Effects of Nebulized Diethylenetetraamine-NONOate in a Mouse Model of Acute Pseudomonas aeruginosa Pneumonia: NONOates

When NONOates are administered IV, they have been shown to cause both systemic and pulmonary vasodilation in animals. The rate of NO release and the resulting degree of vasodilation are related to the chemistry of the nucleophile moiety of the individual NONOate compounds. The intratracheal instillation of NONOate has been shown to selectively dilate the pulmonary vasculature both in normal rats and in rats with U-46619-induced pulmonary hypertension. Aerosolized NONOate also has been shown to attenuate pulmonary hypertension and improve oxygenation in several animal models.
The effects of NONOates have been presumed to be NO-mediated. However, the majority of studies of the effects of NONOates have not assessed the direct effects of the respective nucleophile-backbone moieties. Indeed, in one study the lack of increase in plasma NOx— levels following nebulized NONO-ate may argue against the observed pulmonary vasodilator effect being NO-dependent. Although an antibacterial effect of DETA-NO was demonstrated both in vivo and in vitro in the present study, it is clear that this effect was not necessarily NOmediated. Indeed, significant antibacterial activity appears to reside in the DETA nucleophile moiety. Similarly, it is conceivable that some of the previously reported effects of various NONOates also may be NO-independent and may be related to the unstudied effects of the various nucleophile moieties. ventolin inhaler

In vivo assessment of the effects of nebulization of the DETA moiety itself may have been of interest, but access to a commercial source of DETA proved difficult and costly. Moreover, during the process used to generate exhausted DETA in vitro from DETA-NO, the released NO yielded a significant amount of soluble nitrite. Thus, the nebulization of this exhausted DETA-NO solution, as an in vivo control for DETA-NO exposure, would have been associated with the concomitant exposure of mice to significant levels (ie, 5 to 50 mM) of nitrite. It has been recognized that peroxidase activity, in the presence of nitrite, can oxidize tyrosine to generate 3-nitrotyrosine.