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locus for the enzyme is a susceptibility locus for infantile pyloric stenosis (Chung, Curtis et
al. 1996).
NO also has many roles in the reproductive system (Rosselli, Keller et al. 1998), an example
being a reduction of NO being associated with pre-eclampsia and premature delivery. NO
functions as the NANC transmitter which leads to relaxation of the corpus cavernosum and
thus the development of penile erections with its effect able to be blocked in animal studies
(Burnett, Lowenstein et al. 1992). A local reduction in NO is associated with decreased
bladder capacity and hyperactivity (Burnett, Calvin et al. 1997) with knock-out mice
displaying hypertrophied urinary bladders and loss of neurally mediated relaxation of urethral
and bladder muscle, which provides a model for voiding disorders in humans. Studies in
animals show that there is increased expression of NOS during pregnancy with increased
urinary excretion of nitrite and nitrate (Conrad, Joffe et al. 1993; Conrad, Vill et al. 1993).
The vasodilatation and decrease in blood pressure during pregnancy is likely to be also due to
increased NO secretion with uterine NO synthesis preventing myometrial contraction.
2.3.4 (iii) Host defence
That NO was used in host defence was discovered in one of the original areas of research that
delineated the importance of NO. The use of NO may have originated in evolution as a first
line defence against invading micro-organisms (Hibbs 1991; Bogdan 2001). Resistance to
tumour cells and cancer development was shown to be enhanced in a non-specific way by
bacterial products (Nathan t992), Activated macrophages were demonstrated to synthesise
nitrite and nitrate, with generation dependant on L-arginine and inhibited by analogues of L-
arginine (Hibbs, Vavrin et al. 1987). The generation of NO is now a known feature of many
immune cells (dendritic cells, NK cells, mast cells, monocytes, macrophages, microglial cells,
Kupffer cells, eosinophils and neutrophils) as well as other cells involved in the immune
reaction (such as endothelial cells, epithelial cells, vascular smooth muscle cells, fibroblasts,
keratinocytes, chondrocytes, hepatocytes, mesangial cells and Schwann cells), (Bogdan
2001). The NO produced in these cells comes from the inducible form of NOS having the
ability to generate much larger amounts of NO than the other enzyme types; the local
concentration of NO synthesis is an important determinant of cytotoxicity. NO is a ubiquitous
pathogen-killing agent and it is truly a generalist with a non specific response to infection. It
can be toxic to many kinds of pathogen including viruses, bacteria and parasites (both
intracellular and extracellular) as well as some metazoan parasites (James 1995; Bogdan
2O0L; Colasanti, Gradoni et al. 2002). NO mediated killing of bacteria is thought to have been
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