The sensitivity of guinea-pig lung trachealis muscle to a variety of bronchodilator drugs was examined after removal of the epithelium. Lung preparations with and without epithelium were precontracted with 2 micromolar (microM) or 1microM methacholine-chloride, respectively, prior to incubation with increasing concentrations of bronchodilators. Drugs tested included isoproterenol, salbutamol, papaverine, sodium-nitroprusside, and adenosine. Tissue responses to isoproterenol, salbutamol, and papaverine were tested with and without a 30 minute preincubation with corticosterone; and adenosine response curves were obtained with and without the adenosine uptake blocker, dipyridamole, and the adenosine-deaminase inhibitor, erythro-9,2-hydroxyl-3-nonyl-adenine (EHNA), in the incubation medium. Epithelium removal enhanced trachealis relaxation regardless of drug treatment. Epithelium removal had no effect on the sensitivity of tracheal strips to papaverine or salbutamol, but significantly enhanced sensitivity to isoproterenol and sodium- nitroprusside. The sensitivity of denuded lung trachealis compared to intact trachealis to adenosine was increased significantly in the presence of the adenosine uptake and degradation inhibitors. Adenosine effects were comparable in intact and epithelium stripped preparations in the absence of dipyridamole and EHNA. Corticosterone pretreatment enhanced tissue sensitivity to isoproterenol but had no effect on tissue responses to either salbutamol or papaverine. The authors conclude that guinea-pig tracheal epithelium represents a primary mechanism for extraneuronal catecholamine uptake.