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

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

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-1 Receptor Antagonists / pharmacology
  • Adrenergic beta-1 Receptor Antagonists / therapeutic use*
  • Animals
  • Benzopyrans / pharmacology
  • Benzopyrans / therapeutic use*
  • Cell Communication / drug effects
  • Cell Culture Techniques
  • Cell Proliferation
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiopathology
  • Ethanolamines / pharmacology
  • Ethanolamines / therapeutic use*
  • Humans
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / pathology
  • Hypertension, Pulmonary / physiopathology
  • Male
  • Metoprolol / pharmacology
  • Metoprolol / therapeutic use
  • Monocrotaline
  • Myocytes, Smooth Muscle
  • Nebivolol
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / pathology
  • Pulmonary Artery / physiopathology
  • Rats
  • Rats, Wistar
  • Vascular Remodeling / drug effects*

Substances

  • Adrenergic beta-1 Receptor Antagonists
  • Benzopyrans
  • Ethanolamines
  • Nebivolol
  • Monocrotaline
  • Metoprolol