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Targeting the Molecular Pathways That Cause PAH: What We Know

Medically reviewed by Steven C. Pugliese, M.D.
Written by Torrey Kim
Updated on October 25, 2023

Pulmonary arterial hypertension (PAH) is a serious condition that causes high blood pressure in the arteries of the lungs. A range of therapies and medications can help people with PAH experience fewer symptoms and a better quality of life. Some of these treatments work to target three of the molecular pathways involved in PAH.

Read on to discover more about the main molecular pathways involved in PAH and how medications work to address imbalances in them.

The Three Key Pathways in People With PAH

There are three main pathways involved in PAH. In people with PAH, one of three key natural chemical levels may be out of balance in the body: endothelin, nitric oxide (NO), or prostacyclin. People with PAH can have either too much or not enough of these chemicals. People with PAH typically have:

  • Too much endothelin
  • Not enough nitric oxide
  • Not enough prostacyclin

These chemical imbalances cause changes in the arteries of the lungs. These changes include:

  • Narrowing of the vessels
  • Stiffening of the vessel walls
  • Scarring that can block the vessels
  • Inflammation

How PAH Medications Target These Pathways

Since people with PAH may have either too much or too little of one of the three key signaling pathways, some PAH medicines are tailored to target one of these chemical imbalances. Treating these imbalances can help reduce symptoms and slow disease progression.

Sometimes, a health care provider will treat PAH with two or more of these therapies — a practice known as combination therapy — to help manage the condition.

Endothelin

Endothelin is a protein present in the blood that assists in regulating blood pressure. When levels of it are too high, PAH may result. While three endothelin types are present in the body, the one that’s been researched the most is endothelin-1 (ET-1).

When endothelin levels are too high and levels of prostacyclin and nitric oxide are too low, an overall imbalance occurs, leading the blood vessels within the lungs’ arteries to narrow. This puts pressure on the heart’s structures and may eventually result in heart disease or heart failure if left untreated.

High ET-1 levels can be detected through blood testing. If yours are elevated, your doctor may prescribe medication to help lower the ET-1 volume in your body. Endothelin receptor antagonists (ERAs) have been shown to reduce the blood pressure in the lungs by blocking ET-1 from binding to cells in the body.

The U.S. Food and Drug Administration (FDA) has approved three ERAs for the treatment of pulmonary arterial hypertension:

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

Members of myPHteam often discuss how ERAs affect their symptoms. “I was diagnosed in 2009 and the first medication I was put on treated the endothelin pathway, which was the only medication I was on till 2019,” one member wrote.

Nitric Oxide

Nitric oxide is found naturally in the human body. It helps keep blood flowing by ensuring vasodilation (that your blood vessels stay open), thereby keeping blood pressure levels stable. When levels of nitric oxide are too low, the heart has to work harder to pump blood, which can lead to PAH.

Your provider may prescribe inhaled nitric oxide to help stabilize abnormalities in your NO levels. This approach can target the blood vessels in your lungs, opening them up and allowing your blood flow to improve. This reverses the stress on your heart, lowering blood pressure.

Inhaled nitric oxide is considered a targeted medication rather than a systemic one, meaning it directly targets the level of NO in your body rather than treating your entire body to reduce PAH symptoms. “Nitric oxide has helped improve my breathing and strength,” one myPHteam member wrote.

To use this medication, you’ll breathe the gas in through your mouth or nose, and the nitric oxide will make its way to the area where it’s deficient. During the therapy regimen, your doctor will monitor the oxygen levels in your blood, your pulmonary arterial pressure, and your whole-body blood pressure to ensure it’s working appropriately.

Nitric oxide is available to people who are hospitalized and on an outpatient basis for compassionate use (unauthorized use for treating serious illness).

Prostacyclin

Prostacyclin is a chemical that’s naturally present in the body. It’s important for reducing blood clotting and inflammation, relaxing pulmonary artery smooth muscle cells, and keeping blood pressure in check. When prostacyclin levels are too low, vasoconstriction (narrowing of blood vessels in the lungs) may occur, potentially leading to symptoms of PAH.

To help raise prostacyclin levels and improve the movement of vascular smooth muscle cells, your doctor may prescribe prostacyclin analogs (or prostanoids). These medications essentially take the place of the naturally occurring prostacyclin. Options for this type of medication include:

  • Epoprosteno ( Flolan, Veletri) — Administered through an IV
  • Iloprost (Ventavis) — Inhaled through the nose or mouth
  • Selexipag (Uptravi) — Taken as a tablet by mouth
  • Treprostinil (Tyvaso) — Can be taken by mouth, inhaled, or administered through an IV

“I’m feeling good — just had a Ventavis treatment,” one myPHteam member wrote.

Another said, “I take Tyvaso and it has helped!”

Your pulmonology and cardiology care teams will work together to determine which of these medications might be the most effective for your specific situation.

Talk With Others Who Understand

On myPHteam, the social network for people with pulmonary hypertension and their loved ones, more than 51,000 members come together to ask questions, give advice, and share their stories.

Has your doctor mentioned that your prostacyclin, nitric oxide, or endothelin levels are off? What helped in managing this? Share your experience in the comments below, or start a conversation by posting on your Activities page.

    Updated on October 25, 2023
    All updates must be accompanied by text or a picture.

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    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
    Torrey Kim is a freelance writer with MyHealthTeam. Learn more about her here

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