Medicine (Austin & Northern Health) - Theses
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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.