NOS enzyme inhibitors are currently being evaluated for efficacy in diseases associated with elevated NO production, such as inflammatory conditions, sepsis, and neurodegenerative diseases. The majority of these inhibitors are arginine analogs that bind to the NOS
O−Nitric oxide (NO) Vasodilator, platelet inhibitor, immune regulator, neurotransmitter Oxidant and nitrating agent Can form from nonspecific donation of an electron from metals to NO Exhibits NO-like effects, possibly by first being oxidized to NO Anesthetic Auto-oxidation product of NO that can nitrosylate protein thiols Stable oxidation product of NO Slowly metabolized to nitrosothiols, and decomposes to NO at acidic pH Stable oxidation product of NO N=O•O=N−O−O−N−=O N−=N+=O O=N=O−Peroxynitrite (NO3 −) Nitrite (NO2 −) Nitrate (NO3 −) Nitroxyl anion (NO−) Nitrous oxide (N2O) Dinitrogen trioxide (N2O3) O=N−N+=O O=N+−O−O− arginine-binding site. Since each of the NOS isoforms has high structural similarity, most of these inhibitors do not exhibit selectivity for individual NOS isoforms. In inflammatory disorders and sepsis (see below), inhibition of the iNOS isoform is potentially beneficial, whereas in neurodegenerative conditions, nNOS-specific inhibitors may be useful. However, administration of nonselective NOS inhibitors leads to concurrent inhibition of eNOS, which impairs its homeostatic signaling and also results in vasoconstriction and potential ischemic damage. Thus, NOS isoform-selective inhibitors are being designed that exploit subtle differences in substrate binding sites between the isoforms, as well as newer isoform-selective inhibitors that prevent NOS dimerization, the conformation required for enzymatic activity. The efficacy of NOS isoform-selective inhibitors in medical conditions is under investigation.
NO donors, which release NO or related NO species, are used clinically to elicit smooth muscle relaxation. Different classes of NO donors have differing biologic properties, depending on the nature of the NO species released and the mechanism that is responsible for its release.
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Organic Nitrates—Nitroglycerin, which dilates veins and coronary arteries, is metabolized to NO by mitochondrial aldehyde reductase, an enzyme enriched in venous smooth muscle, accounting for the potent venodilating activity of this molecule. Venous dilation decreases cardiac preload, which along with coronary artery dilation accounts for the antianginal effects of nitroglycerin. Other organic nitrates, such as isosorbide dinitrate, are metabolized to an NO-releasing species through a poorly understood enzymatic pathway. Unlike NO, organic nitrates have less significant effects on aggregation of platelets, which appear to lack the enzymatic pathways necessary for rapid metabolic activation. Patients taking organic nitrates exhibit rapid tolerance during continuous administration. This nitrate tolerance may derive from the generation of reactive oxygen species that inhibit mitochondrial aldehyde reductase, endogenous NO synthesis, and other pathways (see Chapter 12).
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Organic Nitrites—Organic nitrites, such as the antianginal inhalant amyl nitrite, also require metabolic activation to elicit vasorelaxation, although the responsible enzyme has not been identified. Nitrites are arterial vasodilators and do not exhibit the rapid tolerance seen with nitrates. Amyl nitrite is abused for euphoric effects, and combining it with phosphodiesterase inhibitors, such as sildenafil, can cause lethal hypotension. In clinical medicine, amyl nitrite has been largely replaced by nitrates, such as nitroglycerin, which are more easily administered.
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