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J Am Coll Cardiol. 2015 Feb 24;65(7):668-80. doi: 10.1016/j.jacc.2014.11.050.

Nebivolol for improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function in pulmonary hypertension.

Author information

1
University Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France. Electronic address: frederic.perros@inserm.fr.
2
University Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
3
Inserm U1046, Université Montpellier, Montpellier, France.
4
Department of Pulmonary Medicine, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands.
5
University Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France; AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France; Service d'Anatomie Pathologique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
6
Service de Chirurgie Thoracique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.

Abstract

BACKGROUND:

Endothelial cell (EC) dysfunction plays a central role in the pathogenesis of pulmonary arterial hypertension (PAH), promoting vasoconstriction, smooth muscle proliferation, and inflammation.

OBJECTIVES:

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).

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

endothelial dysfunction; inflammation; nebivolol; pulmonary hypertension; β-blocker

PMID:
25677428
DOI:
10.1016/j.jacc.2014.11.050
[Indexed for MEDLINE]
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