Sitaxsentan sodium (TBC11251 sodium salt) is a highly selective antagonist of endothelin A receptors.

ETA:1.4 nM

Sitaxsentan（低氧发作前10分钟注射5 mg/kg）完全阻断低氧诱导的血管收缩,并且该组与空气对照没有差异.Sitaxsentan的口服给药显著减弱MPAP的增加,而对暴露于正常氧气水平的大鼠施用Sitaxsentan不会影响MPAP.单独使用Sitaxsentan可以限制分流引起的MT增加.

Sitaxsentan和Bosentan在较高浓度下减弱NTCP转运,并抑制人肝转运蛋白,这为在临床环境中观察到的这些药物增加肝毒性提供了潜在的机制。Sitaxsentan及Sitaxsentan联合西地那非可以完全阻止内皮素-1和ETB受体的表达增加。单独使用Sitaxsentan部分恢复了BMPR-1A和BMPR-2的表达。西地那非和Sitaxsentan联用进一步恢复了BMPR-1A和BMPR-2的表达,然而,与对照相比仍然是降低的水平。

Ligand binding studies: Binding studies are performed in a 30 mM HEPES buffer, pH 7.4, containing 150 mM NaCl, 5 mM MgCl2, and 0.05% bacitracin using 2 mg/tube (ETA) or 0.75 mg/tube (ETB) membrane. Sitaxentan sodium is dissolved in DMSO and diluted with the assay buffer to give a final concentration of 0.25% DMSO. Competitive inhibition experiments are performed in triplicate in a final volume of 200 μL containing 4 pM [125I]ET-1 (1.6 nCi). Nonspecific binding is determined in the presence of 100 nM ET-1. Samples are incubated for 16 hours?18 hours at 24 °C. One milliliter of PBS is then added and the assay centrifuged at 2000 g for 25 minutes at 4 °C. The supernatant is decanted and the membrane bound radioactivity counted on a Genesys gamma counter.

TE 671 or transfected COS 7 cells are grown to confluence in six-well plates. Sixteen hours prior to use, the media in each well is replaced with 2 mL of inositol-free RPMI-164 (IF-RPMI) media containing 10% inositol-free FCS and 2 mCi [3H]myoinositol and incubated at 37 °C in the presence of 6% CO2. The media is aspirated, and the cells are washed twice with PBS. Cells are preincubated for 10 minutes in 1 mL of lithium buffer (15 μM HEPES, pH 7.4, 145 μM NaCl, 5.4 μM KCl, 1.8 μM CaCl2, 0.8 μM MgSO4, 1.0 μM NaH2PO4, 11.2 μM glucose, 20 μM LiCl) with or without Sitaxentan sodium prior to the addition of 100 μM of ET-1 at different concentrations. Cells are then incubated for an additional 45 minutes. The buffer is discarded, and the accumulated inositol phosphates are extracted with ice cold methanol. The total cell protein in each well is measured using the BCA assay after solubilizing the cells in 0.1 M NaOH.(Only for Reference)

Sitaxsentan is formulated in water.After an initial 2-week period of hypoxic exposure (10% O2) sitaxsentan (15 or 30 mg/kg body weight per day in the drinking water) is administered for 4 weeks during continuous exposure to hypoxia. At the conclusion of the 4 week period of hypoxia, femoral and pulmonary arterial cannulation and measurement of MPAP, MSAP, and HR are performed.