Endothelin Receptor Antagonists for the Treatment of Pulmonary Arterial Hypertension

Abstract

There are distinct endothelin (ET) isoforms, ET-1, ET-2 and ET-3, of which ET-1 is considered the most active. Local ET-1 synthesis in vascular endothelial cells appears to play an important role in the pathobiological and pathophysiological processes of pulmonary arterial hypertension (PAH), promoting vasoconstriction, smooth muscle cell proliferation, as well as inflammation and fibrosis. ET acts via two different receptors: ETA receptors on vascular smooth muscle cells and ETB receptors on vascular smooth muscle cells and endothelial cells. Both ETA and ETB receptors mediate vascular smooth muscle cell proliferation. ETA receptors mediate vasoconstriction. ETB receptors may have a role in either vasoconstriction (via actions on smooth muscle cell ETB receptors) or vasodilation, owing to release of nitric oxide and prostacyclin via actions on endothelial cell ETB receptors. Clearance of ET-1 appears to be due to the ETB receptors on endothelial cells. Plasma levels of ET-1 correlate with the severity of PAH and prognosis and clearance of ET-1 in the pulmonary vasculature in this disease is reduced. Although the clinically available drugs that work via ET receptor antagonism bear substantial similarities, and although it would appear that a number of class effects exist, they are distinct entities, and will be discussed separately in this chapter. Adverse effects such as elevated liver function test levels, peripheral edema, and anemia appear to be ET receptor antagonist (ERA) class effects. Although most of the available data on teratogenicity are with bosentan, this is quite likely to be a class effect. Studies in animals have shown dose-dependent teratogenic effects, including malformation of the head, mouth, face, and large blood vessels, occurring during the first trimester of pregnancy. Thus, education and careful monitoring of treatment are crucial.