Role of Thromboxane and Prostacyclin in Pulmonary Vasomotor Changes after Endotoxin in Dogs

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Abstract

Cyclooxygenase inhibitors prevent the pulmonary vasomotor changes in response to low-dose endotoxin. We, therefore, explored the role of two highly vasoactive prostanoids, thromboxane A2, a vasoconstrictor, and prostacyclin, a vasodilator, in the transient pulmonary vasoconstriction and subsequent loss of alveolar hypoxis vasoconstriction (AHPV) that follows endotoxin. AHPV was tested in the dog with a double-lumened endotracheal tube allowing ventilation of one lung with nitrogen as a hypoxic challenge while the other lung was ventilated with oxygen to maintain systemic oxygenation. Relative distribution of perfusion to the two lungs was assessed with intravenous 133Xe and external scintillation detectors. The stable metabolites of thromboxane and prostacyclin, i.e., thromboxane B2 and 6-keto-prostaglandin F1α were measured in plasma with radioimmunoassay. 15 μg/kg i.v. of endotoxin induced no rise in pulmonary vascular resistance (PVR), but prevented AHPV so that the initial 33% (±2 SEM) decrease in perfusion to the hypoxic lung became only a 2% (±1) decrease. Circulating levels of thromboxane and prostacyclin concurrently rose (P < 0.01) from nondetectable levels to 380 pg/ml (±40) and 360 pg/ml (±130). 150 μg/kg of endotoxin induced a transient rise in PVR from 4.09 to 9.00 mm Hg/liter per min in association (r = 0.89, P < 0.01) with a sharp rise in thromboxane levels to 4,460 pg/ml (±1,350) whereas prostacyclin levels were elevated less markedly to 550 pg/ml (±400). Prostaglandin F2α, another vasoconstrictor, was not elevated. 30 min after endotoxin when PVR was again base line and AHPV lost, thromboxane fell significantly (P < 0.01) to 2,200 pg/ml (±1,100) whereas prostacyclin remained elevated at 360 pg/ml (±135), a level similar to that seen when 15 μg/kg of endotoxin induced loss of AHPV. Indomethacin prevented the rise in thromboxane and prostacyclin after endotoxin as well as the changes in pulmonary vasomotor tone. Thus, a complex interaction between thromboxane and prostacyclin is involved in the pulmonary vasomotor response to low-dose endotoxin.

Authors

C. A. Hales, L. Sonne, M. Peterson, D. Kong, M. Miller, W. David Watkins