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Garthwaite l99l), and the non adrenergic, non cholinergic (NANC) peripheral nerves (Bredt,
Hwang et al. 1990; Rand 1992).
NO was subsequently found, with likely mediator roles, in the renal cortex epithelial cells,
adrenal glands, gut, genital system and has also been found in amniotic fluid (Nathan 1992).
Thus NO was realised to be an important gas used in biological systems in many species
including humans, and within humans NO was seen in a wide variety of tissues as a gaseous
mediator. The type of roles it fulfils in three of these key systems (cardiovascular,
neurological and immunity) will be discussed briefly below, while the role of NO in the lung
is discussed in more depth in Chapter 4,preparatory to measuring levels from the airway.
2.3.4 Nitic oxide in physiological roles
2.3.4(i) Cardiovascular
NO is produced by nitric oxide synthases (NOS) which generate NO from the semi-essential
amino acid L-arginine and release picomolar amounts of NO in response to receptor
stimulation (see Chapter 3 and 4 for detail on chemical reactions and pathways). In this way
NO is responsible for the basal vasomotor tone and essential for the regulation of blood flow
and blood pressure. NO dependent vasodilator tone is in part maintained through the release
of NO in response to physical activation of endothelium cells by stimuli such pulsatile flow
and shear stress. This role was in part determined by the studies described above before NO
was so-named, and in part been determined subsequently by the use of the non-functioning
competitive inhibitor of this enzyme, L-NMMA. A potent vasoconstrictor, L-NMMA
constricts vascular beds and produces a hypertensive response in animals with high potency
@lsner, Muntze et al. 1992) and has been shown to cause vasoconstriction in the forearm
circulation in humans (Gardiner, Compton et al. 1990). As documented below, NO is also
released by non-adrenergic non-cholinergic (NANC) nerve terminals and this may also
contribute to the regulation of blood flow and pressure. The success of compounds used in
angina and hypertension such as nitro glycerine and sodium nitroprusside are now known to
be because these compounds imitate endogenous nitro-vasodilator compounds by relaxing
blood vessels @oel, Godber et al. 2000).
NO also inhibits platelet aggregation and adhesion. This occurs with the increase in cGMP
activity within platelets and subsequent phosphorylation of proteins that regulate platelet
activation (Radomski, Palmer et al. 1987; Radomski, Palmer et al. 1987). It can also be
generated either by the endothelium or the platelets themselves generating NO to act as a
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