Researchers at the Nagoya University Graduate School of Medicine in Japan demonstrated that the endothelin receptor antagonist bosentan can improve endothelial dysfunction parameters in patients with pulmonary arterial hypertension (PAH), but not in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH).
The findings were published in the Pulmonary Circulation journal in the study titled “Effects of bosentan on peripheral endothelial function in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension.”
Endothelial cells, the cells that line the blood vessels, can produce active substances that modulate the vessel’s dilation state. Therefore, endothelial cell injury and dysfunction, which results in an imbalanced production of vasodilators and vascoconstrictors, is central to the development of the abnormalities seen in pulmonary hypertension (PH). A reduction in prostacyclin (PGI2) and nitric oxide (NO) levels, and a upregulation of endothelin 1 (ET-1), are often observed in patients with PH.
Circulating and pulmonary levels of ET-1 are strongly correlated with disease severity and prognosis in PAH, as it contributes to smooth muscle vasoconstriction, fibrosis, and inflammation, leading to pulmonary arteriolar constriction and right ventricular hypertrophy. This has led to the development of endothelin receptor antagonists (ERAs), such as bosentan, which have been shown to improve PAH symptoms and patients’ prognosis.
The standard of care for patients with CTEPH is pulmonary endarterectomy, an operation meant to remove blood clots from the pulmonary arteries in the lungs. However, not all patients with CTEPH are eligible for this treatment approach, and pharmacological treatments are needed. Although bosentan has been shown to benefit patients with CTEPH, its efficacy in inoperable CTEPH patients has not been studied.
Now, researchers led by Takahisa Kondo examined the effects of the ERA bosentan on endothelium-dependent vasodilation in lung arteries of 18 patients with PAH and eight patients with CTEPH. Vasodilation was measured before and after three months of bosentan treatment.
Although bosentan revealed beneficial effects in PAH patients, improving endothelial dysfunction and increasing vasodilation, patients with inoperable CTEPH showed no alterations following bosentan treatment. However, the parameter measuring vasodilation — flow-mediated vasodilation (FMD) — did not seem to correlate with the severity of the disease.
“Taken together, these data show that bosentan improves peripheral endothelial function in patients with PAH but not in those with CTEPH,” the authors concluded in their study. “FMD is useful for assessing the effects of therapeutics on peripheral endothelial function in patients with PAH. Additional investigations are needed to confirm our results.”