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 vasoconstriction and cell proliferation, while the predominant actions of ETB are vasodilation, antiproliferation, and ET-1 clearance.

In patients with 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 pathogenesis
and progression of PAH.

Ambrisentan is a high-affinity (Ki=0.011 nM) ETA receptor antagonist with a high selectivity for the ETA versus ETB receptor (>4000-fold). The clinical impact of high selectivity for ETA is not known.

Letairis is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):
• To improve exercise ability and delay clinical worsening.
• In combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to
improve exercise ability.

Studies establishing effectiveness included trials predominantly in patients with WHO Functional Class II–III symptoms and etiologies of
idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%).

• Initiate treatment at 5 mg once daily.
• May be started with tadalafil.
• Titrate at 4-week intervals as needed and tolerated.
• Do not split, crush, or chew tablets.

Most common adverse reactions (>3% compared to placebo) are peripheral edema, nasal congestion, sinusitis, and flushing.
• When used in combination with tadalafil, most common adverse reactions (>5% compared with either monotherapy) are peripheral edema, headache, nasal congestion, cough, anemia, dyspepsia, and bronchitis.

• Pregnancy
• Idiopathic Pulmonary Fibrosis

• Fluid retention may require intervention.
• If patients develop acute pulmonary edema during initiation of therapy with Letairis, consider underlying pulmonary venoocclusive disease and discontinue treatment if necessary.
• Decreases in sperm count have been observed in patients taking endothelin receptor antagonists.
• Decreases in hemoglobin have been observed within the first few weeks; measure hemoglobin at initiation, at 1 month, and periodically thereafter.