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) in duced peritoneal eicosanoid biosynthesis in the rat. Intraperitoneal i njection of A-23187 (20 mu g/rat) stimulated marked biosynthesis of 6- keto-PGF(1 alpha)(6-KPA), TxB(2), LTC(4) and LTB(4), with no detectabl e changes on levels of PGE(2). Levels of all eicosanoids decreased rap idly after a peak which was seen as early as 5 min. Enzyme markers of cellular contents of neutrophils and mononuclear cells, MPO and NAG re spectively, decreased rapidly after ionophore injection; this was foll owed by increases after 60 min. Indomethacin, a selective cyclooxygena se inhibitor, and zileuton and ICI D-2138, two selective 5-lipoxygenas e inhibitors attenuated prostaglandin and leukotriene pathways respect ively. Oral administration of zileuton (20 mg/kg, p.o.) inhibited LTB( 4) biosynthesis for up to 6 h suggesting a long duration of pharmacolo gical activity in the rats consistent with its longer half-life. The r apid onset and the magnitude of increases in levels of eicosanoids ren der the ionophore induced peritoneal eicosanoid biosynthesis a useful model to evaluate pharmacological profiles of inhibitors of eicosanoid pathways in vivo.