Perfusion of 0.1 n HC1 5 cm above the lower esophageal sphincter (LES) in cats for 30 min on 4 consecutive days produced biopsy-documented esophagitis and marked decreases in LES pressure. Using this model the effects of experimental esophagitis on the LES response to edrophonium, pentagastrin, and bethanechol were determined. The sphincter response to both edrophonium and pentagastrin after esophagitis was induced was significantly less than preperfusion responses. When the esophagitis had resolved, the pressure response to edrophonium and pentagastrin returned to preperfusion levels. In contrast, the sphincter response to bethanechol during esophagitis was not different from the preperfusion response and remained unchanged after resolution of the esophagitis. Lower esophageal smooth muscle taken from cats with active esophagitis appeared normal by both light and electron microscopy. These studies indicate that besides decreasing resting LES tone, esophageal inflammation causes functional impairment of a cholinergic mechanism regulating LES pressure. In contrast, the smooth muscle appears to be unaffected by inflammation despite the LES hypotension.