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

• Published in: Cardiovascular research Vol. 117; no. 5; pp. 1391 - 1401
• Main Authors: Chaumais, Marie-Camille, Djessas, Mohamed Reda Amar, Thuillet, Raphaël, Cumont, Amélie, Tu, Ly, Hebert, Guillaume, Gaignard, Pauline, Huertas, Alice, Savale, Laurent, Humbert, Marc, Guignabert, Christophe
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 23.04.2021; Oxford University Press (OUP)
• Subjects: Aminobutyrates - pharmacology; Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Atrial Natriuretic Factor - blood; Biphenyl Compounds - pharmacology; Bosentan - pharmacology; Cardiology and cardiovascular system; Cell Proliferation - drug effects; Cells, Cultured; Cellular Biology; Cyclic GMP - blood; Disease Models, Animal; Disease Progression; Drug Combinations; Drug Therapy, Combination; Endothelin Receptor Antagonists - pharmacology; Familial Primary Pulmonary Hypertension - drug therapy; Familial Primary Pulmonary Hypertension - metabolism; Familial Primary Pulmonary Hypertension - physiopathology; Human health and pathology; Humans; Life Sciences; Male; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Neprilysin - antagonists & inhibitors; Protease Inhibitors - pharmacology; Pulmonary Arterial Hypertension - drug therapy; Pulmonary Arterial Hypertension - metabolism; Pulmonary Arterial Hypertension - physiopathology; Pulmonary Artery - drug effects; Pulmonary Artery - metabolism; Pulmonary Artery - physiopathology; Pulmonology and respiratory tract; Rats; Rats, Wistar; Valsartan - pharmacology; Vascular Remodeling - drug effects; Pulmonary arterial hypertension; Pulmonary vascular remodelling; Entresto; Cardiac dysfunction; Pulmonary vascular remodeling
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvaa200

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. Graphical Abstract