Potential Oral Treatment Reverses Advanced PAH in Rats, Study Shows
An orally available small molecule, BI113823, successfully reversed the progression of severe, advanced pulmonary arterial hypertension (PAH) in a rat model, a study demonstrated.
The experimental medicine lowered pulmonary blood pressure, reduced blood vessel thickening, suppressed inflammatory responses, and prevented right heart failure and death.
These findings support the further development of this therapy in people with established PAH, the scientists noted.
The study, “Reversal of pulmonary arterial hypertension and neointimal formation by kinin B1 receptor blockade,” was published in the journal Respiratory Research.
PAH is characterized by the thickening of the walls of the pulmonary arteries, which are blood vessels that transport blood from the heart to the lungs. This restricts blood flow and increases blood pressure (hypertension), which can lead to right heart failure.
Inflammation is a prominent feature of PAH, in which immune cells and elevated pro-inflammatory signaling proteins are often found in PAH patients’ lungs.
Kinins are short chains of amino-acids called peptides found in the bloodstream. They trigger inflammation by binding to and activating the kinin receptor called B1. This receptor is typically produced at low levels, but its level increases after injury or exposure to pro-inflammatory agents.
Recently, researchers based at the Chonbuk National University in South Korea demonstrated that the levels of kinin B1 receptors was enhanced in an experimental rat model of PAH and played an essential role in the development of PAH.
Furthermore, they showed that early treatment with BI113823, which selectively blocked kinin B1 receptors, reduced lung inflammation, suppressed the thickening of pulmonary arteries’ walls (vascular remodeling), and prevented PAH development.
As PAH is often not diagnosed until the disease is relatively advanced, finding a medicine that effectively halts or reverses well-established PAH would be helpful.
This same research team now evaluated the efficacy of BI113823 in a rat model with severe, advanced PAH.
“The present study was designed to examine whether treatment with a small molecule orally-active, non-peptide B1 receptor [blocker] BI113823 can rescue preexisting PAH and vascular remodeling, and prevent right heart failure and death in rats,” the team wrote.
To create the model, the left lungs of the rats were surgically removed, then one week later, rats were treated with monocrotaline, which causes injury to the pulmonary arteries and hypertension.
Three weeks after the rats developed severe PAH — characterized by vascular remodeling and right heart enlargement — they were randomly assigned to receive BI113823 treatment or a placebo for three weeks.
Results revealed that late BI113823 treatment reversed the progression of PAH, prevented the transition of PAH to right heart failure, and prolonged the animals’ long-term survival.
Compared with placebo, BI113823 therapy reduced pulmonary arterial blood pressure by 50%, blood pressure in the right heart ventricle by 41%, and improved the cardiac index, a measure of heart performance, by 42%.
Six months after PAH was induced, nine out of the 13 (69%) placebo-treated animals died compared with one out of eight (13%) BI113823-treated animals.
Detailed tissue analysis showed BI113823 therapy reversed disease-related changes in the lung and heart, with a significant decrease in arterial wall thickness by 41% and scores for blood vessel blockage. BI113823 therapy also prevented the progression of fibrosis (scarring) in the lung and right heart, as well as markers for fibrosis.
Consistently, compared with the control animals, BI113823 reduced the number of inflammatory-related immune cells and pro-inflammatory immune signaling proteins in the rats’ airways.
Molecular analysis of rat lung tissue showed kinin B1 receptors were produced at low levels in healthy animals but were markedly increased in placebo-treated PAH lung tissue. In contrast, B1 receptor levels were significantly reduced following BI113823 treatment. Treatment also lowered markers of disease in the right heart.
“These findings confirm that kinin B1 receptors play an important role in the [development] and progression of pulmonary hypertension,” the researchers wrote.
Additional experiments demonstrated that BI113823 significantly decreased the levels of proteins and signaling pathways associated with PAH in rat lung tissue compared with placebo.
Finally, the recruitment of immune cells called macrophages to the lungs is highly implicated in the development of PAH. Macrophages treated with BI113823 significantly reduced the production of two pro-inflammatory immune signaling proteins, TNF-alpha and interleukin-1-beta, following induced inflammation.
“We conclude that BI113823 reverses the progression of vascular remodeling, lessens pulmonary arterial hypertension, and prevents right heart failure and death,” the scientists wrote. “The protective effects afforded by BI113823 are mediated through inhibition [of] macrophage infiltration, and subsequently [reduction] of pro-inflammatory mediators.
“This regimen offers a unique novel approach for anti-inflammatory and remodeling therapy in progressed pulmonary hypertension,” they added.
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