Additive protective effects of sacubitril/valsartan and bosentan on vascular remodelling in experimental pulmonary hypertension.

Abstract

AIMS:

Although right ventricular (RV) function is an important determinant of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), there is no treatment targeting directly the RV. We evaluate the efficacy of sacubitril/valsartan (LCZ 696) as add-on therapy to bosentan in rats with severe pulmonary hypertension (PH).

METHODS AND RESULTS:

Combination therapy of LCZ 696 and bosentan has additive vascular protective effects against the pulmonary vascular remodelling and PH in two preclinical models of severe PH. Compared with monotherapy, co-treatment of LCZ 696 (30 or 68 mg/kg/day for 2 weeks, per os) and bosentan (100 mg/kg/day for 2 weeks, per os) started 7 days after monocrotaline (MCT) injection substantially reduces pulmonary pressures, vascular remodelling, and RV hypertrophy and fibrosis in rats. Consistent with these observations, co-treatment of rats with established PH induced by sugen/hypoxia (SuHx) with LCZ 696 (30 mg/kg/day for 3 weeks, per os) and bosentan (100 mg/kg/day for 3 weeks, per os) started 5 weeks after Sugen injection partially attenuate total pulmonary vascular resistance and cardiovascular structures. We also obtained evidence showing that LCZ 696 has anti-proliferative effect on cultured human pulmonary artery smooth muscle cells derived from patients with idiopathic PAH, an effect that is more pronounced in presence of bosentan. Finally, we found that the plasma levels of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) are higher in rats co-treated with LCZ 696 (30 mg/kg/day) and bosentan (100 mg/kg/day) than in MCT and SuHx rats treated with vehicle.

CONCLUSION:

Dual therapy with LCZ 696 plus bosentan proved significantly superior beneficial effect to LCZ 696 or bosentan alone on vascular remodelling and severity of experimental PH.

• Authors: Marie-Camille Chaumais, Mohamed Reda Amar Djessas, Raphaël Thuillet, Amélie Cumont, Ly Tu, Guillaume Hebert, Pauline Gaignard, Alice Huertas, Laurent Savale, Marc Humbert, Christophe Guignabert
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 117 Issue 5 Pg. 1391-1401 (04 23 2021) ISSN: 1755-3245 [Electronic] England
• PMID: 32653925 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected].

Chemical References

• Aminobutyrates
• Angiotensin II Type 1 Receptor Blockers
• Biphenyl Compounds
• Drug Combinations
• Endothelin Receptor Antagonists
• Protease Inhibitors
• Valsartan
• Atrial Natriuretic Factor
• Neprilysin
• Cyclic GMP
• Bosentan
• sacubitril and valsartan sodium hydrate drug combination

Topics

• Aminobutyrates (pharmacology)
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Animals
• Atrial Natriuretic Factor (blood)
• Biphenyl Compounds (pharmacology)
• Bosentan (pharmacology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cyclic GMP (blood)
• Disease Models, Animal
• Disease Progression
• Drug Combinations
• Drug Therapy, Combination
• Endothelin Receptor Antagonists (pharmacology)
• Familial Primary Pulmonary Hypertension (drug therapy, metabolism, physiopathology)
• Humans
• Male
• Muscle, Smooth, Vascular (drug effects, metabolism, pathology)
• Myocytes, Smooth Muscle (drug effects, metabolism, pathology)
• Neprilysin (antagonists & inhibitors)
• Protease Inhibitors (pharmacology)
• Pulmonary Arterial Hypertension (drug therapy, metabolism, physiopathology)
• Pulmonary Artery (drug effects, metabolism, physiopathology)
• Rats, Wistar
• Valsartan (pharmacology)
• Vascular Remodeling (drug effects)
• Rats