Beta Blocker Nebivolol Shows Promise In Pulmonary Arterial Hypertension

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A French research team was able to demonstrate nebivolol’s beneficial effects in treating pulmonary arterial hypertension (PAH), suggesting that new clinical studies should be conducted to further test the drug. The study entitled: “Nebivolol for Improving Endothelial Dysfunction, Pulmonary Vascular Remodeling, and Right Heart Function in Pulmonary Hypertension” was published on February 24, 2015 in the Journal of American College of Cardiology. Nebivolol is a third generation β1 receptor blocker with nitric oxide-potentiating vasodilatory effect.

Pulmonary arteries are composed primarily of endothelial cells that lose their vascular function in PHA.  The disease leads to constriction of pulmonary arteries affecting both the blood carried from the heart to the lung and the oxygen delivered to the different body regions. As a result, the heart is forced to work faster and the blood pressure rises in the lungs. Vasodilators are used as therapy against PHA but with limited success.

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The adrenergic system is the major regulator of cardiac and vascular endothelial function through α and β adrenergic receptors (ARs) activation.  This study addresses the role of ARs in PHA by using nebivolol. Researchers found that nebivolol but not metoprolol (a first-generation b1-AR blocker) reverted several pathological features of pulmonary endothelial cells in PAH such as: proliferation, stimulation of smooth muscle cell division, production of inflammatory factors (IL-6 and MCP-1), the fibroblast growth factor, and the potent vasoconstrictive agent endothelin-1.

Using a rat model of PHA, researchers measured several parameters: right ventricular systolic pressure (RVSP), mean pulmonary artery pressure (mPAP), cardiac output (CO), and total pulmonary vascular resistances (PVR). Rats with PAH have a high RVSP and high mPAP, but these did not change with nebvivolol treatment. In contrast, the nebivolol-treated rats showed significant improvements in CO and PVR.

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PAH is associated with progressive remodeling of pulmonary precapillary arteries. The analysis of the neomuscularization of normally non-muscularized (NM) small distal PA is a common and robust way to quantify the degree of remodeling of the rat pulmonary vasculature. Nebivolol increased the percentage of NM PA in PAH rats. Finally, nebivolol significantly decreased the accumulation of macrophages (inflammatory cells) in the lung.

In conclusion, nebivolol was also more potent than metoprolol in improving cardiac function, pulmonary vascular remodeling, vasodilation and inflammation.

A translational outlook is given in the publication:  “Although b-adrenergic receptor blockade is not currently recommended for treatment of patients with pulmonary arterial hypertension, clinical trials of nebivolol are warranted on the basis of this distinguishing mechanism of action.”