Nebivolol for Improving Endothelial Dysfunction, Pulmonary Vascular Remodeling, and Right Heart Function in Pulmonary Hypertension

• Published in: Journal of the American College of Cardiology Vol. 65; no. 7; pp. 668 - 680
• Main Authors: Perros, Frédéric, Ranchoux, Benoît, Izikki, Mohamed, Bentebbal, Sana, Happé, Chris, Antigny, Fabrice, Jourdon, Philippe, Dorfmüller, Peter, Lecerf, Florence, Fadel, Elie, Simonneau, Gerald, Humbert, Marc, Bogaard, Harm Jan, Eddahibi, Saadia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.02.2015; Elsevier Limited; Elsevier
• Subjects: Adrenergic beta-1 Receptor Antagonists - pharmacology; Adrenergic beta-1 Receptor Antagonists - therapeutic use; Animals; Benzopyrans - pharmacology; Benzopyrans - therapeutic use; Cardiology; Cardiovascular; Cell Communication - drug effects; Cell Culture Techniques; Cell growth; Cell Proliferation; Disease Models, Animal; Endothelial Cells - drug effects; endothelial dysfunction; Endothelium, Vascular - drug effects; Endothelium, Vascular - pathology; Endothelium, Vascular - physiopathology; Ethanolamines - pharmacology; Ethanolamines - therapeutic use; Heart; Humans; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - pathology; Hypertension, Pulmonary - physiopathology; inflammation; Life Sciences; Male; Metoprolol - pharmacology; Metoprolol - therapeutic use; Monocrotaline; Mortality; Myocytes, Smooth Muscle; Nebivolol; Pulmonary arteries; Pulmonary Artery - drug effects; Pulmonary Artery - pathology; Pulmonary Artery - physiopathology; Pulmonary hypertension; Rats; Rats, Wistar; Smooth muscle; Studies; Vascular Remodeling - drug effects; Veins & arteries; β-blocker; pulmonary hypertension; SPH; IPAH; endothelial dysfunction; ET; β-blocker; AR; PA; nebivolol; inflammation; PAH; PH; EC; PASMC; P-EC; MCT; pulmonary artery; pulmonary artery smooth muscle cell; monocrotaline; secondary pulmonary hypertension; pulmonary arterial hypertension; endothelial cell; adrenergic receptor; idiopathic pulmonary arterial hypertension; endothelin; pulmonary endothelial cell
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2014.11.050

Endothelial cell (EC) dysfunction plays a central role in the pathogenesis of pulmonary arterial hypertension (PAH), promoting vasoconstriction, smooth muscle proliferation, and inflammation. This study sought to test the hypothesis that nebivolol, a β1-antagonist and β2,3-agonist, may improve PAH and reverse the PAH-related phenotype of pulmonary ECs (P-EC). We compared the effects of nebivolol with metoprolol, a first-generation β1-selective β-blocker, on human cultured PAH and control P-EC proliferation, vasoactive and proinflammatory factor production, and crosstalk with PA smooth muscle cells. We assessed the effects of both β-blockers in precontracted PA rings. We also compared the effects of both β-blockers in experimental PAH. PAH P-ECs overexpressed the proinflammatory mediators interleukin-6 and monocyte chemoattractant protein-1, fibroblast growth factor-2, and the potent vasoconstrictive agent endothelin-1 as compared with control cells. This pathological phenotype was corrected by nebivolol but not metoprolol in a dose-dependent fashion. We confirmed that PAH P-EC proliferate more than control cells and stimulate more PA smooth muscle cell mitosis, a growth abnormality that was normalized by nebivolol but not by metoprolol. Nebivolol but not metoprolol induced endothelium-dependent and nitric oxide–dependent relaxation of PA. Nebivolol was more potent than metoprolol in improving cardiac function, pulmonary vascular remodeling, and inflammation of rats with monocrotaline-induced pulmonary hypertension. Nebivolol could be a promising option for the management of PAH, improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function. Until clinical studies are undertaken, however, routine use of β-blockers in PAH cannot be recommended.