Inducible nitric oxide synthetase

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. 

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). 

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. 

Hoffman, R. A., Langrehr, J. M., and Simmons, R. L. (1992). The role of inducible nitric oxide synthetase during graft-versus-host disease. Transplant. Proc. 24, 2856. 

Mascolo, N., Izzo, A. A., Babato, F, and Capasso, F. (1993) Inhibitors of nitric oxide synthetase prevent caster-oil-induced diarrhea in the rat. Br. J. Pharmacol. 108, 861-864. 

Kosenko, E., Kaminsky, Y., Grau, E., Minana, M.D., GrisoUa, S., and Felipo, V. 1995. Nitroarginine, an inhibitor of nitric oxide synthetase, attenuates ammonia toxicity and anuno-nia-induced alterations in brain metabolism. Neurochem. Res. 20 451-456. 

Pb also functions in experimental hypertensive and other vascular disease systems by inducing oxidative stress via ROS and nitric oxide, with increased superoxide, elevated malondialdehyde (MDA) and increased 3-nitrotyrosine. Vaziri et al. (1997) dosed adult male rats with low levels of Pb in drinking water (100 ppm, 12 weeks) followed by treatment with the antioxidant lazaroid. Pb treatment produced experimental hypertension in concert with increased ROS level and decreased NO excretion. The antioxidant abolished the Pb-induced hypertension and normalized both plasma MDA and urinary NO - Similarly, these workers (Vaziri et al., 1999) showed that vitamin E obliterated the hypertension while normalizing nitrotyrosine and urinary NO levels. Table 13.11 also notes the role of tempol, a superoxide dismutase (SOD)-mimetic drug, in modifying the oxidative stress induction of the hypertensive response in Pb-exposed rats (Vaziri et al., 2001). In particular, the drug reversed the upregulation of NO synthetase isoforms. 

---