Sacubitril/valsartan treatment relieved the progression of established pulmonary hypertension in rat model and its mechanism.

Abstract

AIMS:

Pulmonary hypertension (PH) is a fatal disease identified by progressive elevated pulmonary arterial pressure, which neurohormonal activation is a notable contributor to its development. Sacubitril/valsartan is a complex of sacubitril [via enhancing the natriuretic peptide (NP) system] and valsartan [via blocking the renin-angiotensin-aldosterone system (RAAS)]. Regulation of the two neurohormonal system had been shown to attenuate PH. This study was to explore the role of sacubitril/valsartan in both monocrotaline (MCT)-induced and hypoxia-induced rat models and the underlying mechanism.

MAIN METHODS:

The rats were treated with MCT or hypoxic environment for 14 days, after that sacubitril/valsartan were given for another 14 days. Hemodynamic measurements and histological assessments were performed. The expression of NPs was measured using RT-PCR and ELISA, while the protein level of natriuretic peptide receptors (NPRs) and AT1 receptor were detected by western blot, the concentrations of cGMP, IL-1β, IL-6, TNF-α and TGF-β1 were tested by ELISA.

KEY FINDINGS:

We found that sacubitril/valsartan significantly improved the hemodynamic and histological data of two PH models. Sacubitril/valsartan suppressed the protein expression of AT1 receptor (P < 0.05). The intervention increased the expression of ANP and CNP (P< 0.05) and therefore upregulated the protein expression of NPRs (P < 0.05), raised the concentration of cGMP (P < 0.05). In addition, the treatment reduced the concentration of IL-1β, IL-6 and TNF-α (P < 0.05) but have no effects on TGF-β1.

SIGNIFICANCE:

Sacubitril/valsartan alleviated PH in MCT-induced and hypoxia-induced rat models by inhibiting the activated RAAS, promoting ANP/NPR-A/cGMP and CNP/NPR-B/cGMP pathway, restoring the NPR-C signaling and the anti-inflammatory effects.

• Authors: ShuangYe Liu, Ya Wang, Shuai Lu, Jing Hu, XiaoHui Zeng, WenHu Liu, Yan Wang, ZhaoHui Wang
• Journal: Life sciences (Life Sci) Vol. 266 Pg. 118877 (Feb 01 2021) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 33310048 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Aminobutyrates
• Angiotensin Receptor Antagonists
• Biphenyl Compounds
• Drug Combinations
• Tetrazoles
• Monocrotaline
• Valsartan
• sacubitril and valsartan sodium hydrate drug combination

Topics

• Aminobutyrates (pharmacology)
• Angiotensin Receptor Antagonists (pharmacology)
• Animals
• Biphenyl Compounds
• Body Weight
• Disease Models, Animal
• Disease Progression
• Drug Combinations
• Hypertension, Pulmonary (etiology, pathology, prevention & control)
• Hypoxia (physiopathology)
• Male
• Monocrotaline (toxicity)
• Rats
• Rats, Sprague-Dawley
• Tetrazoles (pharmacology)
• Valsartan