin, which quickly became apparent to the physicians and physiologists in local communities. But what was the mechanism of this vasodilator action of the most powerful explosive chemical discovered in the nineteenth century? The answer to this question was not to come for another century. In the late 1970s and early 1980s, the vasodilator effect of nitroglycerin was discovered to be caused by nitric oxide (NO), which was apparently generated from nitroglycerin in vascular smooth muscle (1–4). These early observations on NO culminated less than 10 years later, in 1986, with the discovery that mammalian cells synthesize NO (5). In 1998, about 130 years after Alfred Nobel's invention of dynamite and the first observed clinical benefit of nitroglycerin, the Nobel Prize in Physiology or Medicine was awarded for “Nitric Oxide as a Signaling Molecule in the Cardiovascular System”. Despite these achievements, the precise molecular mechanism by which NO is generated from nitroglycerin remained elusive until the work of Chen et al. (6), reported in this issue of PNAS.