Improvement of respiratory function by bosentan during endotoxic shock in the pig

We evaluated the role of endothelin-1 (ET-1) and the involvement of nitric oxide in cardiovascular and respiratory dysfunction, during endotoxic shock , in 18 anaesthetised, mechanically ventilated pigs, divided into three gro ups. Group 1 was i.v. infused with LPS (20 mug/Kg/h for 240 min). Group 2 w as pre-treated with bosentan, a dual inhibitor of ET-1 receptors, and at 18 0 min of endotoxic shock, L-NAME (N-G-nitro-L-argininemethyl ester, 10 mg/K g), a non-selective inhibitor of NO synthases, was i.v. administered. Group 3 was infused with LPS and L-NAME was administered similarly to group 2. R esults show that LPS caused systemic hypotension, pulmonary biphasic hypert ension, decrease in compliance (C-rs) and increase in resistance (R-max,R-r s) Of respiratory system. Bosentan completely abolished the pulmonary hyper tension and the changes in C-rs and R-max,R-re. L-NAME does not affect the LPS-dependent changes in respiratory mechanics, but it worsens the cardiova scular effects, causing death of pigs. Pre-treatment with bosentan prevents this deleterious effect. Our study demonstrates that the LPS-dependent respiratory effects are media ted by ET-1, which, probably causing pulmonary oedema, is responsible for t he decrease in C-rs and the increase of R-max,R-rs. (C) 2001 Harcourt Publi shers Ltd.