<p>Endothelin-1 (ET-1) is a potent autocrine and paracrine peptide. Two receptor subtypes, ETA and ETB, mediate the effects of ET-1 in the vascular smooth muscle and endothelium. The primary actions of ETA are&nbsp;vasoconstriction&nbsp;and cell proliferation, while the predominant actions of ETB are&nbsp;vasodilation, antiproliferation, and ET-1 clearance.<br />
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In patients with&nbsp;PAH, plasma ET-1 concentrations are increased as much as 10-fold and correlate with increased mean right atrial pressure and disease severity. ET-1 and ET-1 mRNA concentrations are increased as much as 9-fold in the lung tissue of patients with PAH, primarily in the endothelium of pulmonary arteries. These findings suggest that ET-1 may play a critical role in the&nbsp;pathogenesis&nbsp;and progression of PAH.<br />
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Ambrisentan is a high-affinity (Ki=0.011 nM) ETA receptor&nbsp;antagonist&nbsp;with a high selectivity for the ETA versus ETB receptor ( &gt; 4000-fold). The clinical impact of high selectivity for ETA is not known.</p>