Mode of action of calcium antagonists on responses to spasmogens and antigen challenge in human airway smooth muscle

Calcium antagonists have been shown to inhibit exercise-induced asthma. The mechanism of inhibition is unclear, but may involve inhibition of mediator release and/or blockade of the mediator effects. We studied the effects of methoxyverapamil (D600) on human airway responses to spasmogens as well as on histamine release from passively sensitized human lung challenged with ragweed antigen. The concentrations of D600 required to inhibit 50% of the spasmogen responses (IC50) were calculated from the concentration-response relationships and were: histamine 4 x 10(-6) M; KCl 7 x 10(-7) M; leukotriene C4 4 x 10(-5) M; electrical field stimulation 5 x 10(-5) M; and for ragweed antigen in passively sensitized muscle 2 x 10(-6) M. Histamine release by antigen challenge from sensitized lung fragments was not blocked by D600, up to a concentration of 10(-5) M. The data suggest that the contractile effects of agonists are mediated through voltage- and receptor-operated calcium channels. The differential inhibitory effects of D600 on antigen-induced mediator release vs the smooth muscle effects of the various agonists may suggest multiple mechanisms of release or sources of mediators in human airway anaphylaxis.