Nitrated metabolites from nitrite

Given that hydroxylamine reacts rapidly with heme proteins and other oxidants to produce NO [53], the hydrolysis of hydroxyurea to hydroxylamine also provides an alternative mechanism of NO formation from hydroxyurea, potentially compatible with the observed clinical increases in NO metabolites during hydroxyurea therapy. Incubation of hydroxyurea with human blood in the presence of urease results in the formation of HbNO [122]. This reaction also produces metHb and the NO metabolites nitrite and nitrate and time course studies show that the HbNO forms quickly and reaches a peak after 15 min [122]. Consistent with earlier reports, the incubation ofhy-droxyurea (10 mM) and blood in the absence of urease or with heat-denatured urease fails to produce HbNO over 2 h and suggests that HbNO formation occurs through the reactions of hemoglobin and hydroxylamine, formed by the urease-mediated hydrolysis of hydroxyurea [122]. Significantly, these results confirm that the kinetics of HbNO formation from the direct reactions of hydroxyurea with any blood component occur too slowly to account for the observed in vivo increase in HbNO and focus future work on the hydrolytic metabolism of hydroxyurea. 

These compounds contain the fragment R as an alkyl or aryl moiety. In other words, they result from the esterification of an alcohol or a phenol with nitrous acid, nitric acid, phosphoric acid, sulfuric acid, or sulfamic acid, respectively. Many of the esters to be examined in this chapter must be activated prior to eliciting their effects, e.g., the organic nitrites and nitrates, which act as donors of nitric oxide or an analogous molecule, and phosphates, which are activated by hydrolysis or even by phosphorylation (antiviral agents). Sulfates are very seldom active or used as prodrugs, but they have significance as metabolites and as industrial xenobiotics. 

It has long been known that nitrosamines derived from nicotine and certain of its metabolites are carcinogenic to experimental animals and the possibility exists that nitrosation could occur in vivo particularly in areas of high environmental nitrite/ nitrate. At present, there seems to be no evidence that implicates this process in smoking cessation programmes. However, it is important that evidence of addiction, cardiovascular diseases and carcinogenesis are carefully monitored in populations exposed to "medicinal" nicotine for long periods. 

The limits of detection were less then 200 fmol and the concentrations of nitrite and nitrate were typically 2 and 12 mM, respectively. A more recent report involved CE separations of arginine, citmllene, nitrate, and nitrite with LIE and conductivity detection Contrary to previous results, it was determined that nitrates are not always reliable indicators of NO synthase activity. Similarly, other metabolites associated with NO—arginine, citmllene, arginosuccinate, ornithine, and arginine phosphate—were quantified in Pleurobranchaea and Aplysia with limits of detection ranging from 5 nM to 17... 

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