OBJECTIVES: Endothelin (ET) is a major therapeutic target in cardiopulmonary 
diseases. The purpose of this review is to present the main concepts concerning 
ET biology, its pathophysiological roles and the major pharmacological and 
medical advances recently developed around the concept of ET receptor blockade.
METHODS: Analysis of PubMed database (keywords: endothelin, endothelin receptor 
antagonists, pulmonary hypertension, etc.), and of abstract originating from 
recent international meetings.
RESULTS: ET is a peptide produced by vascular endothelial cells as well as by 
many other tissues. Both its production and its effects are activated in 
pathological situations associated with endothelial dysfunction. ET is 
characterized by a strong tropism toward tissues because of its polarized 
release, the strong tissue receptor density and high affinity of the receptors 
for the peptide. ET exerts several vascular effects, including vasoconstriction, 
proliferation and hypertrophy, as well as non-vascular effects, notably 
stimulation of cardiac hypertrophy, tissue fibrosis and inflammation. Both 
vascular and non-vascular effects depend on the stimulation of two receptor 
subtypes, ETA and ETB. ET receptor antagonists (ERA) demonstrated beneficial 
effects in many different pre-clinical models of cardiovascular and pulmonary 
diseases, and constitute a first-line treatment of patients with pulmonary 
arterial hypertension (PAH). Recently, the targeted search for a novel ERA led 
to the development of macitentan which, compared to existing ERA, show optimized 
tissue penetration, increased receptor affinity and in vivo pharmacological 
efficacy in pre-clinical models, associated with a favorable profile, in terms 
of hepatic safety and drug interactions. The clinical efficacy of macitentan in 
the treatment of PAH was recently demonstrated in the SERAPHIN trial, which 
contrasts with previous PAH trials because of its long duration, the high number 
of patients enrolled, and its primary endpoint evaluating morbidity/mortality. 
Results show a significant reduction of the primary composite 
morbidity/mortality endpoint (taking into account both progression of PAH and 
death) by 30 and 45% with macitentan 3 and 10mg, respectively, compared to 
placebo, and confirm on the large scale the favorable tolerance profile, 
especially at the hepatic level.
CONCLUSION: The extensive knowledge on the complexity of the ET system allowed 
the synthesis of a new antagonist optimized, in terms of pharmacological 
efficacy and safety, which also show promising therapeutic effects in PAH 
patients, with demonstrated results in a prospective study using a composite 
primary endpoint of morbidity-mortality.