Effects of angiotensin-(1–7) and angiotensin II on vascular tone in human cirrhotic splanchnic vessels

Casey, Stephen; Herath, Chandana B; Rajapaksha, Indu G; Jones, Robert; Angus, Peter W

doi:10.1016/j.peptides.2018.08.008

Cited by 6 publications

(5 citation statements)

References 45 publications

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“…These findings were however not in agreement with earlier findings which showed that AT1R-independent G-protein stimulation with AlCl 3 /NaF induced an intact contractile response of hepatic artery which is similar in magnitude to that of the control vessels obtained from organ donors and suggested that hyporesponsive to Ang II may be related to a receptor-specific phenomenon localized upstream from the G-protein level[ 243 ]. In marked contrast to these findings however, recent work published by our laboratory using splanchnic arterial vessels isolated from liver transplant recipients demonstrated that they were not hyporesponsive to the pressor effect of Ang II[ 84 ]. Thus, there is conflicting literature data regarding the vasoactivity of splanchnic arteries[ 84 , 243 , 245 ] and forearm arteries[ 240 , 246 ] to vasopressors such as Ang II, implying more work is needed to clarify the vasoactivity of mesenteric arterial vessels in portal hypertension as not only different vascular beds may respond differently to vasopressors but also differences in vasoactive responses may be due to the compounding effects of different experimental conditions[ 248 ].…”

Section: The Ras and Splanchnic Vascular Resistancementioning

confidence: 88%

“…It has also been suggested that despite the attenuated reactivity to vasoconstrictors, expression and affinity of some receptors to their endogenous vasoconstrictors are not altered, and therefore, alterations in downstream signal transduction pathways is likely to be primarily responsible for this vascular hypo-reactivity[ 81 - 83 ]. However, this phenomenon of hypo-contractility of cirrhotic splanchnic vessels was questioned by a recent study published by our laboratory, demonstrating that pressor response of splanchnic vessels obtained from liver transplant recipients to Ang II was similar to that of control splanchnic vessels[ 84 ]. Taken together, these results imply more work is needed to clarify splanchnic vascular hypo-responsiveness to various vasoconstrictors in portal hypertension.…”

Section: Increased Splanchnic Blood Flowmentioning

confidence: 99%

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Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Gunarathne¹,

Rajapaksha²,

Shackel³

et al. 2020

WJG

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Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin II type receptor 1 blockers, which target the components of the classical renin angiotensin system (RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant off-target effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective -blockers (NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs. Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.

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Section: The Ras and Splanchnic Vascular Resistancementioning

confidence: 88%

Section: Increased Splanchnic Blood Flowmentioning

confidence: 99%

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Gunarathne¹,

Rajapaksha²,

Shackel³

et al. 2020

WJG

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“…In cirrhotic patients, Ang1-7 and the MasR are upregulated in the liver, as well as in splanchnic vessels. In extrahepatic vessels, Ang1-7 antagonizes AT1R signaling potently [90,91]. Experimental manipulation of the system by MasR inhibition increased the portal pressure.…”

Section: Renin-angiotensin Systemmentioning

confidence: 99%

Novel Targets and Drug Development in Portal Hypertension

Schierwagen

Klein

Uschner

et al. 2019

Curr Hepatology Rep

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Purpose of the Review This review aims to introduce animal models of portal hypertension in which targets and drugs can be tested and presents current advances in the field of preclinical and early clinical settings. Recent Findings The interest in this field has risen in recent years and many promising targets and potential drugs have been tested in preclinical and early clinical studies. Most of these targets are intrahepatic and aim to decrease hepatic stellate cell activity, as this cell type mediates both fibrosis and portal hypertension. Summary Liver cirrhosis with portal hypertension is a global health burden due to their complications. Besides that, there are only a few therapies available, those are ineffective in a large part of the patients. Therefore, novel targets and treatment options are vastly needed.

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“…[5][6][7] In patients with advanced cirrhosis, the circulating Ang-(1-7)/Ang II ratio is increased and correlates with the degree of vasodilatation, [7] and Ang-(1-7) levels have been shown to correlate with liver disease severity and clinical surrogates of vasodilatation, including increased cardiac output. [8] Mechanistic support for these findings comes from evidence that mesenteric Ang-(1-7) production is increased in cirrhotic rats and mediates splanchnic vascular hypocontractility and that the specific MasR blocker A779 increases splanchnic vascular resistance (SPVR), thus lowering portal pressure. [5,6] Recent work has shown that the vasodilatory effects of Ang-(1-7) may also be mediated through a receptor named Mas-related G protein-coupled receptor type D (MrgD), [9] and we recently demonstrated that blockade of this receptor acutely can reduce portal pressure in cirrhotic rat models of portal hypertension.…”

Section: Introductionmentioning

confidence: 97%

“…[ 5 , 6 , 7 ] In patients with advanced cirrhosis, the circulating Ang‐(1–7)/Ang II ratio is increased and correlates with the degree of vasodilatation, [ 7 ] and Ang‐(1–7) levels have been shown to correlate with liver disease severity and clinical surrogates of vasodilatation, including increased cardiac output. [ 8 ] Mechanistic support for these findings comes from evidence that mesenteric Ang‐(1–7) production is increased in cirrhotic rats and mediates splanchnic vascular hypocontractility and that the specific MasR blocker A779 increases splanchnic vascular resistance (SPVR), thus lowering portal pressure. [ 5 , 6 ]…”

Section: Introductionmentioning

confidence: 99%

Mas‐related G protein‐coupled receptor type D antagonism improves portal hypertension in cirrhotic rats

et al. 2022

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Splanchnic vasodilatation contributes to the development and aggravation of portal hypertension (PHT). We previously demonstrated that in cirrhosis, angiotensin‐ mediates splanchnic vasodilatation through the Mas receptor (MasR). In this study, we investigated whether the recently characterized second receptor for angiotensin‐(1–7), Mas‐related G protein‐coupled receptor type D (MrgD), contributes to splanchnic vasodilatation in cirrhotic and noncirrhotic PHT. Splanchnic vascular hemodynamic and portal pressure were determined in two rat models of cirrhotic PHT and a rat model with noncirrhotic PHT, treated with either MrgD blocker D‐Pro 7 ‐Ang‐(1‐7) (D‐Pro) or MasR blocker A779. Gene and protein expression of MrgD and MasR were measured in splanchnic vessels and livers of cirrhotic and healthy rats and in patients with cirrhosis and healthy subjects. Mesenteric resistance vessels isolated from cirrhotic rats were used in myographs to study their vasodilatory properties. MrgD was up‐regulated in cirrhotic splanchnic vessels but not in the liver. In cirrhotic rats, treatment with D‐Pro but not A779 completely restored splanchnic vascular resistance to a healthy level, resulting in a 33% reduction in portal pressure. Mesenteric vessels pretreated with D‐Pro but not with A779 failed to relax in response to acetylcholine. There was no splanchnic vascular MrgD or MasR up‐regulation in noncirrhotic PHT; thus, receptor blockers had no effect on splanchnic hemodynamics. Conclusion : MrgD plays a major role in the development of cirrhotic PHT and is a promising target for the development of novel therapies to treat PHT in cirrhosis. Moreover, neither MrgD nor MasR contributes to noncirrhotic PHT.

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Effects of angiotensin-(1–7) and angiotensin II on vascular tone in human cirrhotic splanchnic vessels

Cited by 6 publications

References 45 publications

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Novel Targets and Drug Development in Portal Hypertension

Mas‐related G protein‐coupled receptor type D antagonism improves portal hypertension in cirrhotic rats

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