Effects of selected bronchodilators on antigen- and A23187-induced contraction of guinea-pig trachea.

Antigen and the calcium ionophore A23187 contract isolated tracheal spirals from sensitized guinea pigs and A23187 also contracts normal airways. The contractions appear to be the result of released bronchoconstrictor mediators, likely products of the lipoxygenase pathway of arachidonic acid metabolism. Pretreatment (10-30 min) with a series of bronchodilators resulted in inhibition of ovalbumin-induced airways contractions. The order of potency on the trachea was isoprenaline greater than forskolin greater than prostaglandin E2 much greater than aminophylline greater than dibutyryl cyclic AMP congruent to prostacyclin. The IC50 values and order of potency were similar to their capacity to relax tracheal smooth muscle. Only isoprenaline (10(-6) M), forskolin (10(-6) M) and aminophylline (10(-3) M) inhibited A23187-induced contraction of trachea. These agents lost their inhibitory capacity 20 to 30 min after A23187 challenge. This was not observed with ovalbumin challenge because the membrane stimulation with ovalbumin occurs immediately whereas A23187 induction of Ca++ influx is continual. The recovery from inhibition is probably not receptor desensitization as recovery also occurs in the presence of forskolin, a direct activator of adenylate cyclase. Sensitized trachea responded to A23187 in the presence of bronchodilators differently than normal tissue. Low concentrations of isoprenaline (10(-8) to 10(-7) M), forskolin (10(-8) to 10(-7) M), prostaglandin E2 (10(-7) to 10(-5) M), aminophylline (10(-4) M) and dibutyryl cyclic AMP (10(-3) M) all enhanced A23187-induced contraction. Pools of cyclic AMP are known to be involved both in secretion and in modulation of mediator release involved in airways smooth muscle contraction and sensitization may affect the differential availability of these pools. That this enhancement occurred only in sensitized trachea emphasized an intrinsic difference between sensitized and normal tissues.