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cerebral artery ligation in several animal models (Dawson, Dawson et al. 1992; Yun, Dawson
et al. 1997) and the NOS knock out mice had smaller infarcts after cerebral ischaemia
(Iadecola 1997). The neurons which actually have high levels of both the NOS and the
NADPH enzymes appear resistant to a variety of toxic insults including Huntington's disease,
Alzheimer's disease and vascular stroke (Ferrante, Kowall et al. 1985; Koh, peters et al.
1986). These neurons are also rich in manganese super oxide dismutase, and if this
contributes to the neuroprotection, it may be similar to the reason for the variation of the half
life initially given in the cardiovascular experiments reported above -
i.e. that it depends on
the extent of super oxide anion availability. Excess NO levels have also been implicated in
demyelinating conditions such as multiple sclerosis (Parkinson, Mitrovic et al. t997) and
periventricular leukomalacia (Koprowski , Zheng et al. 1993). There is evidence showing that
the production of NO is significantly raised within the multiple sclerosis lesions, but also in
the cerebral spinal fluid, blood, and urine of these patients (Lin, Lin et al. 1993). In addition,
the lack of ability to generate NO is important, such as seen in patients with Duchenne
Muscular Dystrophy in whom skeletal muscle lack expression of the neuronal NOS
(Brenman, Chao et al. 1995).
As mentioned, NO is also found in peripheral nerves where it contributes to sensory
transmission and is a transmitter and/or modulator in non-adrenergic non-cholinergic (NANC)
neryes, although there is considerable variation depending on both experimental conditions
and the different species in which the experiments are carried out. The NANC nerves cause
vasodilatation and relaxation of animal and human tracheal muscle via NO release, and this is
not inhibited by NOS inhibitors (Stuart-Smith, Bynoe et al. 1994: Baba, yoshida et al. 199g;
Sipahi, Ercan et al. 1998). In human airway specimens, the NANC NO mediator relaxation is
more important in the distal airways (Belvisi, Stretton et al. 1992: Ellis and Undem lgg2).
This response is reduced in recipient transplanted human bronchial tissue and in specimens
from patients with CF (Stretton, Mak et al. 1990).
In the gastrointestinal tract, NO seems to mediate relaxation including dilatation of the
stomach, the sigmoid colon and the internal anal sphincter in humans. Selectively blocking
the NANC mediated relaxation of the gastrointestinal tract in mice resulted in marked
stomach enlargement and inner circular gut muscle layer hypertrophy, thought to be
compensatory for the inability of the pyloric sphincter to relax (Huang, Dawson et al. 1993;
Bredt 1999). Histochemical studies of biopsy specimens from infants with hypertrophic
pyloric stenosis and biopsy studies from adults with cardiac aplasia seem to confirm this with
reduced NOS enzyme demonstrated (Vanderwinden, Mailleux et al. 1992). Also the gene
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