Effect of the Thromboxane A2-Receptor Antagonists, SQ 29,548 and SQ 28,668, on the Pulmonary Hypertensive Response to Endotoxemia in Swine

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Abstract
The effects of two selective thromboxane (Tx) A2 antagonists (SQ 29,548 and SQ 28,668) on endotoxin-induced pulmonary hypertension were determined in anesthetized pigs. SQ 29,548 (10 µg/kg/min, i.v., n = 6) or vehicle (n = 7) was infused from 15 min before until 60 min after an intravenous infusion of Salmonella enteritidis endotoxin (1.0 µg/kg). Within 20 min, vehicle-treated animals developed an acute 350 ± 25% increase in pulmonary vascular resistance (PVR) with a 43% survival rate. In the presence of SQ 29,548 this initial pulmonary vasoconstriction was absent and all animals survived. However, a delayed increase in PVR of 58 ± 20% was detected. The primary manifestation of the increase in PVR was an increase in pulmonary arterial pressure. In a similar preparation, septicemia was produced by Escherichia coli endotoxin (0.5 µg/kg, i.v.) and SQ 28,668 (3, 10, 30 or 100 µg/ kg/min, i.v., n = 5–6 per dose level) and vehicle (n = 6) treatments were compared. SQ 28,668 doses of 30 and 100 µg/kg/min mitigated the early, but not late, increases in PVR. These data demonstrate that endotoxemia in pigs produces an initial TxA2-receptor-dependent vasoconstriction and also a more slowly developing pulmonary hypertension which is probably due to other mediators.