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.

Mechanisms of alpha-adrenoceptor mediated contractions of rat mesenteric artery.

The nature of the calcium channels associated with the activation of alpha-adrenoceptors in vascular smooth muscle has been investigated. The inhibitory effects of nitrendipine, a calcium antagonist, were studied on the contractions elicited by alpha-adrenoceptor agonists in rat superior mesenteric artery. Responses to equieffective concentrations of phenylephrine (alpha 1-adrenoceptor agonist), clonidine and BHT-920, (alpha 2-adrenoceptor agonists), and noradrenaline (nonselective agonist) were inhibited differentially by the calcium antagonist, with the sensitivity order being as follows: BHT-920 = clonidine greater than phenylephrine greater than noradrenaline. When the contractions to two doses of noradrenaline were compared, the low dose response was more sensitive to nitrendipine inhibition than the high dose response. This differential inhibition was not seen for noradrenaline in the presence of verapamil or for phenylephrine in the presence of nitrendipine. The contractions of the vessel to the agonists in zero calcium conditions were not significantly different from each other. The sensitivity differences among the agonists to nitrendipine may arise from differences in the postreceptor mechanisms of activation. The differential sensitivity of noradrenaline responses suggests a greater heterogeneity of calcium channels than those available for the other agonists.