In a paper recently published in the PLOS ONE journal entitled “Inhibition of Excessive Cell Proliferation by Calcilytics in Idiopathic Pulmonary Arterial Hypertension,” researchers from Kinjo Gakuin University in Japan demonstrated that excessive proliferation of pulmonary arterial smooth muscle cells (PASMC) in patients with pulmonary arterial hypertension (PAH) could be regulated by means of drug-based calcilytics.
Pulmonary hypertension is a rare and progressive disease identified by high blood pressure in the pulmonary artery. The five-year survival rate of PAH after diagnosis is about 57%, with adult females three times more likely to have PAH than adult males. Patients with PAH may suffer from various symptoms like shortness of breath, fainting, dizziness, leg swelling, fatigue, and rarely coughing up blood. Over time, the disease progresses and may lead to severe complications including right-sided heart failure, arrhythmia, bleeding and blood clots. PAH can be managed in part by healthy lifestyle, medications and surgery if treatments fail.
A number of factors have been identified as causing PAH, which includes genetic predisposition, low oxygen conditions, some drugs like the appetite suppressant “fen-phen,” and other medical problems like sleep disorders, heart abnormalities, chronic liver disease, and pulmonary fibrosis. Whatever the cause, PAH involves the narrowing of blood vessels connected to and within the lungs primarily due to an over proliferation of PASMCs. With respect to this, it has been reported that excessive proliferation of cells is associated with increased calcium signaling in PASMCs and that the response of calcium sensing receptor (CaSR) increased in the PASMCs of PAH patients.
In order to understand why cell proliferation occurs in patients with PAH, researchers from Kinjo Gakuin University in Japan performed a series of experimental essays by blocking CaSR. This allowed them to investigate whether the excessive proliferation of PASMCs in PAH patients reduce when CaSR are blocked. The results suggested that the proliferation rate of PASMCs in PAH patients is about 1.5 fold higher than those recorded in normal subjects or patients with chronic thromboembolic pulmonary hypertension. Furthermore, treatment of patients with PAH using two drugs based on an antagonist of CaSR calcilytic (NPS2143 and Calhex 231) resulted in suppression of the proliferation process of PASMCs. Suppression/inhibition of the outgrowth proliferation is observed to correlate well with concentration of the administrated drug. By contrast, administration of an activator of CaSR named R568 significantly increased proliferation of PASMCs in PAH patients.
In summary, these findings suggest that excessive proliferation of PASMCs in PAH patients is regulated by CaSR. The data also reveal that drugs based calcilytics are useful in suppression of PASMC proliferation, and should be considered as a potential novel therapeutic approach for PAH.