Nitrogen Monoxide (Nitric Oxide): Bioinorganic Chemistry

Abstract

The discovery of nitrogen monoxide (nitric oxide, NO) as the vasodilator molecule endothelium‐derived relaxing factor revealed a major physiological role for this simple diatomic molecule. We now know that NO regulates cardiovascular function, is a neurotransmitter, and is a component of the innate immune response to infection and cancer. The physiological effects of NO are mediated by its varied chemistry which includes redox chemistry and interaction with transition metals. NO can interact with iron‐heme‐containing proteins including hemoglobin and cytochrome c oxidase, and nonheme iron proteins such as aconitase and bacterial transcription regulatory proteins. NO reacts with superoxide to form the highly reactive peroxynitrite which decomposes to give the hydroxyl radical. Nitrosothiols, thiol adducts of NO, act to control NO release, and to shuttle NO between proteins and transport NO across cell membranes. NO is produced by one of three nitric oxide synthase (NOS) enzymes, endothelial NOS, neuronal NOS, and inducible NOS. Signaling functions are mediated via interaction with the heme‐containing protein soluble guanylate cyclase (GC), which produces the cell signaling molecule cyclic guanosine monophosphate (cGMP). This, in turn, is hydrolyzed by phosphodiesterase 5 (PDE5), which turns off NO signaling. Perturbation in NO function contributes to the pathophysiology of many disease states. Endothelial dysfunction and subsequent reduced NO production contribute to hypertension and atherosclerosis. Excess NO is a mediator of inflammatory disease, and neurodegenerative disease, due in part to the production of peroxynitrite. The cardiovascular collapse observed in septic shock is caused by the vasodilator action of NO. Targeting the NO pathway theoretically provides many opportunities for therapeutic intervention. The NO donor drugs glyceryl trinitrate, isosorbide mononitrate, isosorbide dinitrate, and amyl nitrate are used to treat acute angina; and inhaled NO is used to treat persistent pulmonary hypertension in new born infants. Conversely, NOS inhibitors and NO scavengers have been explored to counteract NO as a mediator of disease. Though promising results have been obtained in animal models of disease these latter approaches have had little clinical success. However, targeting downstream of NO has been more successful with new clinically approved classes of drugs such as the inhibitors of PDE5 sildenafil, tadalafil, and vardenafil; and the stimulator of the NO receptor soluble GC, riociguat. It has become apparent that the biological actions, and biological chemistry, of NO are very complex. New opportunities for drug discovery could result from an improved understanding of the biology of NO.