Effects of endothelin-1 (ET-1) and thrombin antagonism on cardiovascular and respiratory dysfunctions during endotoxic shock in pig

We evaluated the endothelin-1 (ET-1) and thrombin involvement in cardiovascular and respiratory dysfunction during endotoxic shock in 18 anaesthetized, mechanically ventilated pigs, divided into three groups. Group 1 was pre-treated only with lipopolysaccharide (LPS), group 2 was treated with lepirudin, a thrombin inhibitor, group 3 was pre-treated with bosentan, a dual inhibitor of ET-1 receptors. Results show that LPS caused systemic hypotension, pulmonary biphasic hypertension, increase in lung resistances (R(L)) and decrease in compliance (C(L)). Lepirudin partially reduced the LPS-dependent pulmonary hypertension, without affecting the changes in C(L) and R(L). On the contrary, bosentan completely abolished the pulmonary hypertension and the changes inC(L) and R(L), and worsened the LPS-dependent systemic hypotension. Our results show that ET-1 is largely responsible for pulmonary derangement due to endotoxic shock; at bronchial level, the ET-1 release seems due only to LPS, while, at pulmonary vascular level, it results also from LPS-dependent thrombin activation.