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Endothelin and Pulmonary Arterial Hypertension: 6 Things To Know

Posted on January 23, 2023
Medically reviewed by
Steven C. Pugliese, M.D.
Article written by
Emily Wagner, M.S.

Endothelin is a small protein in the blood that helps regulate blood pressure. High levels of endothelin can be harmful. They can cause high blood pressure and conditions like pulmonary hypertension, which is high blood pressure in the lungs. People with pulmonary arterial hypertension (PAH), a type of pulmonary hypertension, tend to have high levels of endothelin.

Fortunately, medications that block endothelin, called endothelin receptor antagonists (ERAs), are available to help treat PAH. These medications help lower blood pressure and relieve symptoms of PAH. While they may be expensive, there are financial assistance programs to help cover costs.

Read on for six things to know about endothelin and endothelin receptor antagonists if you have PAH.

1. Endothelin Is a Chemical That Helps Your Blood Vessels Function

Your blood vessels are able to dilate (expand) and constrict (tighten) with the help of different enzymes, or chemical signals. These chemicals are released in response to different activities, like exercise or exposure to cold temperatures. Chemicals that expand blood vessels are known as vasodilators, while those that tighten blood vessels are known as vasoconstrictors.

When your blood vessels expand or tighten, the amount of blood that can flow through them changes. These changes can affect blood pressure: It may increase when your blood vessels tighten and decrease when they expand.

Endothelin is a small peptide (protein) that acts as a vasoconstrictor. It’s made by the endothelium, or endothelial cells, which line the insides of your blood vessels — thus getting the name endothelin. There are three types of endothelin, but doctors and researchers know the most about endothelin-1 (ET-1).

2. People With PAH Have Higher Endothelin Levels

Research shows that people with PAH tend to have imbalances in the chemicals that help control blood vessel expansion and tightening. These include endothelin and the vasodilators prostacyclin and nitric oxide. Normally, there’s a fine balance of chemical concentrations in your blood vessels to help control blood pressure.

However, people with PAH tend to have an imbalance — specifically, they have higher levels of endothelin-1 in addition to lower levels of prostacyclin and nitric oxide. Together this imbalance leads to vasoconstriction, tightening of the blood vessels in the lungs’ arteries.

This results in an increase in mean pulmonary artery pressure (mPAP). It may also lead to increased pulmonary vascular resistance (PVR), a situation that forces the right ventricle (chamber of the heart) to work harder to pump blood to the lungs.

Elevated endothelin levels are seen in other health conditions, including:

  • Scleroderma — A connective tissue disease that causes skin thickening and hardening that leads to the buildup of scar tissue
  • Atherosclerosis — Buildup of cholesterol in the arteries leading to thickening or hardening
  • Cardiovascular disease — Heart disease or heart failure
  • Pulmonary fibrosis — Lung disease caused by scarring or damage

3. Endothelin Medications Can Be Used in the Treatment of PAH

A doctor may determine you have high endothelin-1 levels through a blood test. ET-1 is found in plasma, or the liquid part of your blood that separates away from the red and white blood cells and platelets. Typically, endothelin-1 levels are between 1 picogram (pg) per milliliter (mL) and 2 pg/mL of blood.

Doctors sometimes prescribe endothelin receptor antagonists for treating PAH — even for people whose ET-1 levels are normal. These medications work by blocking endothelin-1 from binding to receptors on vascular smooth muscle cells. This inhibition process causes the blood vessels to relax and open up to allow more blood to flow through. ERAs also help promote the production of prostacyclin and nitric oxide. As a result, the blood pressure in your lungs’ arteries decreases.

4. The FDA Has Approved 3 Endothelin Treatments for PAH

Through clinical trials, the U.S. Food and Drug Administration (FDA) has approved three ERAs for the treatment of pulmonary arterial hypertension. These include:

  • Letairis, a formulation of ambrisentan — Blocks endothelin A receptors
  • Tracleer, a formulation of bosentan — Blocks both endothelin A and endothelin B receptors
  • Opsumit, a formulation of macitentan — Blocks both endothelin A and endothelin B receptors

Studies show that these medications can help lower mPAP and improve PAH symptoms and disease outcomes. For example, people with PAH who take ERAs see improvement in their exercise capacity and walking distance during the six-minute walk test.

ERAs have been found to be effective in treating people with:

  • Idiopathic PAH — PAH that can’t be tied to an exact cause
  • PAH associated with connective tissue diseases
  • PAH related to HIV infection
  • PAH associated with congenital heart disease
  • PAH related to anorexigenic medication (appetite suppressant) use

Other Medications for Treating PAH

The FDA has also approved other types of medications for treating PAH. Some of these may be combined to help better manage the vascular disease.

Treatments for PAH include:

5. Endothelin Medications Come With a Risk of Side Effects

As with all medications, ERAs present a risk of side effects. The major side effects doctors look for include:

  • Fluid retention
  • Anemia
  • Abnormal liver function
  • Headache
  • Nasal congestion

Other ERA side effects include:

  • Fever
  • Respiratory tract infections like bronchitis
  • Sinus infections
  • Urinary tract infections
  • Edema, or fluid buildup that causes swelling in the arms and legs
  • Flushed skin

More serious side effects that have been reported include:

  • Pulmonary edema, or fluid in the lungs
  • Decreased sperm count
  • Blood disorders

Before beginning an ERA or other PAH medication, talk to your doctor about what effects you can expect. They can help you prepare for what to expect and which side effects require medical attention. Be sure to let your doctor know if any side effects begin interfering with your daily activities or make it difficult to continue treatment. They can change the dosage or create a new treatment plan that better works for you while managing your PAH.

6. Financial Assistance Programs Help Cover the Costs of Endothelin Medications

ERAs, along with other PAH medications, are expensive in the U.S. The Pulmonary Hypertension Association offers a list of nonprofit assistance programs that help make treatment more affordable.

Many drug manufacturers have assistance programs that provide reimbursement for some costs of medication. Your doctor’s office may also have information on these programs and other resources that can help cover the costs of PAH treatment.

Talk With Others Who Understand

On myPHteam, the social network for those who live with PH, more than 49,000 members come together to ask questions, give advice, and share their experiences of life with pulmonary hypertension.

Do you take an endothelin receptor antagonist to help manage your PAH? Share your experience in the comments below, or start a conversation by posting on your Activities page.

    All updates must be accompanied by text or a picture.
    Steven C. Pugliese, M.D. is affiliated with the Hospital of the University of Pennsylvania in Philadelphia, serving as the director of the pulmonary embolism response team, co-director of the comprehensive pulmonary embolism program, and an assistant professor of clinical medicine. Review provided by VeriMed Healthcare Network. Learn more about him here.
    Emily Wagner, M.S. holds a Master of Science in biomedical sciences with a focus in pharmacology. She is passionate about immunology, cancer biology, and molecular biology. Learn more about her here.

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