Fernando, Bimbi Shiran; (1999) Oxidant stress and the hyperdynamic circulation in portal hypertension. Doctoral thesis (M.D), University of London, Royal Free Hospital School of Medicine.

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Abstract

The partial portal vein ligation rat model of portal hypertension is associated with the development of a hyperdynamic circulation characterised by an increased cardiac index and a reduced systemic vascular resistance. Recent studies have shown that tumour necrosis factor-α is involved in the development of the hyperdynamic response. Studies on tumour necrosis factor-α in vitro have shown that the signal transduction pathways involve activation of the transcription factor NF-κB by reactive oxygen species and that this can be inhibited by antioxidants. It is not known however, whether involvement of these pathways can be demonstrated in vivo in this model, and whether treatment with antioxidants can inhibit these signalling pathways and thus the development of the hyperdynamic circulation. This thesis concentrated on the signal transduction pathways and the possible role of oxidant stress in the generation of the hyperdynamic circulation in the partial portal vein ligated rat model compared with sham controls. Firstly, a group of compounds known as the F2-isoprostanes were studied as markers of lipid peroxidation. Secondly, activation of the transcription factor NF-κB was measured in whole liver from different study groups. Levels of plasma TNF-α levels were then measured, as were plasma levels of nitrite and nitrate. Finally, haemodynamic studies were performed in different groups to evaluate the pharmacodynamic effects of different reagents including N-acetylcysteine, pyrrolidine dithiocarbamate and BB-1101. Partial portal vein ligation is associated with increased lipid peroxidation, activation of hepatic NF-κB and increased nitric oxide synthesis. Furthermore, the hyperdynamic circulation can be inhibited by the chronic administration of N-acetylcysteine, pyrrolidine dithiocarbamate and BB-1101 to PPVL rats. The precise mechanism of action of these reagents remains unclear and further work needs to be performed to answer these questions.

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