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

Abstract

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.

Counter-regulatory renin-angiotensin system in hypertension: Review and update in the era of COVID-19 pandemic

“…Recently, the alamandine glycoside analogs were synthesized and evaluated for their ability to antagonize the MrgDR to produce antinociceptive effects and neuropathic pain modulation in vitro [436] . The blockade of MrgDR by D-Pro improved portal hypertension in cirrhotic rats, indicating the major role of MrgDR in the development of cirrhotic portal hypertension [437] . However, due to the absence of a specific structure to explicate the activation process in the cardiovascular system, research on the activation of MrgDR by alamandine and its mimetics to combat hypertension is currently limited.…”

The Renin–Angiotensin System in Liver Disease

“…The overall downstream effects of this receptor–ligand binding are anti-inflammatory, vasodilatory, and anti-fibrotic, in contradistinction to AngII-mediated effects within the classical pathway. Interestingly, MasR appears to act both locally (intrahepatically) and extrahepatically, whereas MrgD exerts only an extrahepatic influence [ 13 , 26 ]. As a result, the vasodilatory properties of each are somewhat paradoxical in cirrhosis—intrahepatic vasodilatation is beneficial to improve blood flow but dilation of the splanchnic vessels contributes to arterial underfilling and systemic hypotension [ 27 ].…”

“…In contrast, the effects of MasR on portal hypertension are mixed ( Table 2 ). Some studies report that MasR agonism decreases portal pressure in cirrhosis [ 26 , 164 ], while others report that antagonism does the same [ 27 , 71 ]. These contrary results can be reconciled by understanding the twofold role of MasR in liver disease.…”

“…Observed effects of alternative pathway receptors on fibrosis and portal pressure in animal studies[26,27,49,50,71,164]. There are no corresponding human studies.…”

The role of Mas receptor on renal hemodynamic responses to angiotensin II administration in chronic renal sympathectomized male and female rats

“…The stimulation of the Mas receptor (MasR) by Ang-(1-7) results in vasodilator, natriuretic, and diuretic effects ( 13 14 15 ). A779 is a specific Ang-(1-7) antagonist (MasR blocker) ( 16 ).…”