0123 : Nebivolol for improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function in pulmonary hypertension

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 β 1 antagonist and β 2,3 -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 β 1 -selective β-blocker on human cultured PAH and control P-EC proliferation, vasoactive and proinflammatory factor production and crosstalk with PA smooth cells (PASMC). We assessed the effects of both β-blockers in precontracted PA rings. We also compared the effects of both β-blockers in experimentalPAH. Results PAH P-EC overexpressed the proinflammatory mediators IL-6 and MCP-1, the growth factor FGF2, and the potent vasoconstrictive agent endothelin-1 as compared to 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 PASMC mitosis, a growth abnormality which was normalized by nebivolol but not by metoprolol. Nebivolol but not metoprolol induced an endothelium- and nitric oxide-dependant 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 beta-blockers in PAH cannot be recommended.