Endothelin receptors as drug targets in chronic cardiovascular diseases: The rationale for dual antagonism

Endothelin has been described as the most potent vasoconstrictor known. Recent research shows that it is also a growth factor, a promoter of fibrosis and inflammation, and a key initiator of endothelial dysfunction. Endothelin becomes, therefore, a candidate in the pathogenesis of many chronic cardiovascular and fibrotic diseases, and inhibition of endothelin function is a potential therapeutic approach for those diseases. Endothelin receptor antagonists are now established therapy in the treatment of pulmonary arterial hypertension, and present promising perspectives in diabetic nephropathy, peripheral arterial disease, hypertension, heart failure, and pulmonary diseases. Endothelin binds to two endothelin receptors, ETA and ETB, and their respective roles are actively debated. A major challenge lies in the understanding of what is the preferred profile for new drugs: selective ETA antagonism or dual ETA and ETB receptor antagonism. A number of cardiovascular diseases are characterized by an up-regulation of smooth muscle cell ETB receptors mediating vasoconstriction and proliferation, and a down-regulation of endothelial ETB receptors, as compared to the physiological state, creating a situation where both ETA and ETB receptors contribute to vasoconstriction and remodeling. When these two receptor subtypes co-exist, a cross-talk between them, probably a result of receptor heterodimerization, suggests that dual ETA/ETB receptor antagonism may be necessary to obtain maximal efficacy.