Inhibitors of the arachidonic acid cascade dissociate 48/80-induced Ca2+ influx and Ca2+ release in mast cells.
Effects of inhibitors of the arachidonic acid cascade on Ca2+ release from intracellular stores and Ca2+ influx through the plasma membrane during stimulus-secretion coupling were examined using rat peritoneal mast cells loaded with fura-2. Compound 48/80 (48/80) was used as a secretagogue. A phospholipase inhibitor, p-bromophenacyl bromide (PBPB), or a lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), inhibited the 48/80 (1 microgram/ml)-induced release of histamine, Ca2+, and Mn2+ influxes, but the cyclooxygenase inhibitor, indomethacin (approximately 50 microM), inhibited neither Ca2+ nor Mn2+ influxes. The Ca2+ release induced by 1 microgram/ml of 48/80 was little inhibited by PBPB, NDGA, or indomethacin. The Ca2+ release was activated and saturated with lower concentrations of 48/80 than was the Ca2+ influx. The percent inhibition of the Ca2+ release by 25 microM PBPB was increased by lowering the concentration of 48/80, but NDGA (10 microM) did not inhibit the Ca2+ release induced by low concentrations of 48/80 (0.03-0.1 microgram/ml). These results suggest that activation of the Ca2+ release and the Ca2+ influx were differently regulated and that full activation of Ca2+ influx needs the arachidonic acid cascade produced by higher concentrations of 48/80 than does the Ca2+ release. Lipoxygenase metabolites of arachidonic acid are potential modulators of the Ca2+ influx.
Kuno
M
M
Department of Physiology, Osaka City University Medical School, Japan.
Kawawaki
J
J
Shibata
T
T
Gotani
H
H
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors*; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002469:Cell Separation / Q000379:methods; D004305:Dose-Response Relationship, Drug; D006636:Histamine Release / Q000187:drug effects*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008345:Manganese / Q000378:metabolism; D009637:Masoprocol / Q000494:pharmacology; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology*
D000098:Acetophenones; D001095:Arachidonic Acids; D003189:p-Methoxy-N-methylphenethylamine; D008345:Manganese; D009637:Masoprocol; D010741:Phospholipases A; C006821:4-bromophenacyl bromide; D002118:Calcium; D007213:Indomethacin