The endothelium
The endothelium is an organ consisting of a single layer of cells between the blood stream and the blood vessel wall. The main functions of the endothelium include:

• maintenance of blood vessel tone, which is critical for regulating blood pressure levels
• prevention of blood clots forming on the vessel wall by providing a non-adhesive surface

Endothelial cells produce several vasoactive chemical factors including endothelin, nitric oxide and prostacyclin. 

Endothelin
Endothelial cells produce several vasoactive chemical factors, among them endothelin and nitric oxide, which work in opposition. Nitric oxide dilates blood vessels, prevents platelet adhesion, and inhibits cell proliferation.

Endothelin, however, is a powerful blood vessel constrictor that also promotes cell proliferation. In a normal healthy state, the body maintains a balance between nitric oxide and endothelin. In contrast, in certain disease states endothelin is produced in excess. In addition to causing vasoconstriction – the narrowing of blood vessels – excessive endothelin can:

• stiffen blood vessels and tissues by promoting fibrosis, the accumulation of connective tissue
• cause vascular remodeling (a change in the vessels' structure), vascular hypertrophy (an increase in the thickness of blood vessel walls), and cardiac hypertrophy
• predispose the vessels to inflammation

Endothelin receptors
Endothelin binds to two types of receptors found on the blood vessel walls and in tissues: ET_A receptors, which are found predominantly in smooth muscle cells in the blood vessels, and ET_B receptors, which are also found in fibroblasts, neuronal cells, endothelial cells, and hormone-producing cells.

The activation of the endothelin system plays a critical role in chronic cardiovascular diseases, such as pulmonary hypertension, and in acute cardiovascular conditions, such as right heart failure and cerebral vasospasm – a constriction of blood vessels in the brain following subarachnoid hemorrhage. It is also implicated in connective tissue diseases such as scleroderma and pulmonary fibrosis. Endothelin levels have been shown to correlate with disease severity. Among Actelion's endothelin receptor antagonists are oral dual ET_A-ET_B antagonists, and an intravenous selective ET_A antagonist for cerebral vasospasm, which block the consequences of excessive endothelin.