It is a 21 amino acid peptide produced by the vascular endothelium.
It is a very potent vasoconstrictor that binds to smooth muscle endothelin receptors, of which there are two subtypes: ET A and ET B receptors.
These receptors are coupled to the Gq protein, and activation of the receptor leads to the formation of IP3.
This causes calcium release from the sarcoplasmic reticulum (RS) and increases smooth muscle contraction and vasoconstriction.
There are also receptors located in the endothelium that stimulate the formation of nitric oxide, which produces vasodilation in the absence of smooth muscle ET A and ET B as receptor activation.
This receptor distribution helps explain the phenomenon that endothelin administration causes transient vasodilation and hypotension.
Endothelin receptors in the heart are also linked to the Gq and IP3 protein signal transduction pathway.
Therefore, endothelin in the heart causes the release of calcium RS, which increases contractility. Endothelin also increases the heart rate.
Endothelin receptor antagonists
Endothelin receptor antagonists are targeted therapy used to treat people with pulmonary hypertension (PH).
Targeted therapies slow the progression of PH and may even reverse some of the damage to the heart and lungs.
There are currently three types of endothelin receptor antagonists presently used to treat PH; these are:
- Ambrisentan (Volibris).
- Bosentan (Tracleer).
- Macitentán (Opsumit).
All endothelin receptor antagonists should be taken as tablets.
How do they work?
Endothelin receptor antagonists work by reducing the amount of endothelin in the blood.
Endothelin is produced in the layer of cells that line the heart and blood vessels. It causes blood vessels to constrict (become narrower).
In people with HP, the body makes too much endothelin. This causes the blood vessels in the lungs to narrow, increasing the blood pressure in the pulmonary arteries.
Endothelin receptor antagonists reduce the amount of endothelin in the blood, thus limiting the damage that too much endothelin can cause.
Liver function tests
If the patient takes any of the three endothelin receptor antagonists, he will need regular blood tests to ensure his liver is not damaged.
These blood tests can show whether the liver will be damaged or have difficulty if the patient continues to take medicine.
A PH physician should provide the patient with more information about the risks associated with using endothelin receptor antagonists.
This may include the risks of taking endothelin receptor antagonists during pregnancy for women.
Due to its powerful vasoconstrictive properties and its effects on intracellular calcium, endothelin has been implicated in the pathogenesis of:
- Coronary vasospasm.
- Heart failure.
Several studies suggest that endothelin plays a role in pulmonary hypertension, as well as in systemic hypertension.
Endothelin is released from the defective myocardium, which can contribute to cardiac calcium overload and hypertrophy.
Endothelin receptor antagonists, by blocking the vasoconstrictor and cardiotonic effects of endothelin, produce vasodilation and cardiac inhibition.
Endothelin receptor antagonists have been shown to decrease mortality and improve hemodynamics in experimental models of heart failure.
At present, the only approved indication for endothelin antagonists is pulmonary hypertension.
Bosentan is a non-selective endothelin receptor antagonist (blocks ET A and ET B receptors) that are currently used to treat pulmonary hypertension.
Another drug that is also used for pulmonary hypertension is ambrisentan, which is a selective antagonist of the ETA receptor.
Side effects and contraindications
Some of the endothelin antagonist side effects are common to most vasodilators; these are:
- Skin redness
- Edema formation.
This drug class can cause congenital disabilities in the baby and is, therefore, contraindicated in pregnancy.
Importantly, these medications can also cause liver damage.