Allen M J, Coleman R A
Department of Pharmacology 1, Glaxo Research & Development Ltd., Ware, Herts, UK.
Eur J Pharmacol. 1995 Feb 14;274(1-3):7-15. doi: 10.1016/0014-2999(94)00689-5.
The permeability of bovine pulmonary artery endothelial (CPAE) monolayers to Evans blue-labelled albumin (Evans blue-albumin) has been measured in vitro. Thrombin caused a concentration-dependent increase in Evans blue-albumin clearance across endothelial monolayers. Isoprenaline inhibited thrombin-induced Evans blue-albumin clearance in a concentration-dependent manner (EC50 21 nM). This effect was mimicked by the selective beta 2-adrenoceptor agonists salbutamol (EC50 64 nM) and salmeterol (EC50 2.7 nM), but not by the selective beta 1-adrenoceptor agonist, RO-363 ((1-[3',4'-dihydroxyphenoxy]-2-hydroxy-[3",4"- dimethoxyphenethylamino]-propane)oxalate), nor by the selective beta 3-adrenoceptor agonist, CL-316,243 (disodium (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1,3- benzodioxole-2,2-dicarboxylate). Isoprenaline, salbutamol and salmeterol, but not RO-363 or CL-316,243 produced small, but significant reductions in Evans blue-albumin clearance across unstimulated endothelial monolayers. Inhibition of the response to thrombin by isoprenaline was antagonised by the selective beta 2-adrenoceptor antagonist, ICI-118,551 ((erythro-DL-1(7-methylindan-4- yloxy)3-isopropylaminobutan-2-ol), pKB 8.4). Salmeterol also inhibited hydrogen peroxide-stimulated Evans blue-albumin clearance. Hence, the widely used beta 2-adrenoceptor agonists, salbutamol and salmeterol, are able to reduce endothelial permeability at nanomolar concentrations.
已在体外测量了牛肺动脉内皮（CPAE）单层对伊文思蓝标记白蛋白（伊文思蓝 - 白蛋白）的通透性。凝血酶导致伊文思蓝 - 白蛋白跨内皮单层的清除率呈浓度依赖性增加。异丙肾上腺素以浓度依赖性方式抑制凝血酶诱导的伊文思蓝 - 白蛋白清除（半数有效浓度[EC50]为21 nM）。选择性β2 - 肾上腺素能受体激动剂沙丁胺醇（EC50为64 nM）和沙美特罗（EC50为2.7 nM）可模拟此效应，但选择性β1 - 肾上腺素能受体激动剂RO - 363（(1 - [3',4'-二羟基苯氧基]-2 - 羟基-[3",4"-二甲氧基苯乙氨基]-丙烷)草酸盐）和选择性β3 - 肾上腺素能受体激动剂CL - 316,243（(R,R)-5 - [2 - [[2-(3 - 氯苯基)-2 - 羟乙基]-氨基]丙基]-1,3 - 苯并二恶唑-2,2 - 二羧酸钠）则不能。异丙肾上腺素、沙丁胺醇和沙美特罗，但不是RO - 363或CL - 316,243，使未受刺激的内皮单层的伊文思蓝 - 白蛋白清除率产生小幅但显著的降低。选择性β2 - 肾上腺素能受体拮抗剂ICI - 118,551（(赤藓糖-DL - 1(7 - 甲基茚满-4 - 基氧基)3 - 异丙氨基丁醇），平衡解离常数[ pKB]为8.4）可拮抗异丙肾上腺素对凝血酶反应的抑制作用。沙美特罗也抑制过氧化氢刺激的伊文思蓝 - 白蛋白清除。因此，广泛使用的β2 - 肾上腺素能受体激动剂沙丁胺醇和沙美特罗在纳摩尔浓度下就能降低内皮通透性。
