Impact of endothelin-1 in endotoxin-induced pulmonary vascular reactions

Objectives: Elevated endothelin-1 (ET-1) levels have been detected during s epsis. The aim of the study was to examine the role of thromboxane A(2) (TX A(2)) and ET-1 in pulmonary vascular reactions after endotoxin (LPS) challe nge. Design: Prospective experimental study in rabbits. Setting: Experimental laboratory in a university teaching hospital, Subjects: Twenty-four adult rabbits of either sex. Interventions: Experiments were performed on 30 isolated and ventilated rab bit lungs, which were perfused with a saline solution containing 10% autolo gous blood. Measurements and Main Results: Pulmonary arterial pressure and lung weight gain were continuously registered. Perfusate samples were drawn intermitten tly to determine ET-1, TXA(2), and prostacyclin (PGI(2)) concentrations. LP S isolated from Escherichia coli (0.5 mg/mL; n = 6) was added to the perfus ate. A marked pulmonary arterial pressure increase followed by massive edem a formation after 60 mins was observed after LPS injection. At the same tim e, elevated TXA(2) and PGI(2) levels in the perfusate were measured. ET-1 w as detected 30 mins after LPS infusion (13.4 +/- 2.6 fmol/L). Pretreatment with the ETA receptor antagonist LU135252 (10(-6) M; n = 6) almost complete ly suppressed the pressure reaction after endotoxin injection (p < .01 at 5 0 and 60 mins) and reduced edema formation (p < .05). The cyclooxygenase in hibitor diclofenac (10 mu g/mL; n = 6) was as effective as LU135252 in prev enting vascular reactions after LPS injection. Conclusions: Pretreatment with the ET, receptor antagonist LU135252 and the cyclooxygenase inhibitor diclofenac reduced pulmonary vascular reactions a fter LPS challenge. Based on the current data, we conclude that the pulmona ry arterial pressure increase and edema formation after LPS injection are r elated to an ET-1- and TXA(2)-dependent mechanism. (Crit Care Med 2000; 28: 2851-2857).