Rat Study Supports Promise Seen in PAH Patients of Natural Factor BH4 as Potential Treatment

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by Magdalena Kegel |

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Researchers offer new and additional evidence that a naturally occurring compound may be a valuable treatment for pulmonary hypertension. The factor, called tetrahydrobiopterin (BH4), had beneficial effects on both lung blood vessels and the heart in a rat model of the disease.

Their work also supports findings from early stage clinical testing of BH4 in patients with pulmonary arterial hypertension (PAH), according to the researchers at Imperial College London in the U.K. and Bar-Ilan University in Israel.

BH4 should now be explored in larger and placebo-controlled studies, the team suggests, underscoring that the treatment may be effective for both lung hypertension and right heart failure.

The study, “Tetrahydrobiopterin (BH4): Targeting endothelial Nitric Oxide Synthase as a potential therapy for Pulmonary Hypertension,” was published in the journal Cardiovascular Therapeutics.

BH4 is a factor controlling the production of endothelial nitric oxide synthase (eNOS) in the human body. eNOS — producing nitric oxide — is crucial for healthy endothelial cells, which line the inside of blood vessels. Nitric oxide dilates blood vessels, working to lower lung blood pressure.

When there is too little BH4, eNOS starts producing the oxidative compound superoxide instead of beneficial nitric oxide. Researchers know that this imbalance contributes to the development of lung hypertension.

Mice that were genetically engineered to lack the BH4 factor had increased pressure in the heart’s right ventricle and signs of heart enlargement, the researchers noted.

Rats were injected with a chemical that triggered pulmonary hypertension. However, when these animals received one injection of BH4, their lung blood pressure dropped within five minutes. A similar injection had no impact on the lung blood pressure in normal rats serving as a control group.

The treatment also improved the blood pressure in the right side of the heart and made the heart contractions stronger.

Next, researchers tested the treatment’s chronic effects by giving rats BH4 in their food.

The experiments showed that giving rats BH4 before the hypertension-triggering chemical prevented the development of pulmonary hypertension, without impacting blood pressure in the rest of the body.

Treatment affected features in both the lung blood vessels and the heart. Blood vessels in the lungs did not develop the thick layers of smooth muscle that is typical of lung hypertension. Moreover, BH4 prevented inflammation, which is a key component of the disease.

Humans rarely receive a treatment before they develop a disease. Therefore, the team also tested if BH4 had the ability to reduce disease in animals that had already developed pulmonary hypertension.

These treated animals showed a slower disease progression, with lower lung and right heart blood pressure. They also developed less smooth muscle around their lung blood vessels and had lower levels of inflammation — just as animals treated in a preventive manner.

Treatment at a higher dose allowed some features to return to normal levels, the study reports.

Importantly, the treatment was safe and well-tolerated with outcomes similar to  published results from a small Phase 1 clinical trial (NCT00435331) testing BH4, given orally, in PAH patients. The study also showed that eight weeks of treatment improved the patients’ exercise capacity, as measured by the 6-minute walk distance test.

The new data from animal models of pulmonary hypertension support the idea that BH4 may be a valuable treatment avenue for patients with the disease, researchers said, while underscoring the need for larger clinical trials.

A Conversation With Rare Disease Advocates