Journal of Applied Physiology, Vol 61, Issue 1 185-191, Copyright © 1986 by American Physiological Society
Methylprednisolone on circulating eicosanoids and vasomotor tone after endotoxin
C. A. Hales, R. D. Brandstetter, C. F. Neely, M. B. Peterson, D. Kong and W. D. Watkins
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.
