Endothelin is a peptide, which is a small protein, primarily made and released by endothelial cells. These cells form the endothelium, the thin layer lining the inside of all blood vessels. One can imagine the circulatory system’s arteries and veins as a complex network of garden hoses, and the endothelium would be the smooth inner lining of those hoses.
Endothelial cells are not just a passive lining; they are an active organ in the body. These cells produce a variety of substances that regulate the cardiovascular system’s function, including endothelin.
The Function of Endothelin
The primary role of endothelin in the body is to cause the tightening, or constriction, of blood vessels. This action, known as vasoconstriction, is a mechanism for controlling blood flow and regulating blood pressure. The effect is similar to squeezing a garden hose; the narrowing of the tube increases the pressure of the water flowing through it.
The body produces three distinct types of endothelin: ET-1, ET-2, and ET-3. Endothelin-1 (ET-1) is the most studied isoform and is considered the most potent vasoconstrictor made by the human body. While ET-2 is mostly found in the kidney and intestines and ET-3 in the central nervous system, ET-1 is the primary type in cardiovascular regulation.
For endothelin to exert its effects, it must first bind to specific docking stations on the surface of cells called receptors. There are two main types of endothelin receptors, known as endothelin receptor type A (ETA) and endothelin receptor type B (ETB). ETA receptors are located mainly on vascular smooth muscle cells, the very cells that contract to narrow blood vessels. When ET-1 binds to ETA receptors, it triggers a cascade of events inside the muscle cell that leads to contraction and vasoconstriction. ETB receptors are more complex; they are found on both endothelial cells and smooth muscle cells, where they can have varied effects.
Role in Disease
While the endothelin system is a normal part of regulating the body’s vascular tone, problems arise when it becomes overactive. An excessive amount of endothelin, particularly ET-1, leads to harmful and sustained vasoconstriction, contributing to the development and progression of several diseases. This imbalance is a factor in conditions affecting the heart, lungs, and kidneys.
A primary example of a disease driven by endothelin overactivity is pulmonary arterial hypertension (PAH). In PAH, the blood vessels within the lungs become severely constricted. This narrowing makes it much harder for the right side of the heart to pump blood through the lungs, leading to dangerously high blood pressure in the pulmonary arteries. Patients with PAH have elevated levels of ET-1 in both their plasma and lung tissue, which drives this harmful vascular constriction and remodeling.
The damaging effects of excess endothelin extend beyond the lungs. In heart failure, a struggling heart muscle releases more ET-1, which can contribute to a damaging cycle of further vasoconstriction and fluid retention, placing even more strain on the already weakened heart. Similarly, in chronic kidney disease, high levels of endothelin can constrict the blood vessels within the kidneys, reducing blood flow and impairing their function. The peptide also promotes fibrosis, the growth of scar-like tissue, which can further damage the structure and function of these organs over time.
Medical Treatments Targeting Endothelin
Given the role of excess endothelin in certain diseases, a specific class of medications has been developed to counteract its effects. These drugs are known as Endothelin Receptor Antagonists, or ERAs. They work by directly blocking the ETA and/or ETB receptors, preventing endothelin from binding to them and initiating its harmful actions. This mechanism is akin to placing a cover over a keyhole, which stops the key—in this case, endothelin—from entering and unlocking the door to vasoconstriction.
These treatments have become a primary therapy for pulmonary arterial hypertension (PAH). By blocking the receptors, ERAs help to relax and dilate the constricted pulmonary arteries, reducing the high blood pressure in the lungs. This action lessens the strain on the right side of the heart and can improve a patient’s ability to exercise and perform daily activities.
Several specific ERA drugs are now in use, including bosentan, ambrisentan, and macitentan. Bosentan is a dual antagonist, meaning it blocks both ETA and ETB receptors, and was the first of its class to be approved for treating PAH. Ambrisentan is more selective, primarily targeting the ETA receptor.