Methylprednisolone on circulating eicosanoids and vasomotor tone after endotoxin.
Acute pulmonary and systemic vasomotor changes induced by endotoxin in dogs have been related, at least in part, to the production of eicosanoids such as the vasoconstrictor thromboxane and the vasodilator prostacyclin. Steroids in high doses, in vitro, inhibit activation of phospholipase A2 and prevent fatty acid release from cell membranes to enter the arachidonic acid cascade. We, therefore, administered methylprednisolone (40 mg/kg) to dogs to see if eicosanoid production and the ensuing vasomotor changes could be prevented after administration of 150 micrograms/kg of endotoxin. The stable metabolites of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured by radioimmunoassay. Methylprednisolone by itself did not alter circulating eicosanoids but when given 2.5 h before endotoxin not only failed to inhibit endotoxin-induced eicosanoid production but actually resulted in higher circulating levels of 6-keto-PGF1 alpha (P less than 0.05) compared with animals receiving endotoxin alone. Indomethacin prevented the steroid-enhanced concentrations of 6-keto-PGF1 alpha after endotoxin and prevented the greater fall (P less than 0.05) in systemic blood pressure and systemic vascular resistance with steroid plus endotoxin than occurred with endotoxin alone. Administration of methylprednisolone immediately before endotoxin resulted in enhanced levels (P less than 0.05) of both TxB2 and 6-keto-PGF1 alpha but with a fall in systemic blood pressure and vascular resistance similar to the animals pretreated by 2.5 h. In contrast to the early steroid group in which all of the hypotensive effect was due to eicosanoids, in the latter group steroids had an additional nonspecific effect. Thus, in vivo, high-dose steroids did not prevent endotoxin-induced increases in eicosanoids but actually increased circulating levels of TxB2 and 6-keto-PGF1 alpha with a physiological effect favoring vasodilation.
D000818:Animals; D004285:Dogs; D004537:Eicosanoic Acids / Q000097:blood*; D004731:Endotoxins / Q000494:pharmacology*; D004926:Escherichia coli; D006439:Hemodynamics / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D008775:Methylprednisolone / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects; D014666:Vasomotor System / Q000187:drug effects*
D004537:Eicosanoic Acids; D004731:Endotoxins; D008775:Methylprednisolone; D007213:Indomethacin