[Experimental study on the pathophysiology of endotoxin shock as analysed by alterations in thromboxane B2 and...

To evaluate the pathophysiological role of thromboxane A2 (TXA2) in endotoxin shock, plasma concentrations of TXA2 and PGI2 following E. coli endotoxin (ET) administration were measured in dogs and rats by radioimmunoassay of their stable metabolites TXB2 and 6-keto-PGF1 alpha, respectively. Also, the effects of TXA2 synthetase inhibitor (OKY046) on eicosanoid levels, haemodynamics and survival were assessed. The following results were obtained: 1) Survival rates of the rats given 50 mg/kg of ET were 31% at 12 hrs and 17% at 24 hrs. Pretreatment with OKY046 markedly improved the survival rates. 2) Plasma concentrations of TXB2 were rapidly elevated in untreated control dogs and rats following ET administration, whereas plasma 6-keto-PGF1 alpha levels were gradually elevated. TXB2/6-keto-PGF1 alpha ratio showed an early elevation at 15 minutes after ET administration. The ratio became lower than base line, thereafter. 3) In contrast to the controls, animals pretreated with OKY046 did not exhibit significant elevations in plasma TXB2 levels. On the other hand, plasma levels of 6-keto-PGF1 alpha were not altered by OKY046 treatment. 4) In the control dogs given ET, the early elevations in pulmonary artery pressure (PAP) and reduction in lung compliance correlated with the early elevation in plasma TXB2/6-keto-PGF1 alpha ratio. 5) In OKY046-treated dogs, the early elevation in TXB2/6-keto-PGF1 alpha ratio was not seen and PAP increase and lung compliance reduction were prevented. The results suggest that TXA2 plays an important pathophysiological role in the development of endotoxin shock.