Hemsén A, Modin A, Wanecek M, Malmström R E, Weitzberg E
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Eur J Pharmacol. 1996 Dec 30;318(2-3):369-76. doi: 10.1016/s0014-2999(96)00807-2.
The effects of the mixed endothelin ET(A)/endothelin ET(B) receptor antagonist Ro 47-0203 (bosentan, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-( 2-methoxy -phenoxy)-2,2'-bipyrimidin-4-yl] -benzenesulfonamide) and the selective endothelin ET(A) receptor antagonist PD155080 (sodium 2-benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-me thoxy-phenyl)-4-oxobut+ ++-2-enoate) on plasma half-life and regional extraction of exogenous endothelin-1 as well as on the regional vascular effects of endothelin-1 were investigated in the pig in vivo. Bosentan but not PD155080 (5 mg/kg, i.v. bolus, both drugs) increased the arterial plasma levels of endothelin-1-like immunoreactivity. Neither of the drugs affected the plasma half-life of infused endothelin-1. In the spleen, both the extraction and vascular effects of exogenous endothelin-1 were attenuated by both bosentan and PD155080 whereas renal extraction and vascular effects in the kidney were unaffected by both drugs. In the lung, only bosentan decreased pulmonary extraction of endothelin-1. In conclusion, the bosentan-induced increase of circulating endothelin-1 seems to be related to blockade of endothelin-1 binding to endothelin ET(B) receptors. Blockade of these receptors does not influence the overall elimination of endothelin-1, however.
在猪体内研究了混合内皮素ET(A)/内皮素ET(B)受体拮抗剂Ro 47-0203（波生坦，4-叔丁基-N-[6-(2-羟基-乙氧基)-5-(2-甲氧基-苯氧基)-2,2'-联嘧啶-4-基]-苯磺酰胺）和选择性内皮素ET(A)受体拮抗剂PD155080（2-苯并[1,3]二氧杂环戊烯-5-基-3-苄基-4-(4-甲氧基-苯基)-4-氧代丁酸酯钠）对外源性内皮素-1血浆半衰期和局部摄取以及内皮素-1局部血管效应的影响。波生坦（而非PD155080，5mg/kg，静脉推注，两种药物）可提高动脉血浆中内皮素-1样免疫反应性水平。两种药物均不影响输注的内皮素-1的血浆半衰期。在脾脏中，外源性内皮素-1的摄取和血管效应均被波生坦和PD155080减弱，而两种药物均不影响肾脏的肾摄取和血管效应。在肺中，只有波生坦可降低内皮素-1的肺摄取。总之，波生坦诱导的循环内皮素-1增加似乎与内皮素-1与内皮素ET(B)受体结合的阻断有关。然而，阻断这些受体并不影响内皮素-1的总体清除。
