Mixed endothelin ET(A) and ET(B) antagonist bosentan inhibits oleic acid-induced lung plasma extravasation in mouse.

The possible participation of endogenous endothelins (ETs) in enhancement of plasma extravasation induced by oleic acid was assessed in mice. Oleic acid (0.5-2%/kg, i.v.) increased accumulation of Evans blue in lungs in dose-dependent fashion, with a clearcut peak at 1 h (lung Evans blue content: control 0.17 +/- 0.01; oleic acid 1%/kg 0.63 +/- 0.04 microg per 10 mg wet tissue). Pretreatment with the mixed endothelin-ET(A) and ET(B) (ET(A)/ET(B)) receptor antagonist bosentan (30 mg/kg, i.v., 30 min before oleic acid) markedly reduced lung Evans blue content (to 0.24 +/- 0.04), as did pretreatments with prazosin (1 mg/kg), meloxicam (5 mg/kg) and dexamethasone (1 mg/kg/day, for 3 days). Thus, ETs play a pivotal role in the increase in lung microvascular permeability caused by oleic acid in the mouse. The ET receptors involved in the pulmonary vascular changes associated with this experimental model of adult respiratory distress syndrome (ARDS), as well as the relationship between ETs and the sympathetic system, eicosanoids and cytokines remain to be clarified.