BETA(2)-ADRENOCEPTORS MEDIATE A REDUCTION IN ENDOTHELIAL PERMEABILITY IN-VITRO

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 (EC(50) 21 nM). This effect was mimicked by the selective beta(2)-adrenoceptor agonists salbutamol (EC(50) 64 nM) and salmeterol (EC(50) 2.7 nM), but not by the selective beta(1)-adrenoceptor agonist, RO-363 ((1-[3',4'-dihydroxyphenoxy]-2-hydroxy-[3'',4''-dimethoxyphenethylaminol-propane)oxalate), nor by the selective beta(3)-adrenoceptor agonist, CL-316,243 (disodium (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethl]- 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), pK(B) 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.