Prevention and reversal of endotoxin-induced pulmonary hypertension by a leukotriene antagonist

We investigated the role of leukotrienes in endotoxin-induced changes in pulmonary circulation. In six conscious sheep, haemodynamic measurements were obtained for the calculation of pulmonary vascular resistance (PVR), along with measurements of arterial oxygen tension (PaO₂), leucocyte count (WBC), thromboxane B₂ (TxB₂), 6-Keto-PgF(1α) and PgF(2α), before and at predetermined intervals after a 10-min infusion of E. coli endotoxin (0.3 μg/kg), with an without treatment with the leukotriene receptor antagonist, FPL-57231. Endotoxin caused a biphasic response (i.e., phase I = 0-1 h, phase II = 1.5-4 h), with a mean ± SE increase in PVR to 415 ± 112% of baseline during phase I and a lesser increase of 175% (range = 153-199%) of baseline during phase II. Mean ± SE PaO₂ decreased from 86 ± 4 to 67 ± 6 mmHg and WBC count decreased from 8.6 ± 0.6 to 2.8 ± 0.7 thousand/mm³ during phase I, whereas TxB₂ increased from 145 ± 28 to 3164 ± 1082 pg/ml, 6-Keto-PgF(1α) from 129 ± 14 to 438 ± 114 pg/ml and PgF(2α) from 122 ± 7 to 242 ± 43 pg/ml. One hour infusion of FPL-57231 (1 mg/kg/min) administered prior to and throughout phase I attenuated the phase I increases in PVR without preventing the increases in TxB₂; however, it partly attenuated 6-Keto-PgF(1α) and enhanced generation of PgF(2α) during phase I. Discontinuation of FPL-57231 was followed by exaggerated response of PVR during phase II to an average of 209% of baseline (range = 186-235%). Four hours post-endotoxin, 10 min infusion of FPL-57231 (1 mg/kg/min) effectively reversed the increased PVR to basal levels. FPL-57231 had no effect on endotoxin-induced decreases in WBC count. We conclude that endotoxin-induced pulmonary hypertension is effectively prevented and reversed by a leukotriene antagonist.