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内皮素受体拮抗剂GF-063和BQ-485对低氧培养大鼠肺动脉平滑肌细胞增殖的影响

《心脏杂志》[ISSN:1009-7236/CN:61-1268/R]

期数:
2010年第1期
页码:
20-24
栏目:
基础研究
出版日期:
2010-01-04

文章信息/Info

Title:
Effects of a novel endothelin receptor antagonist GF-063 on proliferation of cultured rat pulmonary arterial smooth muscle cells
作者:
张燕1; 冯华松1; 高峰2; 梁远军2; 刘克良2
1.海军总医院呼吸内科，北京 100037；2.军事医学科学院毒物药物研究所，北京 100850
Author(s):
ZHANG Yan1;  FENG Hua-song1;  GAO Feng2;  LIANG Yuan-jun2;  LIU Ke-liang2
1.Department of Respiratory Disease, Navy General Hospital, Beijing 100037, China; 2.Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China
关键词:
内皮素受体拮抗剂; 低氧; 肺动脉平滑肌细胞; 增殖
Keywords:
endothelin receptor antagonist;  cell hypoxia;  pulmonary arterial smooth muscle cell;  proliferation
分类号:
R543.3
DOI:
-
文献标识码:
A
摘要:
目的: 探讨新型内皮素受体拮抗剂GF-063和BQ-485对低氧培养的大鼠肺动脉平滑肌细胞(PASMCs)增殖的影响。方法: 贴壁原代培养PASMCs。实验分为4组：常氧组（氧浓度210 ml/L）、低氧组（氧浓度20 ml/L）、低氧+内皮素A（ETA）受体拮抗剂BQ-485组(BQ-485的终浓度分别为1×10-6、1×10-7、1×10-8和1×10-9 mo1/L)和低氧+GF-063组(GF-063的终浓度分别为1×10-6、1×10-7、1×10-8和1×10-9 mo1/L)。上述4组细胞均分别培养24、48和72 h。采用MTT比色法(波长492 nm)检测BQ-485和GF-063对PASMCs增殖的影响（A值）。用流式细胞仪测定细胞周期；放射免疫检查法测定细胞培养上清液中内皮素-1(ET-1)的含量。结果: 培养24 h时，各实验组的A值差异不明显；培养48 h时，低氧组的A值明显增加(P<0.01)，低氧+BQ-485组和低氧+GF-063组在二者的终浓度为1×10-8、1×10-7、1×10-6 mo1/L时A值下降，与低氧组比较具有统计学意义(P<0.01)；在培养72 h时，低氧组的A值仍高于常氧组，但较培养48 h显著下降(P<0.05)。培养48 h时，低氧组G2、S期细胞的比率及DNA合成增加，与常氧组比较有统计学意义(分别为P<0.01，P<0.05)；与低氧组比较,低氧+BQ-485组和低氧+GF-063组G2、S期细胞的比率下降（P<0.05），G1期细胞增多（P<0.05），DNA合成减少。在培养48 h时，与常氧组比，低氧组ET-1的水平增高（P<0.01），给予BQ-485、GF-063后ET-1的水平降低，BQ-485为1×10-7 mol/L、GF-063为1×10-9 mol/L时，可明显降低ET-1的水平（P<0.01）。结论: GF-063和BQ-485作为两种新型的内皮素受体拮抗都剂能抑制低氧培养的PASMCs增殖，减少ET-1的生成，且GF-063的其作用较BQ-485强。
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.

参考文献/References

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备注/Memo

备注/Memo:
收稿日期：2009-1-16.基金项目：全军医药卫生科研课题基金项目资助(01MA049) 通讯作者：冯华松，主任医师， 主要从事心肺血管基础和临床研究Email:fenghs99@163.com 作者简介：张燕，主治医师，硕士Email:changyan511@sohu.com
更新日期/Last Update: 2010-01-05