Endothelin receptor antagonists are a new class of drugs for the treatment of a number of major diseases, including pulmonary arterial hypertension. Endothelin is a peptide made by the body in the endothelium (a layer of cells which line the heart and blood vessels). Endothelin constricts blood vessels and elevates blood pressure. Endothelin is a potent vasoconstrictor that plays an important role in blood flow.

Endothelin and Pulmonary Arterial Hypertension (PAH):
In PAH, the body produces excess endothelin, contributing to the constriction of blood vessels and affecting the blood pressure in the lungs. Although endothelin is present in healthy people, high concentrations of the substance have been found in the plasma and lungs of patients with PAH suggesting it is capable of causing PAH or increasing the symptoms of PAH

How ETRAs Work:
Endothelin must connect with an endothelin receptor in order to be activated. Endothelin receptor antagonists block endothelin receptors, thereby limiting harmful excess endothelin in the blood vessels.

There are two classes of endothelin receptors: Endothelin A (ET-A) and Endothelin B (ET-B) receptors, which play significantly different roles in regulating blood vessel diameter. The binding of endothelin to ET-A receptors located on smooth muscle cells causes vasoconstriction, whereas the binding of endothelin to ET-B receptors located on the vascular endothelium causes vasodilatation through the production of nitric oxide. This latter activity of the ET-B receptor is thought to be counter-regulatory and protects against excessive vasoconstriction.

Two Kinds of ETRAs:
Two types of ETRAs have been developed: dual ETRAs, which block the receptors for both ET-A and ET-B, and selective ETRAs, which block only the ET-A receptor.

There is debate over whether dual ETRAs or selective ETRAs are more therapeutically useful. The argument for dual ETRAs is that both endothelin receptors constrict blood vessels, but that ET-B also dilates the vessels. Blocking both receptors limits the amount of endothelin in the blood vessels. The argument for ET-A selective ETRAs is that ET-B dilates the vessels and also removes excess endothelin from circulation, so blocking only the ET-A receptor is the most effective treatment.

Dual Endothelin Receptor Antagonist:
The first generation ETRAs are non-selective and block both the ET-A and ET-B receptors. Tracleer® is the first FDA approved ETRA and it is a dual ETRA.

Selective Endothelin Receptor Antagonist:
Second generation ETRAs bind to the ET-A receptor in preference to the ET-B receptor.

There are two ETRAs approved in the United States for the treatment of pulmonary hypertension:

• Letairis™ (Ambrisentan)
• Tracleer® (Bosentan)

For Additional Information Visit:

• Actelion; Tracleer
• Gilead, Letaris
• FDA Drug Search: For information about this drug and any other drug approved by the U.S. FDA - patient info sheets, label info, approval history etc.