Isosorbide-5-mononitrate and endothelial function: a wolf in sheep's clothing

Abstract

This editorial refers to ‘Chronic therapy with isosorbide-5-mononitrate causes endothelial dysfunction, oxidative stress, and a marked increase in vascular endothelin-1 expression’[†][1], by M. Oelze et al. , on page 3206 In 1846, Ascanio Sobrero first synthesized nitroglycerin and observed that a small quantity of the oily substance placed on the tongue caused a severe headache. In its pure form—without an inert carrier such as lactose—nitroglycerin is explosive. It was therefore used by Alfred Nobel to manufacture dynamite. It took until the end of the 1860s before the antianginal effect of nitroglycerin was discovered. What had happened? Two findings were crucial: first, workers suffering from angina pectoris at the weekend were free of pain during the week; secondly, some workers described severe headaches on Mondays, but felt relief of pain at the end of the week and were absolutely free of pain at the weekends. Those observations were attributed to the vasodilatory properties of nitroglycerin. More than 100 years later, the mechanisms of action were discovered. The molecule nitric oxide (NO) is produced by nitroglycerin in smooth muscle cells. NO activates guanylyl cyclase, increasing intracellular levels of cyclic guanosine 3',5'-monophosphate (cyclic GMP), leading to vasodilation. This was the basis for further studies revealing that mammalian cells produce NO, culminating in awarding the Nobel Prize in Medicine and Physiology to Furchgott, Ignarro, and Murad for ‘their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system’ in 1998. As well-established drugs, organic nitrates still belong to the … [1]: #fn-2