Calcium ionophore (A-23187) induced peritoneal eicosanoid biosynthesis: a rapid method to evaluate inhibitors of arachidonic acid metabolism in vivo.
The present investigation characterizes calcium ionophore (A-23187) induced peritoneal eicosanoid biosynthesis in the rat. Intraperitoneal injection of A-23187 (20 mug/rat) stimulated marked biosynthesis of 6-keto-PGF(1alpha) (6-KPA), TxB(2), LTC(4) and LTB(4), with no detectable changes on levels of PGE(2). Levels of all eicosanoids decreased rapidly after a peak which was seen as early as 5 min. Enzyme markers of cellular contents of neutrophils and mononuclear cells, MPO and NAG respectively, decreased rapidly after ionophore injection; this was followed by increases after 60 min. Indomethacin, a selective cyclooxygenase inhibitor, and zileuton and ICI D-2138, two selective 5-lipoxygenase inhibitors attenuated prostaglandin and leukotriene pathways respectively. Oral administration of zileuton (20 mg/kg, p.o.) inhibited LTB(4) biosynthesis for up to 6 h suggesting a long duration of pharmacological activity in the rats consistent with its longer half-life. The rapid onset and the magnitude of increases in levels of eicosanoids render the ionophore induced peritoneal eicosanoid biosynthesis a useful model to evaluate pharmacological profiles of inhibitors of eicosanoid pathways in vivo.
Rao
T S
TS
Inflammatory Diseases Research Searle Research and Development c/o Monsanto Company St Louis MO 63198 USA.
Currie
J L
JL
Shaffer
A F
AF
Isakson
P C
PC