Calmodulin antagonism: a pharmacological approach for the inhibition of mediator release from mast cells.
Several Ca2+ antagonists with either Ca2+-entry blocking or calmodulin (CaM) antagonistic properties and antiallergic drugs were investigated for their effects on mediator release from mast cells induced by different secretagogues (compound 48/80, concanavalin A, antigen-IgE and Ca2+ ionophore A23187) and for their ability to inhibit the function of CaM or phospholipid/Ca2+-dependent protein kinase (C-kinase). The effects of the different agents--with the only exception of cromolyn sodium--on histamine release elicited by compound 48/80 correlated well with their actions on two CaM-dependent enzymes whereas the activity of C-kinase was far less altered, or not altered at all. CaM antagonism of cloxacepride, picumast, oxatomide, fendiline and bepridil correlated not only with the inhibition of exocytosis evoked by compound 48/80 but also with that induced by A23187, concanavalin A and antigen-IgE. This indicates an action of these substances distal to the generation of the Ca2+ signal since the various secretagogues elevate the intracellular Ca2+ concentration by different mechanisms. However, prenylamine and thioridazine inhibited concanavalin A- and antigen-IgE-induced mediator release more potently and more effectively than that elicited by compound 48/80 or A23187. Therefore inhibition of allergic histamine release by these drugs may in part be dependent on an impairment of the Ca2+ signal. Since for each of two agents inhibition of histamine release (evoked by different releasers) parallels that of serotonin release it may be concluded that these mediators are secreted via the same mechanism. The results obtained with agents exhibiting different pharmacological properties but which share one common property, namely antagonism of CaM, strengthen the view that CaM is involved in exocytosis of mediators from mast cells.
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D006636:Histamine Release / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010770:Phosphotransferases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism
D002121:Calcium Channel Blockers; D002147:Calmodulin; D012701:Serotonin; D010770:Phosphotransferases