Abstract: AIM: To study the effects of a novel endothelin receptor antagonist GF-063 on the proliferative behavior of cultured rat pulmonary arterial smooth muscle cells (PASMCs) by hypoxia stimulation. METHODS: Primary culture of rat PASMCs was prepared by tissue block anchorage. PASMCs were divided into four groups: normoxia (210 ml/L O2), hypoxia (20 ml/L O2), hypoxia+BQ-485 (1×10-6, 1×10-7, 1×10-8, 1×10-9 mol/L), and hypoxia+GF-063 (1×10-6, 1×10-7, 1×10-8, 1×10-9 mol/L). Proliferation of PASMCs was determined by MTT (492 nm) assay and the cell cycle was measured by flow cytometry. Endothelin level in the supernatant was detected by radioimmunoassay. RESULTS: At 24 h, the A value exerted no significant effect on each group. At 48 h, the A value increased significantly in hypoxia group, but decreased significantly in both hypoxia+BQ-485 group and hypoxia+GF-063 (1×10-6, 1×10-7, 1×10-8 mol/L) group, compared with hypoxia group (P<0.01, respectively). At 72 h, the A value in the hypoxia group increased, but less than at 48 h (P<0.05). The percentage of cell and DNA synthesis of hypoxia increased significantly at G2 and S periods (P<0.01, P<0.05). Compared with that in hypoxia group, the percentage of cell in hypoxia+BQ-485 group and hypoxia+GF-063 group decreased at G2 and S periods (P<0.05), and the percentage of cell increased at G1 periods (P<0.05). The ET-1 level of supernatant in hypoxia group increased (P<0.01). The ET-1 level of supernatant in hypoxia group and BQ-485- (10-7 mol/L) treated groups and GF-063- (10-9 mol/L) treated groups decreased, respectively (P<0.01). CONCLUSION: GF-063 is a novel endothelin receptor antagonist that inhibits proliferation of PASMCs induced by hypoxia. GF-063, more than BQ-485, decreases the supernatant of ET-1 level. GF-063 is a promising drug in the treatment of pulmonary artery hypertension.