Effect of endothelin antagonists, including the novel ETA receptor antagonist LBL 031, on endothelin-1 and lipopolysaccharide-induced microvascular leakage in rat airways

1 The effect of the novel ETA receptor antagonist LBL 031 and other selecti ve and mixed endothelin receptor antagonists on endothelin-l (ET-l)-induced and lipopolysaccharide (LPS)-induced microvascular leakage was assessed in rat airways. 2 Intravenously administered ET-1 (1 nmole kg(-1)) or LPS (30 mg kg(-1)) ca used a significant increase in microvascular leakage in rat airways when co mpared to vehicle treated animals. 3 Pre-treatment with the selective ETA receptor antagonists, LBL 031 or PD 156707, or the mixed ETA/B receptor antagonist, bosentan (each at 30 mg kg- l), reduced ET-l-induced leakage to baseline levels. ET-l-induced leakage w as not reduced by pre-treatment with the ETB selective antagonist BQ 788 (3 mg kg(-1)). 4 pre-treatment with the selective ETA receptor antagonist, LBL 031 (0.1 mg kg(-1)) or PD 156707 (10 mg kg(-1)), or the mixed ETA/B receptor antagonis t, bosentan (30 mg kg(-1)), reduced LPS-induced leakage by 54, 48 and 59% r espectively. LPS-induced leakage was not affected by pre-treatment with the ETU selective antagonist BQ 788 (3 mg kg(-1)). 5 The data suggests that ET-1-induced microvascular leakage in the rat airw ay is ETA receptor mediated and that part of the increase induced by LPS ma y be due to the actions of ET-L. Therefore, a potent ETA receptor selective antagonist, such as LBL 031, may provide a suitable treatment for inflamma tory diseases of the airways, especially those involving LPS and having an exudative phase, such as the septic shock-induced adult respiratory distres s syndrome.