ENDOGENOUSLY GENERATED NITRIC OXIDE
NO is an environmental pollutant, the finding that NO is synthesized by cells
and activates specific intracellular signaling pathways was unexpected. The
first indication that NO is gener-ated in cells came from studies of cultured
macrophages, which showed that treatment with inflammatory mediators, such as
bac-terial endotoxin, resulted in the production of nitrate and nitrite,
molecules that are byproducts of NO breakdown. Similarly, injec-tion of endotoxin
in animals elevated urinary nitrite and nitrate.
second indication came from studies of vascular regulation. Several molecules,
such as acetylcholine, were known to cause relaxation of blood vessels. This
effect occurred only when the ves-sels were prepared so that the luminal
endothelial cells covering the smooth muscle of the vessel wall were retained.
Subsequent studies showed that endothelial cells respond to these vasorelaxants
by releasing a soluble endothelial-derived
relaxing factor (EDRF). EDRF acts on vascular muscle to elicit relaxation.
These findings prompted an intense search for the identity of EDRF.
the same time, it was observed that exogenous application of NO or organic
nitrates, which are metabolized to NO, elicit a variety of effects including
inhibition of platelet aggregation and vasorelaxation. These effects were
particularly intriguing, since they appeared to involve the activation of
highly specific cellular responses, rather than more general cytotoxic
responses. Comparison of the biochemical and pharmacological properties of EDRF
and NO provided initial evidence that NO is the major bioactive component of
EDRF. These findings also made it clear that exogenously applied NO and
NO-releasing compounds (nitrates, nitrites, nitroprusside;) elicitedtheir
effects by recruiting physiologic signaling pathways that normally mediate the
actions of endogenously generated NO.