Effect of calmidazolium (R24571) on histamine release from isolated rat mast cells.

The effects of selected calmodulin-antagonists, i.e. calmidazolium (R24571), trifluoperazine, cis- and transflupenthixol, chlorpromazine, and imipramine, on rat mast cells and on mast cell histamine release were investigated. The drugs induced histamine release, apparently by cytotoxic effects, with a rank order of potency in accordance with their lipid solubility and with maximal release at calmidazolium (5 mumol/l), trifluoperazine (40 mumol/l), cis- and trans-flupenthixol (50 mumol/l), chlorpromazine (100 mumol/l), and imipramine (500 mumol/l). Inhibition of the histamine release induced by antigen, compound 48/80, and the ionophore A23187 was only observed with some of the drugs tested, with maximal inhibition at calmidazolium (2 mumol/l), chlorpromazine (25-50 mumol/l), and imipramine (100-250 mumol/l). The concentration-response curve for histamine release induced by calmidazolium was significantly shifted to the right by antigen (i.e. horse serum) in the medium and the addition of antigen was capable of immediately stopping the release induced by calmidazolium, indicating binding of calmidazolium by antigen. Similar effects on the actions of calmidazolium were observed with phosphatidylserine. The inhibition by calmidazolium of the histamine release induced by antigen, compound 48/80, and the ionophore A23187 was significantly counteracted by glucose in the medium. The findings do not confirm an involvement of calmodulin in the histamine release process in rat mast cells. The ability of calmidazolium to bind to proteins and phospholipids in the medium indicates multiple cellular targets for calmidazolium, and the observations with glucose suggest an impaired mitochondrial function to be of major significance.(ABSTRACT TRUNCATED AT 250 WORDS)