Cromolyn and nedocromil are often used in the treatment of asthma. Recently, these agents have been shown to block Cl- currents and/or Ca2+ currents in a variety of cell preparations. Ca2+ and Cl- currents play central roles in excitation-contraction coupling in airway smooth muscle. This study therefore aimed to investigate the effects of these agents on membrane currents, elevations of [Ca2+] and contractions evoked by depolarization and/or acetylcholine in airway smooth muscle. Patch-clamp, fura-2 fluorimetric and muscle-bath techniques were used to monitor ion currents, [Ca2+] and contractions, respectively, in canine tracheal smooth muscle in the presence and absence of the chromones. Cromolyn and nedocromil eliminated voltage-dependent Ca2+ currents, leading to a reduction in depolarization-evoked K+ currents. Both chromones had little or no effect on either acetylcholine-evoked release of internal Ca2+ or the subsequent contraction; however, cromolyn (but not nedocromil) at high concentrations suppressed Ca2+-dependent Cl- currents triggered by acetylcholine. In conclusion, cromolyn and nedocromil abolished voltage-dependent Ca2+ currents and cromolyn also suppressed Ca2+-dependent Cl- currents in airway smooth muscle; neither chromone greatly altered either the release of internally sequestered Ca2+ or the resultant contractions. Further investigation is needed to determine whether the local concentrations obtained by inhaled chromones within the airway wall allow these cellular effects to occur in patients in vivo.