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 se cretagogue. A phospholipase inhibitor, p-bromophenacyl bromide (PBPB), or a lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), inhibi ted the 48/80 (1 mug/ml) -induced release of histamine, Ca2+, and Mn2 influxes, but the cyclooxygenase inhibitor, indomethacin (approximate ly 50 muM), inhibited neither Ca2+ nor Mn2+ influxes. The Ca2+ release induced by 1 mug/ml of 48/80 was little inhibited by PBPB, NDGA, or i ndomethacin. The Ca2+ release was activated and saturated with lower c oncentrations of 48/80 than was the Ca2+ influx. The percent inhibitio n of the Ca2+ release by 25 muM PBPB was increased by lowering the con centration of 48/80, but NDGA (10 muM) did not inhibit the Ca2+ releas e induced by low concentrations of 48/80 (0.03-0.1 mug/ml). These resu lts suggest that activation of the Ca2+ release and the Ca2+ influx we re 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.