Key result
The combination of an ETA receptor antagonist (BQ123) with iloprost provided greater inhibition of human pulmonary artery smooth muscle cell proliferation than either agent alone.
Why the study?
The mechanisms underlying the positive or negative effects of combination therapy with PGI2 analogues and ET-1 receptor antagonists in PH Group-III were not well documented.
Does the combination of a PGI2 analogue and an ERA improve inhibition of hPASMCs proliferation compared to either agent alone in preparations from PH Group-III patients?
Does the combination of a PGI2 analogue and an ERA improve inhibition of hPASMCs proliferation compared to either agent alone in preparations from PH Group-III patients?
Combining a PGI2 analogue with a selective ETA receptor antagonist provides greater inhibition of pulmonary artery smooth muscle cell proliferation in Group-III pulmonary hypertension models.
May support dual ERA-PGI2 testing in Group-III PH models; leaves open clinical translation.
Pulmonary hypertension (PH) is characterized by an elevation of mean pulmonary artery pressure and it is classified into five groups. Among these groups, PH Group-III is defined as PH due to lung disease or hypoxia. Prostacyclin (PGI 2 ) analogues (iloprost, treprostinil) and endothelin-1 (ET-1) receptor antagonists (ERA) (used alone or in combination) are therapies used for treating PH. The mechanisms underlying the positive/negative effects of combination treatment are not well documented, and in this study, we tested the hypothesis that the combination of a PGI 2 analogue (iloprost, treprostinil) and an ERA may be more effective than either drug alone to treat vasculopathies observed in PH Group-III patients. Using Western blotting, ET A and ET B receptor expression were determined in human pulmonary artery (HPA) preparations derived from control and PH Group-III patients, and the physiologic impact of altered expression ratios was assessed by measuring ET-1 induced contraction of ex vivo HPA and human pulmonary veins (HPV) in an isolated organ bath system. In addition, the effects of single agent or combination treatments with a PGI 2 analogue and an ERA on ET-1 release and HPA smooth muscle cells (hPASMCs) proliferation were determined by ELISA and MTT techniques, respectively. Our results indicate that the increased ET A /ET B receptor expression ratio in HPA derived from PH Group-III patients is primarily governed by a greatly depressed ET B receptor expression. However, contractions induced by ET-1 are not impacted in HPA and HPV derived from PH Group-III patients as compared to controls. Also, we found that the combination of an ET A receptor antagonist (BQ123) with iloprost provides greater inhibition of hPASMCs proliferation (-48±14% control; -32±06% PH) than either agent alone. Of note, while the ET B receptor antagonist (BQ788) increases ET-1 production from PH Group-III patients’ preparations (HPA, parenchyma), even under these more proliferative conditions, iloprost and treprostinil are still effective to inhibit hPASMCs proliferation (-22/-24%). Our findings may provide new insights for the treatment of PH Group-III by combining a PGI 2 analogue and a selective ET A receptor antagonist.
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Özen et al. (2019) studied Pulmonary hypertension Group-III. Combination of a PGI2 analogue and an ERA vs. Single agent or control was evaluated on hPASMCs proliferation. The combination of an ETA receptor antagonist (BQ123) with iloprost provided greater inhibition of human pulmonary artery smooth muscle cell proliferation than either agent alone.
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