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negative feedback mechanism to inhibit platelet activation (Mehta, Chen et al. 1995). NO is
also involved in the reaction of leukocytes with vessels walls, again inhibiting activation. NO
inhibits vascular smooth muscle cell hyperplasia which may reduce the development of
pulmonary hypertension (Papapetropoulos, Garcia-Cardena et al. 1997; Ziche, parenti et al.
1997). Endothelial dependant relaxation demonstrated in human vascular tissue is greater in
the arteries than the veins, suggesting that arteries may generate more NO. This relaxation is
inhibited in a number of patient groups with pulmonary vascular disease. The response is
decreased in atherosclerotic coronary arteries compared with normal coronary arteries
(Egashira, Suzuki et al. 1995), in children and adult patients with hypercholesterolemia
(Quyyumi, Mulcahy et al. 1997), and in patients with essential hypertension (panza,Garcia et
al. 1995). It is also Iower in the vessels of diabetic animals (Sobrevia, Nadal et al. 1996) and
in pulmonary arteries obtained from patients undergoing heart lung transplantation @usting
and Macdonald 1995). NO dysfunction has also been noted as contributing to hean failure
(Hanssen, Brunini et al. 1998; Sharma, Coats et al. 2000), and to the pathogenesis of sickle
cell disease @nwonwu, Xu et al. 1990; Waugh, Daeschner et al. 2001). Finally, it has been
shown when solutions of L-arginine (substrate for NO generation) are exposed to cigarette
smoke, there is a depletion of L-arginine and the formation of cyanomethyl-L-arginine and
this is likely to act as a competitive inhibitor and has been shown to have an inhibitory effect
on NOS. This may contribute to the vascular compromise seen in long term smokers (Wong
2000).
NO is also associated with significant pathology within the vascular system in regards to
sepsis (Vallance and Moncada 1993).In endotoxin shock in animals, the generation of NO is
directly related to the degree of systemic hypotension. This is also seen as a characteristic of
septic shock in humans and it is also suggested as being responsible for the hypotension
induced by chemo/radiation therapy seen in patients with cancer who undergo such treatment.
Endotoxin also induces NOS production and activity in venous smooth muscle cells and
increased NO here may play a role in the hypotension seen with endotoxaemia. Similarly
endotoxin induces NOS production in the myocardium, which may contribute to the dilated
cardiomyopathy development. There have been trials using inhibitors of No to reverse the
hypotension which has been induced in animal models by lipopolysaccharide or endotoxin via
TNF0. However the level of inhibition of NOS is crucial for outcome, since high doses cause
severe vasoconstriction and end organ damage in multiple organs and thus causes rapid death.
With titration being the key factor and difficult to control in experiments to date without
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