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.

Pulmonary hypertension medications that block endothelin, called endothelin receptor antagonists (ERAs), are available to help treat PAH. These endothelin receptor blockers help lower blood pressure and relieve symptoms of PAH.

Read on for six important facts about endothelin, endothelin receptor antagonists, and combination therapy for pulmonary hypertension.

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.

Higher levels of endothelin may cause the right ventricle (chamber of the heart) to work harder to pump blood to the lungs.

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

Endothelin is a small peptide (protein) that causes blood vessels to tighten. 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 delicate 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 and lower levels of prostacyclin and nitric oxide. 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, 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 that you have high endothelin-1 levels through a blood test. ET-1 is found in plasma, the liquid part of your blood that can be separated from the red and white blood cells and platelets. Typically, endothelin-1 levels are between 1 and 2 picograms per milliliter of blood.

Endothelin medications can treat people with different kinds of PAH, including idiopathic PAH and PAH caused by other health conditions and infections.

Doctors sometimes prescribe endothelin receptor antagonists (ERAs) for treating PAH. These medications work by blocking endothelin-1 from binding to receptors on vascular smooth muscle cells. This 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 Several 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:

• Ambrisentan (Letairis) — Blocks endothelin A receptors
• Bosentan (Tracleer) — Blocks both endothelin A and endothelin B receptors
• Macitentan (Opsumit) — Blocks both endothelin A and endothelin B receptors

Studies show 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 appetite suppressant use

Combination Therapy With ERAs

Macitentan/tadalafil (Opsynvi) is a combination medication for PAH that combines the ERA macitentan with a PDE inhibitor called tadalafil (Adcirca), which also treats PAH and erectile dysfunction. In clinical trials, macitentan/tadalafil combination therapy was more effective for reducing pulmonary vascular resistance in people with PAH than either drug alone.

According to Mayo Clinic, females with PAH may be prescribed macitentan/tadalafil in a restricted distribution program called the Macitentan-Containing Products REMS (Risk Evaluation and Mitigation Strategy).

Other Medications for Treating PAH

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

Other types of treatments for PAH include:

• Activin signaling inhibitors
• Blood thinners
• Calcium channel blockers
• Phosphodiesterase-5 (PDE5) inhibitors
• Soluble guanylate cyclase stimulators (sGCS)
• Prostacyclin medications

5. Endothelin Medications Come With a Risk of Side Effects

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

• Fluid retention (swelling)
• Anemia
• Abnormalities in liver function
• Headache
• Nasal congestion

Tell your healthcare provider if medication side effects interfere with your daily activities. They can adjust your dose or change your treatment plan.

Other ERA or combination therapy side effects include:

• Fever
• Coughing
• Respiratory tract infections like bronchitis
• Sinus infections
• Urinary tract infections
• Edema, or fluid buildup that causes swelling in the arms and legs
• Flushed skin
• Unusual weight changes
• Lightheadedness or confusion
• Reduced urination
• Vaginal bleeding

More serious side effects include:

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

Before beginning an ERA or other PAH medication, talk to your doctor. 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 57,000 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? Have you noticed a significant difference in your symptoms? Share your experience in the comments below, or start a conversation by posting on your Activities page.