Inhibition of human neutrophil activation by the allergic mediator release inhibitor, CI-922: mechanism of inhibitory activity

3,7-Dimethoxy-4-phenyl-N-1H tetrazol-5-yl-4H-furo3,2-b]-indole-2- carboxamide, L-arginate (CI-922) is a potent inhibitory of human neutrophil functions in response to a variety of stimuli. In this report, the effects of CI-922 on specific processes involved in stimulus-response coupling are evaluated. CI-922 does not inhibit human neutrophil phospholipase C or protein kinase C activities. CI-922 is shown to inhibit calmodulin-dependent enzyme activation. The calmodulin antagonist activity is confirmed by calmodulin-Sepharose affinity chromatography. These results suggest that CI-922 inhibits neutrophil activation by preventing the activation of calmodulin-dependent enzymes, implying a critical role for such enzymes in stimulus-response coupling.