Medicine (Austin & Northern Health) - Theses
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ItemThe role of the alternate renin angiotensin system in human portal hypertension( 2018)The vast majority of morbidity and mortality in human liver cirrhosis occurs due to portal hypertension. In advanced cirrhosis as resistance to intra-hepatic portal flow increases there is vasodilatation of the splanchnic vascular bed, which results in increased flow in the portal circulation thus contributing significantly to portal pressure. The pathophysiology underlying splanchnic vasodilatation in cirrhosis is not well understood. However, recent in-vivo and ex-vivo studies of experimental models of liver injury demonstrate that the novel ‘alternate arm of the renin angiotensin system’ is activated in cirrhosis and mediates vasodilatation through its effector peptide, angiotensin-(1-7). The aim of this thesis was thus to evaluate the role played by the alternate renin angiotensin system in human cirrhosis. The vasoactivity of renin angiotensin system mediators were studied in a myograph device using isolated vessels from animal models of cirrhosis and from human subjects undergoing liver transplantation surgery. Circulating components of both the classical and alternate renin angiotensin system were measured regionally in patients with cirrhosis undergoing liver transplantation or a portosystemic shunt procedure. Finally, the in-vivo response to angiotensin-(1-7) in an isolated peripheral vascular bed was compared between cirrhotic subjects and healthy controls. In-vitro studies showed contractile responses of isolated splanchnic vessels to be attenuated by angiotensin-(1-7) and levels of this peptide and its integral enzyme, angiotensin converting enzyme 2, were upregulated in human cirrhosis. Activation of the alternate renin angiotensin system in human cirrhosis was most marked in patients with clinical and laboratory features of advanced disease whilst deactivation of the system occurred post liver transplantation with restoration of normal circulatory function. Angiotensin-(1-7) elicited vasodilatation in the peripheral circulations of both cirrhotic and control subjects, however, this response was threefold higher among the cirrhotic group. In conclusion the data presented in this thesis provides evidence that the alternate renin angiotensin system is activated in human cirrhosis and through the action of the angiotensin-(1-7) peptide may contribute to pathological vasodilatation.