Stimulation of airway irritant receptors produces reflex bronchoconstriction that can be prevented by pretreatment with anticholinergic drugs or local anesthetics delivered by aerosol or intravenously. We compared therapeutic doses of an orally administered local anesthetic, mexiletine hydrochloride, and intravenously administered lidocaine at blocking histamine-induced bronchoconstriction in five basenji-greyhound dogs, using high-resolution computed tomography (HRCT) to directly measure changes in airway size. In the dogs given placebo, a histamine infusion decreased airway area to 61 +/- 2% (mean +/- SEM) of control (p < 0.01). Mexiletine pretreatment completely prevented histamine-induced airway constriction, with an airway area that was 94 +/- 4% of the control value during the histamine infusion (p = 0.07 compared with baseline). Mexiletine serum levels were therapeutic (1.7 +/- 0.3 mg/L). Similarly, pretreatment with lidocaine significantly blunted the airway constriction provoked by intravenous histamine. In lidocaine-pretreated dogs, histamine decreased airway area to 79 +/- 4% of baseline (p < 0.01). As in the case of mexiletine, lidocaine serum levels were also therapeutic (2.4 +/- 0.3 mg/L). Mexiletine was more effective than lidocaine at preventing histamine-induced bronchoconstriction (p = 0.02). These data suggest that orally administered local anesthetics may be useful in preventing irritant-induced bronchoconstriction in humans.