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

The effect of the novel ETA receptor antagonist LBL 031 and other selective and mixed endothelin receptor antagonists on endothelin-1 (ET-1)-induced and lipopolysaccharide (LPS)-induced microvascular leakage was assessed in rat airways Intravenously administered ET-1 (1 nmole kg−1) or LPS (30 mg kg−1) caused a significant increase in microvascular leakage in rat airways when compared to vehicle treated animals. 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−1), reduced ET-1-induced leakage to baseline levels. ET-1-induced leakage was not reduced by pre-treatment with the ETB selective antagonist BQ 788 (3 mg kg−1). 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 antagonist, bosentan (30 mg kg−1), reduced LPS-induced leakage by 54, 48 and 59% respectively. LPS-induced leakage was not affected by pre-treatment with the ETB selective antagonist BQ 788 (3 mg kg−1). The data suggests that ET-1-induced microvascular leakage in the rat airway is ETA receptor mediated and that part of the increase induced by LPS may be due to the actions of ET-1. Therefore, a potent ETA receptor selective antagonist, such as LBL 031, may provide a suitable treatment for inflammatory diseases of the airways, especially those involving LPS and having an exudative phase, such as the septic shock-induced adult respiratory distress syndrome. British Journal of Pharmacology (2000) 131, 1129–1134; doi:10.1038/sj.bjp.0703691