Exposure of conscious guinea pigs to A23187 aerosol produced a concentration-related increase of excised lung gas volumes (ELGV), i.e., postmortem pulmonary gas trapping. Measurements of ELGV were highly correlated with in vivo measurements of dynamic compliance (Cdyn) and total pulmonary resistance (RL) and were used as an indication of in vivo airway obstruction. We pretreated guinea pigs intravenously with the following drugs: atropine; LY163443, a selective LTD4/E4 antagonist; indomethacin; propranolol; and pyrilamine. The guinea pigs were exposed for 8 minutes to the A23187 aerosol, and ELGV measurements were then made. Atropine or pyrilamine prevented the A23187-induced gas trapping. Indomethacin or propranolol tended to potentiate the response and when combined, they potentiated the gas trapping by 80%. LY163443 had no effect alone, but when combined with indomethacin, propranolol, and pyrilamine, inhibited A23187-induced gas trapping by 67%. We conclude that cholinergic and histaminergic mechanisms play major roles in the ionophore-induced pulmonary gas trapping of the guinea pig. With appropriate pretreatment, sulfidopeptide leukotrienes may produce a substantial effect.