Nitric oxide synthetase

Hope, B.T., Michael, G.J., Knigge, K.M. and Vincent, S.R. (1991). Neuronal NADPH diaphorase is a nitric oxide synthetase. Proc. Natl Acad. Sci. USA 88, 2811-2814. 

Nitric oxide, a vasodilatory hormone released by the endothelium, is found in higher concentrations in HF patients and provides two main benefits in HF vasodilation and neurohormonal antagonism of endothelin.9 Nitric oxide s production is affected by the enzyme inducible nitric oxide synthetase (iNOS), which is up-regulated in the setting of HF, likely due to increased levels of angiotensin II, norepinephrine, and multiple cytokines. In HF, the physiologic response to nitric oxide appears to be blunted, which contributes to the imbalance between vasoconstriction and vasodilation. 

The fungal metabolite, 5-A-acetylardeemin, possessing a hexacyclic structure with a l,4-dihydro-3,6-dioxo-pyra-zino[2,l-A]quinazoline skeleton, is the best multidrug resistance reversal agent known to date <1998MI45>. Hexahydro-3,6-dioxo-pyrazino[2,l-7]quinazolines have been claimed as endothelial nitric oxide synthetase regulators useful in the treatment of cardiovascular disorders <2004EP1471066>. 

Simoncini T, Genazzani AR, Liao JK (2002a) Nongenomic mechanisms of endothelial nitric oxide synthetase activation by the selective estrogen receptor modulator raloxifene. Circulation 105 1368-1373... 

Deleterious protein cross-linking can also be induced by reactive nitrogen species (RNS) such as peroxynitrite ONOO formed by the reaction of superoxide with nitric oxide (NO). The cross-links are formed between tyrosine residues following nitration by peroxynitrite (Sitte, 2003). Carnosine appears to play roles not only in NO generation but also in protection against excess NO production by inducible nitric oxide synthetase (NOS), thereby preventing ONOO-mediated protein modification (Fontana et ah, 2002). Evidence for a carnosine-NO adduct has also been published (Nicoletti et al., 2007). 

Evidence of a behavioral role for central neuronal nitric oxide synthetase has been reported. A knockout mouse deficient in the gene encoding for this enzyme... 

Bredt, D. S., and Snyder, S. H. (1990). Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc. Natl. Acad. Sci. U.S.A. 87, 682-685. 

Mills, C. D. (1991). Molecular basis of suppressor macrophages Arginine metabolism via the nitric oxide synthetase pathway. J. Immunol. 146, 2719-2723. 

An effect secondary to the activation of enzymes by increased calcium levels can be increased production of reactive oxygen and nitrogen species. Thus, activation of mitochondrial dehydrogenases increases NADH production and electron transport, yet increased calcium uncouples ATP synthesis, and the excess electron generates superoxide. Calcium also activates nitric oxide synthetase. 

FIGURE 14—3. Nitric oxide (NO) is formed by the enzyme nitric oxide synthetase (NOS), which converts the amino acid 1-arginine into nitric oxide and 1-citrulline. 

FIGURE 14—14. Some antidepressants such as serotonin selective reuptake inhibitors (SSRIs) may inhibit nitric oxide synthetase (NOS) and thereby reduce NO and cause erectile dysfunction. 

Besides neuropeptides, nitric oxide is an inflammatory mediator in the airways, which is also a vasodilator and a neurotransmitter. Nitric oxide is produced by the enzymatic action of nitric oxide synthetase on L-arginine. Airways contain this enzyme in three different forms, two of which termed neuronal and endothelial nitric oxide synthetase are constitutive whereas the third form called inducible nitric oxide synthetase is inducible. The inflammatory cytokines including IL-1 and TNF-a augment the expression of inducible nitric oxide synthetase in human airway epithelial cells. Nitric oxide causes bronchodilation as a result of the relaxation of bronchial smooth muscles. It has also been suggested that nitric oxide is the neurotransmitter of the inhibitory NANC bronchodilation. The detrimental effects of nitric oxide include airway inflammation and vasodilation. It causes airway edema by increasing the erudition of plasma due to increased blood flow to postcapillary venules. The increased blood flow may also contribute to an increased mucus secretion. The role of nitric oxide in inflammatory responses has not yet been established. 

Nitric oxide may suppress THi subset and its high levels may increase the expression of TH2 subset. The action of inducible nitric oxide synthetase may result in increased exhaled nitric oxide in asthmatics. The airway epithelial cells are the predominant source of increased nitric oxide in asthmatic subjects. Since nitric oxide has both beneficial and adverse effects on bronchial airways, its precise contribution to the etiology and pathogenesis of asthmatic disease requires additional investigation. 

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