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oxide of nitrogen which was more reactive than nitrite or nitrate. It was also shown that
macrophages used an oxidative form of injury associated with iron loss and involving
inhibition of iron-sulphur enzymes to inflict damage on tumour cells and fungi. L-arginine
was then identified as the necessary metabolite in the extracellular medium to sustain this
form of macrophage-mediated cytotoxicity (Hibbs 1991). Substituting L-arginine analogs
blocked the cytotoxicity in a stereospecific manner and blocked the production of nitrite by
activated macrophages. Nitrite or nitrate substances alone could not replicate the cytotoxicity
of the nitrite-producing macrophage except when in an acidic pH - a condition coincidentally
in which nitrite can generate NO (Hibbs, Vavrin et al, 1987; Stuehr, Gross et al. l9g9). NO
(rather than other nitro-oxygen species) specifically mimicked the pattern of macrophage-
mediated cytotoxicity and scavengers of NO blocked the cytostatic effect of macrophages.
Funher investigation showed that this cytostatic effect used by the macrophages was also
operational against yeasts, helminths, protozoa and mycobacteria (Nathan and Hibbs 1991).
2.3.3 Nitric oxide -
a common pathway
These two separate areas of investigation into immune function and vasomotor control came
together in 1989, when Stuler showed that the compound secreted by activated alveolar
macrophages with L-Arginine availability, demonstrated the same bioactivity as that
described for EDRF and coincided with the chemical reactivity profile of NO (Stuehr, Gross
et al. 1989).
When these two major discoveries came together, it suggested NO synthesis from L-arginine
might in fact be a widespread pathway for the regulation of cell function and communication.
NO has the lowest molecular weight of any known bioactive mediator that cells produce. The
molecule's chemical reactivity means that its half life is short and interaction specificity is
minimal. Therefore, it was surprising that such a simple, fleeting, indiscriminating reactant
could convey enough information in a regulatory manner to help control vital mechanisms
such as vascular tone and neurotransmission (see below Section 2.3.4).It was also surprising
that a mediator involved in homeostasis, was also involved in host defence to destroy micro-
organisms and tumour cells (Nathan 1992). Following the demonstration that both
endothelium cells and macrophages were able to synthesis this new mediator, there was an
explosion of research demonstrating that many other cells were able to produce NO. This
molecule was shown to have physiological roles in many neuronal tissues; including the
cerebellum, the cerebral cortex and the hypothalamus, as well as in ganglion cells of the
autonomic nervous system (Garthwaite, Charles et al. 1988; Bredt and Snyder 1990;
6t