An endothelin receptor agonist is a substance that binds to and activates endothelin receptors. To understand this, it helps to define the components. Endothelin is a protein that causes blood vessels to constrict, a receptor is a cell structure that receives signals, and an agonist is a molecule that triggers a response upon binding to a receptor.
Therefore, an endothelin receptor agonist mimics the body’s natural endothelin. When it binds to a receptor, it causes the smooth muscles of blood vessel walls to contract. This action narrows the blood vessels, a process known as vasoconstriction, and is part of the endothelin system.
The Endothelin System’s Role in the Body
The endothelin system is a network that helps manage cardiovascular functions. Its primary components are endothelin peptides—like endothelin-1 (ET-1)—and their corresponding receptors. ET-1 is produced by the endothelial cells that form the inner lining of blood vessels and helps regulate vascular tone, the degree of constriction in a blood vessel.
This regulation is achieved through two main types of endothelin receptors: endothelin type A (ET-A) and endothelin type B (ET-B). The ET-A receptors are found on vascular smooth muscle cells. When ET-1 binds to these receptors, it signals the muscle cells to contract, leading to vasoconstriction and an increase in blood pressure.
The ET-B receptors have a varied role and are located on both endothelial and smooth muscle cells. When ET-1 activates ET-B receptors on smooth muscle, it contributes to vasoconstriction. However, when ET-B receptors on endothelial cells are activated, they trigger the release of substances like nitric oxide that cause vasodilation, the widening of blood vessels. ET-B receptors are also involved in clearing excess ET-1 from the bloodstream.
Beyond blood pressure regulation, the endothelin system influences cell proliferation, meaning it can encourage the growth of certain cells, particularly smooth muscle cells. This function is important for tissue maintenance and repair. The coordinated actions of ET-1 and its receptors ensure that blood vessels can respond to the body’s changing demands.
Endothelin’s Involvement in Disease
Overactivation of the endothelin system can contribute to several diseases. When the body produces excessive amounts of endothelin-1 (ET-1), or when its receptors become dysregulated, vascular control is disrupted. This leads to chronic vasoconstriction and abnormal cell growth, which are underlying factors in various conditions.
A prominent disease linked to endothelin system overactivity is Pulmonary Arterial Hypertension (PAH). In PAH, the small arteries in the lungs become persistently narrowed and stiffened. Elevated levels of ET-1 drive this process by causing sustained vasoconstriction and promoting excessive proliferation of smooth muscle cells in the vessel walls.
This remodeling of the blood vessels increases resistance to blood flow through the lungs. As a result, the pressure in these arteries rises, forcing the right side of the heart to work harder to pump blood, which can lead to heart failure.
The influence of a dysfunctional endothelin system extends to other conditions. In systemic sclerosis, an autoimmune disease characterized by widespread fibrosis, elevated endothelin levels are a contributing factor. The overproduction of ET-1 is thought to contribute to the vascular damage and fibrosis seen in the skin, lungs, and other organs, and is a primary driver of PAH in this patient group.
Therapeutic Intervention with Endothelin Receptor Antagonists
Since an overactive endothelin system drives disease by excessively stimulating its receptors, medical therapies are designed to counteract this effect. It is important to clarify that a therapeutic agent would not be an agonist, as that would worsen the condition. Instead, the medications used are endothelin receptor antagonists (ERAs), which block the receptors and prevent endothelin from initiating its harmful effects.
By occupying the receptor sites, ERAs inhibit the signals for vasoconstriction and cell proliferation. In Pulmonary Arterial Hypertension (PAH), this blockade leads to the relaxation and widening of the pulmonary arteries. This vasodilation reduces the resistance to blood flow within the lungs, which lowers the high blood pressure in these vessels and alleviates the strain on the right side of the heart.
Several ERA medications are approved for use and can be categorized by their selectivity. Some ERAs are non-selective, meaning they block both ET-A and ET-B receptors, such as bosentan. Other ERAs are selective, primarily targeting the ET-A receptor, which is the main mediator of vasoconstriction; ambrisentan and macitentan are examples.
The choice between a non-selective or a selective antagonist depends on clinical factors, but both approaches have proven effective in managing PAH. These therapies have significantly improved outcomes for patients, including survival rates and quality of life.
Administration and Monitoring of Treatment
Endothelin receptor antagonists (ERAs) are prescribed as oral tablets, taken once or twice daily. The use of these medications requires medical supervision due to potential side effects. The primary concern associated with some ERAs is the risk of liver injury.
Because of this risk, patients prescribed certain ERAs, such as bosentan and ambrisentan, must undergo regular blood tests to monitor their liver function. These tests measure liver enzymes in the blood. Elevated enzyme levels can indicate liver stress or damage, which may require an adjustment to the dosage or discontinuation of the medication.
Another safety consideration for ERAs is their high risk of causing severe birth defects, as they are teratogenic. ERAs are strictly contraindicated for patients who are pregnant. Women of childbearing potential must use reliable methods of contraception and undergo regular pregnancy testing before receiving their monthly prescription.