Endothelins are proteins that constrict blood vessels and raise blood pressure. They are normally kept in balance by other mechanisms, but when they are over-expressed, they contribute to high blood pressure (hypertension) and heart disease.

Endothelins are 21-amino acid vasoconstricting peptides produced primarily in the endothelium having a key role in vascular homeostasis. Among the strongest vasoconstrictors known, endothelins are implicated in vascular diseases of several organ systems, including the heart, general circulation and brain^[1][2].

Isoforms and organ distribution

There are three isoforms (identified as ET-1, -2, -3) with varying regions of expression and two key receptor types, ET_A and ET_B^[3].

• ET_A receptors are found in the smooth muscle tissue of blood vessels, and binding of endothelin to ET_A increases vasoconstriction (contraction of the blood vessel walls) and the retention of sodium, leading to increased blood pressure.
• ET_B is primarily located on the endothelial cells that line the interior of the blood vessels. When endothelin binds to ET_B receptors, this leads to the release of nitric oxide (also called "NO" or endothelium-derived relaxing factor), natriuresis and diuresis (the production and elimination of urine) and mechanisms that lower blood pressure.
• Both types of ET receptor are found in the nervous system where they may mediate neurotransmission and vascular functions^[4].

Brain and nerves

Widely distributed in the body, receptors for endothelin are present in blood vessels and cells of the brain, choroid plexus and peripheral nerves. When applied directly to the brain of rats in picomolar quantities as an experimental model of stroke, endothelin-1 caused severe metabolic stimulation and seizures with substantial decreases in blood flow to the same brain regions, both effects mediated by calcium channels^[5]. A similar strong vasoconstrictor action of endothelin-1 was demonstrated in a peripheral neuropathy model in rats^[6].

Examples of physiological interaction

In a healthy individual, a delicate balance between vasoconstriction and vasodilation is maintained by endothelin and other vasoconstrictors on the one hand and nitric oxide, prostacyclin and other vasodilators on the other.

Overproduction of endothelin in the lungs may cause pulmonary hypertension, which can sometimes be treated by the use of an endothelin receptor antagonist, such as bosentan, sitaxentan or ambrisentan. The latter drug selectively blocks endothelin A receptors, decreasing the vasoconstrictive actions and allowing for increased beneficial effects of endothelin B stimulation, such as nitric oxide production. The precise effects of endothelin B receptor activation depends on the type of cells involved.

Disease involvement

The ubiquitous distribution of endothelin peptides and receptors implicates its involvement in a wide variety of physiological and pathological processes in the body. Among numerous diseases potentially occurring from endothelin dysregulation are

• several types of cancer^[7]
• cerebral vasospasm following subarachnoid hemorrhage^[8]
• arterial hypertension and other cardiovascular disorders^[9]
• pain mediation^[10]

References

External links

• Endothelin science (Actelion Pharmaceuticals)

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