Elevated Thromboxane Levels in the Rat during Endotoxic Shock

Abstract

A B S T R A C T The potential deleterious role of the proaggregatory vasoconstrictor, thromboxane A2, in endotoxic shock was investigated in rats. Plasma thromboxane A2 was determined by radioimmunoassay of its stable metabolite thromboxane B2. After intravenous administration of Salmonella enteritidis endotoxin (20 mg/kg), plasma thromboxane B2 levels increased from nondetectable levels (<375 pg/ml) in normal control rats to 2,054±524 pg/ml (n = 8), within 30 min to 2,071+429 at 60 min, and decreased to 1,119+319 pg/ml, at 120 min. Plasma levels of prostaglandin E also increased from 146±33 pg/ml in normal controls (n = 5) to 2,161+606 pg/ml 30 min after endotoxin (n = 5).In contrast to shocked controls, rats pretreated with imidazole, a thromboxane synthetase inhibitor, or essential fatty acid-deficient rats, which are deficient in arachidonate and its metabolites, did not exhibit significant elevations in plasma levels of thromboxane B2. Imidazole did not however inhibit endotoxininduced elevations in plasma prostaglandin E. Essential fatty acid deficiency significantly reduced mortality to lethal endotoxic shock. This refractoriness could be duplicated in normal rats pretreated with the fatty acid cyclo-oxygenase inhibitor, indomethacin (10 mg/kg), intravenously 30 min before endotoxin injection. Imidazole (30 mg/kg) administered intraperitoneally 1 h before or intravenously 30 min before endotoxin, also significantly (P < 0.01) reduced mortality from lethal endotoxin shock to 40% compared to a control mortality of 95% at 24 h. Likewise pretreatment with 13-azaprostanoic acid (30 mg/kg),

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

“…Prostaglandin F2<,X 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 ,g/kg of endotoxin induced Dr. Peterson is an Established Investigator ofthe American Heart Association.…”

“…Therefore, we have sought to clarify the relationship of prostanoids to pulmonary vascular tone by correlating tone changes after endotoxin infusion with endogenous production of two prostanoids, thromboxane and prostacyclin. High circulating levels of thromboxane occur in the rat after endotoxin in doses that cause shock (15). Thromboxane A2 is probably a potent pulmonary and systemic vasoconstrictor but cannot be produced in sufficient quantities to test this thesis directly (16,17).…”

“…The stable metabolites of thromboxane and prostacyclin, i.e., thromboxane B2 and 6-keto-prostaglandin F1,a were measured in plasma with radioimmunoassay. 15 ,ug/kg i.v. ofendotoxin 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.…”

Formation and metabolism of leukotriene C4 in macrophages exposed to bacterial lipopolysaccharide

“…Thus, strong evidence has been provided that prostaglandins are involved in lipopolysaccharideinduced phenomena like fever, diarrhea, abortion, accelerated ovum transport, the generalized Shwartzman reaction, pulmonary hypertension and systemic hypotension and others [8]. However, the participation of other arachidonic acid metabolites in endotoxic events was suggested by the fact that drugs which are known to block the cyclooxygenase pathway were not able to inhibit lipopolysaccharide-induced lethality in normal mice or rats [30]. Furthermore, mice and rats which had been fed with diets largely free of essential fatty acids were found to be less sensitive to endotoxin-induced lethality as compared to mice and rats fed with a normal diet.…”

“…Therefore, the amount of released Table 2. Dependence of lipopolysaccharide-induced LTC, production of mouse peritoneal macrophages on cell preparation and incubation conditions After isolation from the peritoneum, MPM were either treated for 30 min in the cold (A-C) or placed directly on petri dishes (D-1). In some experiments a resting period of 24 h in Iscove's medium (37"C, 8% C 0 2 ) was introduced before lipopolysaccharide treatment of MPM (C, E-G, I).…”