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pulmonary circulation appeared to counteract hypoxic vasoconstriction responses to
catacholamines and prostaglandin F2c, with NO release decreased in chronic hypoxia
(Crawley, Liu et al. 1990). In vivo the NANC nerves were shown to cause vasodilatation and
relaxation of animal and human tracheal muscle using NO as the mediator and these were not
inhibited by NOS inhibitors (Stuart-Smith, Bynoe et al. 1994; Baba, Yoshida et al. 1998;
Sipahi, Ercan et al. 1998). However, human airway specimens suggested this NO mediator
relaxation via the NANC neryes was more important in the response of distal rather than
proximal airways (Ellis and Undem 1992).In addition, the NO-dependent NANC dilatation of
human bronchi was reduced in transplanted tissue and in specimens from patients with CF
@elvisi, Barnes et al. 1995; Belvisi, Ward et al. 1995). Nitrosothiols of low molecular weight,
such as S-nitrosoglutathione, and NOz were also detected in alveolar fluid from normal
individuals at concentrations sufficient to suggest regulation of basal airway tone @arnes
1993; Gaston, Reilly et al. 1993).
The NOS enzymes were considered to have a role in mucociliary clearance, and even now
this remains uncertain as the precise regulation of ciliary beat frequency is still unclear.
Similar to NOS activity, ciliary beat frequency is increased by a rise in intracellular calcium
with possible intracellular mechanisms involving cAMP, calmodulin, and inositol 1,4,5-
triphosphate. Increases of NO have been detected when ciliary beat increases, although no
consistent correlation has been shown between NO levels and cilia activity (Wanner, Salathe
et al. 1996; Dirksen 1998; Yeates 1998; Uzlaner and Priel 1999). Ciliated cells have been
shown to have increased NO production and increased beat frequency after treatment with L
arginine (Li, Shirakami et al. 2000) and L- NMMA caused a 4OVo decrease in ciliary beat
frequency lasting 60 minutes which was reversed with L-arginine administration (Jain,
Rubinstein et al. 1993).
Finally NOS activation in macrophages, neutrophils and mast cells exerts bactericidal and
fungicidal effects primarily through the oxygen superoxide formation of the NO products
such as perioxynitrite as covered in Chapters 2.3.4 and 3.4.2. These are important in host
defence but in excess can have similady detrimental effects on the normal cells. Higher
concentrations of NO in combination with oxidant generation leads to inflammation and
oedema (Beckman, Beckman et al. 1990; Mulligan, Hevel et al. 1991; Mulligan, Warren et al.
L992) and these potent oxidants deplete glutathione, uric acid and ascorbate in lung lining
fluid (Williams, Rhoades et al. I97l; Kelly, Shah et al. t997). Exposure of alveolar type II
cells particularly to perioxynitrite leads to profound inhibition of surfactant synthesis (Gaston,
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