The endothelin receptor antagonists inhibit the binding of endothelin, a vasoconstrictive peptide, to its receptors on smooth muscle cells which results in vasodilation. Endothelin receptors are relatively enriched in pulmonary vasculature and their inibition results in a decrease in pulmonary vascular pressure. In patients with pulmonary arterial hypertension, (PAH) the endothelin receptor antagonists have been shown to improve exercise tolerance and slow progression of disease. Three endothelin receptor antagonists are currently approved and in use in the United States: bosentan (2001: Tracleer), ambrisentan (2007: Letairis) and macitentan (2013: Opsumit). Sitaxsentan, a forth endothelin receptor blocker, was approved in Europe, but not in the United States, and has subsequently been withdrawn because of cases of severe liver injury linked to its use. While all endothelin receptor antagonists have been associated with occasional transient serum enzyme elevations during therapy, only bosentan and sitaxentan have been clearly linked to instances of clinically apparent, acute liver injury.
Endothelin-1 (ET-1) is a 21 amino acid peptide that acts in a paracrine and autocrine fashion as a potent vasoconstrictor. ET-1 appears to play a key role in regulation of vascular tone and can also induce hypertrophy of myocytes, proliferation of fibroblasts and fibrosis. ET-1 acts by engagement of cell surface receptors that result in activation of intracellular pathways leading to vasoconstriction and proliferation of smooth muscle cells. Two forms of endothelin receptors have been identified – type A (ETA) and type B (ETB). The ETA receptor is found predominantly on smooth muscle cells, whereas the ETB receptor is present on both smooth muscle and vascular endothelial cells. The intracellular signaling pathways and overall effects are somewhat different for the two receptors, and there may be an advantage to specific inhibition of the type A receptor as opposed to bimodal inhibition of both.
The use of endothelin receptor antagonists in pulmonary arterial hypertension (PAH) is based upon the proposed pathogenesis of this disease, which is marked by enhanced synthesis of ET-1 and progressive proliferation and hypertrophy of smooth muscle cells in the pulmonary vasculature. In several randomized controlled trials, endothelin receptor antagonists were shown to decrease pulmonary vascular pressure and improve exercise tolerance and symptoms in patients with PAH. Their efficacy has been best demonstrated in patients with idiopathic PAH (World Health Organization [WHO] group 1 PAH) and less well in the secondary forms due to left heart failure [WHO group 2], lung disease or hypoxemia [WHO group 3], chronic pulmonary thromboembolic disease [WHO group 4] or unclear, multifactorial conditions [WHO group 5].