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Hypertension complicates approximately 10% of all pregnancies and is a leading cause of maternal and foetal mortality and morbidity world-wide. Pre-eclampsia is a major subgroup of these hypertensive disorders. It is defined as a rise in blood pressure to 140/90mm Hg or greater accompanied by proteinuria and usually presents after 20 weeks of pregnancy. Much of the early research into this disorder has concentrated on the determination of vasoactive compounds such as the renin-angiotensin system and prostacyclin. In the 1980's it was discovered that an inorganic free radical molecule, nitric oxide (NO), was released from the endothelium cell lining of the vasculature and was involved in regulating vasodilation of the vasculature walls via smooth muscle.It was also shown to have cytotoxic effects on bacteria, to inhibit platelet aggregation and to act as a neurotransmitter. The aim of this research was to assess the role of nitric oxide in preeclampsia. This was accomplished by the analysis of its oxidation products nitrite and nitrate in plasma from women with pre-eclampsia compared with those from normotensive pregnancies. A simple and robust assay for nitrite and nitrate was developed using ion chromatography. Initial experiments using isocratic elution with conductivity detection on a Dionex QIC system with an AS4A-SC column showed promise but were unsatisfactory due to the interference from chloride ions. Successive improvements to the technique involved changing the elution system to a gradient, initially to one with carbonate and subsequently to chloride, changing the detector system to direct UV detection at 214nm and changing the column to a high capacity, strong exchanger type. The resulting method shows good resolution, does not suffer from chloride overload and was simple to use. Control results for 200 serum samples showed that the male mean nitrite and nitrate levels were 3.34 ± 5.17 μmol L" and 42.1 ± 33.1 μmol L-1 respectively while female levels were 4.74 ± 11.7 μmol L-' and 37.5 ± 27.9 μmol L" respectively. Addition information on the free-radical status of the pregnant study groups was assessed by determination of lipid peroxides and the peroxynitrite product, 3-nitrotyrosine. An improved GC-MS method was developed to quantify total fatty acids and lipid peroxides. A new reversed phase HPLC technique for the analysis of free 3-nitrotyrosine in human plasma/serum was also developed although sample numbers were not as great as expected. Statistical analysis using F-tests, t-tests and the Mann-Whitney analysis did not show any difference in nitric oxide metabolites, lipids, lipid peroxides or peroxynitrite between gestation matched normotensive pregnant women and those with pre-eclampsia or pregnancy-induced hypertension. Published research has shown a vital role for nitric oxide in the maintenance of blood flow in normal pregnancy. This research does not support evidence for diminished or enhanced nitric oxide production in pre-eclampsia compared with normal pregnancy.

3 pp. / Revised

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Nitric oxide is generated by the vascular endothelium from L-arginine by a constitutive, Ca2+-dependent, NO synthase. Analogues of L-arginine were characterised as inhibitors of NO synthase to investigate the biological significance of the L-arginine-NO pathway in the vessel wall and its role in the cardiovascular system. These inhibitors attenuate the endothelium-dependent vasorelaxation and hypotension induced by various agents, produce an increase in vascular tone and an increase in blood pressure. This suggests that NO is involved in endothelium-dependent relaxation and its continuous release maintains a vasodilator tone and plays a fundamental role in the regulation of blood flow and blood pressure. The removal of the NO-dependent vasodilator tone, results in an `upregulation' of its intracellular receptor, the soluble guanylate cyclase and an increased sensitivity to those vasodilators which act by stimulating this enzyme. This phenomenon of `supersensitivity' to nitrovasodilators may be an important component of their therapeutic action in certain cardiovasulcar disorders. Vascular tissue also expresses an inducible, Ca2+-independent, NO-synthase after activation by lipopolysaccharide (LPS) which results in the generation of large quantities of NO, predominantly from the smooth muscle layer, with a consequent loss of vascular tone and a hyporeactivity to the vasoconstrictor action of phenylephrine. Induction of NO synthase in the vasculature may therefore be responsible for the hypotension and hyporesponsiveness to pressor agents characteristic of endotoxin shock. The glucocorticoid, dexamethasone inhibits the expression of this enzyme but not its activity, which may explain why steroids are more effective at preventing rather than treating this condition. These results suggest that in the cardiovascular system, NO can be considered to have both a protective and a pathological role. The release of small amounts of NO from the constitutive, Ca2+-dependent NO synthase, acts as an adaptive mechanism whereby the vascular endothelium responds to changes in its environment and regulates blood flow and blood pressure to maintain organ perfusion. In contrast, following the induction of the Ca2+-independent NO synthase, after immunological stimulation, NO is released in large quantities from vascular tissue, which may result in pathological vasodilation and tissue damage.

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No description available.

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No description available.