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.
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ItemThe role of the alternate renin-angiotensin system in the pathogenesis of splanchnic vasodilatation in cirrhosis( 2012)The classic renin-angiotensin system (RAS), mediated by angiotensin II, contributes towards the pathophysiology of fibrogenesis and elevated hepatic resistance in cirrhosis, and the alternate axis of the RAS, comprising angiotensin-converting enzyme-2 (ACE2), angiotensin-(1-7) and the Mas receptor, may have opposing effects. Splanchnic vasodilatation, with consequent increased portal venous inflow, is a key factor in the pathogenesis of portal hypertension in cirrhosis. There is splanchnic vascular hypocontractility to angiotensin II in cirrhosis, but the role of the alternate axis of the RAS in the splanchnic circulation is unknown. The aim of this thesis was to determine whether the alternate axis of the RAS is implicated in the pathophysiology of splanchnic vasodilatation in experimental cirrhosis. Expression of the splanchnic vascular RAS was characterised in rats with portal hypertension induced by chronic biliary cirrhosis. In-vivo levels of angiotensin-(1-7) and angiotensin II, and ex-vivo metabolism of angiotensin peptides was examined in the portal circulation in cirrhosis. Finally, the effect of angiotensin-(1-7) on splanchnic vascular contractility was studied ex-vivo in two models of portal hypertension, that due to chronic biliary cirrhosis, and that due to partial portal vein ligation, where liver injury is absent. In experimental cirrhosis, there was upregulation of ACE2 in the splanchnic vasculature, and portal levels of angiotensin-(1-7) were increased, whereas expression of the classic arm of the RAS was unchanged from controls. There was increased, ACE2-mediated, formation of angiotensin-(1-7), both from angiotensin I and from angiotensin II, in cirrhotic vessels. Angiotensin-(1-7) mediated splanchnic vascular hypocontractility in both portal hypertension due to experimental cirrhosis and that due to partial portal vein ligation. These effects of angiotensin-(1-7) occurred via the Mas receptor and the angiotensin II type 2 receptor, both of which were also upregulated in cirrhotic vessels. In conclusion, the data presented in this thesis provide evidence of a shift towards increased activity and expression of the ACE2/angiotensin-(1-7)/MasR axis in the splanchnic vessels as a novel causal mechanism for vascular hypocontractility in cirrhosis, and identify potential therapeutic targets in portal hypertension.