Dual Angiotensin Receptor and Neprilysin Inhibitor Ameliorates Portal Hypertension in Portal Hypertensive Rats

Abstract

Background: Portal hypertension is characterized by exaggerated activation of the renin-angiotensin-aldosterone axis. Natriuretic peptide system plays a counter-regulatory role, which is modulated by neprilysin. LCZ696 (sacubitril/valsartan) is a dual angiotensin receptor and neprilysin inhibitor. This study evaluated the effect of LCZ696 on portal hypertensive rats. Methods: Portal hypertension was induced by partial portal vein ligation (PVL) in rats. LCZ696, valsartan (angiotensin receptor blocker), or normal saline (control) was administered in PVL rats for 10 days. Then, hemodynamic and biochemistry data were obtained. The hepatic histology and protein expressions were surveyed. On the parallel groups, the portal-systemic shunting degrees were determined. Results: LCZ696 and valsartan reduced mean arterial pressure and systemic vascular resistance. LCZ696, but not valsartan, reduced portal pressure in portal hypertensive rats (control vs. valsartan vs. LCZ696: 15.4 ± 1.6 vs. 14.0 ± 2.3 vs. 12.0 ± 2.0 mmHg, control vs. LCZ696: P < 0.05). LCZ696 and valsartan improved liver biochemistry data and reduced intrahepatic Cluster of Differentiation 68 (CD68)-stained macrophages infiltration. Hepatic endothelin-1 (ET-1) protein expression was downregulated by LCZ696. The portal-systemic shunting was not affected by LCZ696 and valsartan. Conclusion: LCZ696 and valsartan reduced mean arterial pressure through peripheral vasodilation. Furthermore, LCZ696 significantly reduced portal pressure in PVL rats via hepatic ET-1 downregulation.

Looking at the heart failure through the prism of liver dysfunction

“…The responsible mechanisms are not clear, but one can expect correction of deranged haemodynamics and neurohormonal imbalance to play a role. Experimental studies suggest that sacubitril/valsartan significantly reduces portal pressure via hepatic endothelin‐1 downregulation – which may lead to perfusion improvement with a further bilirubin decrease in HF 15 . Whether an improvement of dysfunctional organs or prevention of organ injury are associated with better outcomes needs further studies.…”

Molecular mechanisms of sacubitril/valsartan in cardiac remodeling

“…However, the detrimental efffects of Ang II on the heart and vascular system are blocked by valsartan ( Kaplinsky, 2016 ). Sacubitril/valsartan was also reported to decrease the expresssion of hepatic endothelin-1 ( Hsu et al, 2020 ) and its plasma level ( Clements et al, 2019 ) in hypertensive rats. The inhibition of neprilysin was confirmed by a significant time-dependent reduction in plasma activity of soluble neprilysin as well as an elevation of ANP levels in patients with chronic heart failure after receiving sacubitril/valsartan for 30 and 90 days.…”

Sodium-Glucose Cotransporter-2 Inhibition Exacerbates Hepatic Encephalopathy in Biliary Cirrhotic Rats

“…Sirius red staining was performed to determine the severity of liver fibrosis. Immunohistochemical staining with anti-CD68 antibodies (diluted 1:200, ab31630, Abcam, Cambridge, UK) was also performed to detect CD68-positive macrophages, to measure intrahepatic inflammation (Hsu et al, 2020). The semi-quantitative counting of CD68-positive stained cells was measured.…”