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.
|Original language||English (US)|
|Number of pages||8|
|Journal||European Respiratory Journal|
|State||Published - Jan 1 1988|
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine