Clinical Pharmacology of Endothelin Receptor Antagonists Used in the Treatment of Pulmonary Arterial Hypertension

Marie-Camille Chaumais; Christophe Guignabert; Laurent Savale; Xavier Jaïs; Athénaïs Boucly; David Montani; Gérald Simonneau; Marc Humbert; Olivier Sitbon


Am J Cardiovasc Drugs. 2015;15(1):13-26. 

In This Article

Abstract and Introduction


Pulmonary arterial hypertension (PAH) is a devastating life-threatening disorder characterized by elevated pulmonary vascular resistance leading to elevated pulmonary arterial pressures, right ventricular failure, and ultimately death. Vascular endothelial cells mainly produce and secrete endothelin (ET-1) in vessels that lead to a potent and long-lasting vasoconstrictive effect in pulmonary arterial smooth muscle cells. Along with its strong vasoconstrictive action, ET-1 can promote smooth muscle cell proliferation. Thus, ET-1 blockers have attracted attention as an antihypertensive drug, and the ET-1 signaling system has paved a new therapeutic avenue for the treatment of PAH. We outline the current understanding of not only the pathogenic role played by ET-1 signaling systems in the pathogenesis of PH but also the clinical pharmacology of endothelin receptor antagonists (ERA) used in the treatment of PAH.


Pulmonary arterial hypertension (PAH) is a rare condition characterized by severe remodeling of the small pulmonary arteries, leading to chronic pre-capillary pulmonary hypertension (defined by a mean pulmonary artery pressure ≥25 mmHg with a mean pulmonary artery wedge pressure ≤15 mmHg), right heart failure, and ultimately death. Development of therapeutic agents that modulate the three main dysfunctional pathobiologic pathways (endothelin [ET-1], prostacyclin [PGI2], and nitric oxide [NO]) have revolutionized our approach to the treatment of PAH and have changed the course of this devastating disease.[1] However, although the spectrum of therapeutic options for PAH has expanded in the last decade, available therapies remain essentially palliative. Since 2002, the dual endothelin receptor antagonist (ERA) bosentan has been avail- able for the management of PAH. Research on new ERAs has resulted in the development of two other drugs, ambrisentan and, more recently, macitentan.