Abstract
Portal hypertension (PHT) resulting from splanchnic vasodilatation is a major cause of morbidity and mortality in patients with cirrhosis. The renin-angiotensin system (RAS) plays an important role in splanchnic vasodilatation in cirrhosis. This study investigated whether acute blockade of the vasodilatory receptors of the alternate RAS, Mas (MasR), Mas-related G-protein coupled receptor type D (MrgD), and angiotensin II type-2 receptor (AT2R) improves PHT in cirrhotic and non-cirrhotic portal hypertensive rats and counteracts systemic hypotension associated with angiotensin II type 1 receptor (AT1R) blockade. Cirrhotic bile duct ligated (BDL) or carbon tetrachloride (CCl4) injected and non-cirrhotic partial portal vein ligated (PPVL) rats were used for measurement of portal pressure (PP) and mean arterial pressure before and after an intravenous bolus injection of the MasR, MrgD, and AT2R blockers, A779, D-Pro7-Ang-(1-7) (D-Pro) and PD123319, respectively. Separate groups of rats received a combined treatment with A779 or D-Pro given 20 min after AT1R blocker losartan. Mesenteric expression of MasR, MrgD, and AT2R and circulating levels of peptide blockers were also measured. Treatment with A779 and D-Pro significantly reduced PP in cirrhotic rat models. Despite rapid degradation of A779 and D-Pro in the rat circulation, the PP lowering effect of the blockers lasted for up to 25 min. We also found that PD123319 reduced PP in CCl4 rats, possibly by blocking the MasR and/or MrgD since AT2R expression in cirrhotic mesenteric vessels was undetectable, whereas the expression of MasR and MrgD was markedly elevated. While losartan resulted in a marked reduction in PP, its profound systemic hypotensive effect was not counteracted by the combination therapy with A779 or D-Pro. In marked contrast, none of the receptor blockers had any effect on PP in non-cirrhotic PPVL rats whose mesenteric expression of MasR and MrgD was unchanged. We conclude that in addition to MasR, MrgD, a newly discovered receptor for Angiotensin-(1-7), plays a key role in splanchnic vasodilatation in cirrhosis. This implies that both MasR and MrgD are potential therapeutic targets to treat PHT in cirrhotic patients. We also conclude that the alternate RAS may not contribute to the development of splanchnic vasodilatation in non-cirrhotic PHT.
Highlights
Portal hypertension (PHT) is a clinical syndrome defined by a pathological increase of pressure within the portal vascular system and is the major cause of morbidity and mortality in patients with cirrhosis (Rodriguez-Vilarrupla et al, 2007)
The present study demonstrates that blockade of the receptors of the alternate renin angiotensin system (RAS) is effective in reducing portal pressure in cirrhosis
Peptide-derived blockers such as A779 and D-Pro reduce portal pressure via inhibition of vasodilatory MasR and Mas-related G-protein coupled receptor type D (MrgD), which is likely associated with a subsequent increase in splanchnic vascular resistance, resulting in reduced portal blood flow (Grace et al, 2013) a bolus dose of the blockers was unable to produce a clinically significant reduction
Summary
Portal hypertension (PHT) is a clinical syndrome defined by a pathological increase of pressure within the portal vascular system and is the major cause of morbidity and mortality in patients with cirrhosis (Rodriguez-Vilarrupla et al, 2007). Systemic administration of Ang II type 1 (AT1R) receptor blockers may improve PHT in early cirrhotic patients by reducing intrahepatic vascular resistance (Paizis et al, 2001; Kurikawa et al, 2003; Sookoian et al, 2005; Tandon and GarciaTsao, 2006; Tox and Steffen, 2006; Hennenberg et al, 2007; Kim et al, 2012), they have limited efficacy in advanced liver disease possibly due to the activation of other vasoconstrictive pathways such as the sympathetic nervous system (Tandon et al, 2010) Treatment with these drugs is associated with a number of off-target effects, including systemic hypotension and renal hypoperfusion (Heller et al, 2003, 2005; Schepke et al, 2008; Tandon et al, 2010)
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