Endothelin is a naturally occurring peptide, a small protein, primarily produced by the endothelial cells lining blood vessels. This peptide plays a significant role in regulating blood vessel activity, particularly by narrowing blood vessels and increasing blood pressure. Endothelin receptor antagonists are a class of medications designed to counteract the effects of endothelin. These drugs achieve their therapeutic effect by blocking the specific receptors that endothelin binds to, thereby preventing its actions.
How Endothelin Antagonists Work
Endothelin exerts its effects by binding to specific endothelin receptors, found on the surface of various cell types, especially within the cardiovascular system. There are two primary types: endothelin A (ETA) and endothelin B (ETB). ETA receptors are predominantly located on the smooth muscle cells of blood vessels. Their activation by endothelin leads to vasoconstriction, or the narrowing of blood vessels, and promotes cell proliferation.
ETB receptors are found on both endothelial cells and smooth muscle cells. When endothelin binds to ETB receptors on endothelial cells, it can stimulate nitric oxide production, promoting vasodilation, a widening of blood vessels. However, ETB receptors on smooth muscle cells can also contribute to vasoconstriction and cell growth. By blocking these receptors, endothelin antagonists prevent endothelin from binding. This reduces vasoconstriction and excessive cell proliferation, leading to vasodilation, decreased blood pressure, and improved blood flow, particularly in the pulmonary circulation.
Medical Uses
Endothelin receptor antagonists are primarily prescribed for conditions involving abnormal blood vessel constriction and growth. Their most recognized application is in the treatment of pulmonary arterial hypertension (PAH), a progressive condition characterized by high blood pressure in the arteries of the lungs. In PAH, elevated levels of endothelin-1 contribute to the narrowing and remodeling of the pulmonary arteries, leading to increased resistance to blood flow and eventual heart failure.
By blocking endothelin’s effects, these medications relax pulmonary arteries, reducing vascular resistance and improving blood flow. This alleviates symptoms like shortness of breath and dizziness, enhancing exercise capacity and quality of life. Specific drugs include bosentan (blocks both ETA and ETB), and ambrisentan and macitentan (selective for ETA or block both). While bosentan was the first oral therapy for PAH, macitentan and ambrisentan have shown improved safety profiles.
Important Considerations
Patients taking endothelin antagonists require regular monitoring due to potential side effects. Liver issues are a known concern, with some drugs like bosentan linked to dose-dependent elevations in liver enzymes. Newer agents such as ambrisentan and macitentan have a lower risk of liver toxicity, but ongoing monitoring of liver function tests is advised.
Fluid retention and edema, or swelling, are common adverse effects, ranging from mild peripheral swelling to worsening heart failure. This can be managed with diuretics and dietary sodium restriction. These medications can also cause mild anemia due to hemodilution. Endothelin antagonists are teratogenic, meaning they can cause severe birth defects, and are strictly contraindicated during pregnancy. Women of childbearing potential must use reliable contraception, as hormonal birth control alone may be insufficient due to drug interactions that accelerate its metabolism.