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.
Highlights
In chronic liver diseases, an increase of intrahepatic resistance develops due to chronic inflammation and fibrosis, which impedes hepatic blood flow induces portal hypertension [1]
Our data showed that LCZ696 and valsartan significantly reduced mean arterial pressure (MAP) and systemic vascular resistance (SVR), which was in accordance to the previous studies in the hypertensive patients and experimental animal models [18,19]
We found that LCZ696, but not valsartan, reduced portal venous pressure (PP) and superior mesenteric arterial resistance (SMAR) in portal hypertensive rats, implicating the superior portal hypotensive effects of LCZ696 compared to valsartan
Summary
An increase of intrahepatic resistance develops due to chronic inflammation and fibrosis, which impedes hepatic blood flow induces portal hypertension [1]. The RAAS regulates vascular tone and affects systemic and portal hemodynamics through mainly angiotensin II and aldosterone. NPs activate transmembrane receptors to upregulate guanylate cyclase and to increase levels of the second messenger cyclic guanosine monophosphate and its effector, protein kinase G. Via these actions, NPs counteract the RAAS and elicit vasodilation and diuresis. LCZ696, valsartan (angiotensin receptor blocker), or normal saline (control) was administered in PVL rats for 10 days. Results: LCZ696 and valsartan reduced mean arterial pressure and systemic vascular resistance. Conclusion: LCZ696 and valsartan reduced mean arterial pressure through peripheral vasodilation. LCZ696 significantly reduced portal pressure in PVL rats via hepatic ET-1 downregulation
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