Endothelin is a small protein (called a peptide) that helps control blood pressure, found in the cells lining blood vessels. When endothelin levels get too high, they can cause problems, including hypertension (high blood pressure) and pulmonary hypertension, which is high blood pressure in the arteries of the lungs. People living with pulmonary arterial hypertension (PAH), a specific type of pulmonary hypertension, often have higher levels of endothelin than usual.

There are medications for pulmonary hypertension called endothelin receptor antagonists (ERAs) that block the effects of endothelin. These medicines can help lower blood pressure in the lungs and reduce symptoms of PAH.

Keep reading to learn six key facts about endothelin, endothelin receptor antagonists, and how combination therapy may help people with pulmonary hypertension.

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

Your blood vessels dilate (expand) or constrict (tighten) with help from different chemical signals, including enzymes. Your body releases these chemicals in response to things like exercise or cold temperatures. Chemicals that make blood vessels wider are called vasodilators, and those that make blood vessels tighter are called vasoconstrictors.

When blood vessels widen, more blood can flow through them, and your blood pressure goes down. When blood vessels tighten, less blood flows through and your blood pressure goes up.

Endothelin is a small peptide that causes blood vessels to tighten. There are three types of endothelin, but doctors and researchers know the most about endothelin-1 (ET-1).

Endothelin is a small protein that causes your blood vessels to tighten.

2. People With PAH Have Higher Endothelin Levels

Research shows that people living with pulmonary arterial hypertension (PAH) often have imbalances in the chemicals that control how blood vessels widen and tighten. These chemicals include endothelin and the vasodilators prostacyclin and nitric oxide. Normally, your body maintains a delicate balance of these substances to help keep blood pressure in a healthy range.

In PAH, this balance shifts. People with PAH usually have higher levels of ET-1 and lower levels of prostacyclin and nitric oxide. This imbalance causes the arteries in the lungs to tighten (vasoconstriction), which makes it harder for blood to flow through.

As a result, the average pressure in the pulmonary arteries — called mean pulmonary artery pressure (mPAP) — goes up. This can also raise pulmonary vascular resistance, which means the right side of the heart has to work harder to pump blood into the lungs.

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

• Scleroderma — A connective tissue disease that causes skin thickening and hardening, leading 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 (when the heart can’t pump enough blood to meet the body’s needs)
• Pulmonary fibrosis — Lung disease caused by scarring or damage to lung tissue

3. Endothelin Medications Can Be Used in PAH Treatment

Doctors sometimes prescribe endothelin receptor antagonists for treating PAH. These medications work by blocking ET-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 may help rebalance endothelin signaling alongside other pathways, such as prostacyclin and nitric oxide, which play roles in regulating blood pressure in the lungs’ arteries.

Endothelin receptor antagonists block the endothelin pathway and allow more blood to flow through blood vessels.

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 human immunodeficiency virus (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 phosphodiesterase 5 (PDE5) 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.

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
• PDE5 inhibitors
• Soluble guanylate cyclase stimulators
• 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:

• Edema (swelling), which is fluid buildup in the arms or legs
• Anemia (low red blood cell count)
• Abnormalities in liver function
• Headache
• Nasal congestion

Other ERA or combination therapy side effects include:

• Fever
• Cough
• Respiratory tract infections like bronchitis
• Sinus infections
• Urinary tract infections
• Flushed skin
• Unusual weight changes
• Lightheadedness or confusion
• Reduced urination
• Vaginal bleeding

In rare cases, more serious side effects, such as a reduced sperm count, can occur.

Additionally, some ERAs come with a black box safety warning for the following risks:

• Some ERAs can cause birth defects if taken during pregnancy. Because of this, regular pregnancy testing and reliable birth control are required for people who could become pregnant while taking the medication.
• Certain ERAs (especially bosentan) may affect the liver, so regular blood tests to monitor liver function are necessary. Some ERAs are only available through special FDA safety programs called Risk Evaluation and Mitigation Strategies (REMS).

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, can be expensive in the U.S. The Pulmonary Hypertension Association offers a list of nonprofit assistance programs that help make treatment more affordable.

The Pulmonary Hypertension Association offers a list of nonprofit assistance programs that help make treatment more affordable.

In addition, many drug companies offer financial assistance programs that may pay for some or all of the medication costs. Your healthcare team or doctor’s office may also have information about these programs and other resources to help with the cost of PAH treatment.

Join the Conversation

On myPHteam, people share their experiences with pulmonary hypertension, get advice, and find support from others who understand.

Do you take an endothelin receptor antagonist to help manage your PAH? Have you noticed a significant difference in your symptoms? Let others know in the comments below.