Antagonism of the final common pathway of mast cell histamine secretion by arylalkylamines

The antagonism of histamine secretion from rat peritoneal mast cells by a range of drugs (e.g., antihistamines, local anesthetics, tranquilizers, antidepressants, adrenergics and antiadrenergics) and arylalkylamines was studied. Simple arylalkylamines, those without quaternary ammonium, phenolic or anionic groups, uniformly inhibited histamine secretion induced via three major secretory pathways of mast cells (compound 48/80, A23187 and concanavalin A). That is, each simple arylalkylamine nonselectively inhibited all three secretagogues at about the same concentration (avg. range = 2.2). This nonselective inhibition was rapid in onset (seconds), readily reversible by washing and not related to a decrease in ATP. It is likely that these agents act nonspecifically at a step in the final common pathway in the cell membrane, possibly to inhibit fusion of the secretory granules with the plasma membrane. Other, more complex arylalkylamines were selective in their antagonism of histamine secretion. Quaternary arylalkylammonium compounds selectively antagonized polyamine secretagogues (48/80 and polymyxin B), whereas arylalkylamines, with other hydrophilic groups, selectively inhibited one or another of the secretory pathways. These complex arylalkylamines must act before the final common pathway because of their selective inhibition. At higher concentrations most of the arylalkylamines caused disruption of the mast cells and liberated histamine.