In the isolated, perfused lung lobe of the ferret we evaluated the bronchoconstrictor response of its airways to methacholine and histamine, pharmacologic agents associated with the asthmatic state. The bronchus of excised lobes was cannulated and needle scarifications were made on the pleural surface to allow perfusate to exit. Lung airways were perfused at constant flow with equilibrated 95% O2/5% CO2, warmed Krebs-Ringers solution. Perfusion pressure was measured as a gauge of airway resistance. A concentration-dependent smooth muscle contraction of the ferret lung lobes was observed to methacholine and histamine. The ED50's of methacholine and histamine were 6.41 x 10(-6) M +/- 1.38 x 10(-6) (SEM) and 6.41 x 10(-6) M +/- 1.38 x 10(-6) (SEM) and 2.39 x 10(-6) M +/- 0.53 x 10(-6) (SEM), respectively. The maximum level of bronchoconstriction developed in the ferret (2.42 mmHg/ml/min +/- 0.28 SEM (resistance units] in response to methacholine, was six times greater than that found for histamine (0.42 mmHg/ml/min +/- 0.05 SEM). Responses to both agonists were less pronounced in the ferret lung preparation than those in a similar lung preparation of guinea pig. Compliance changes in both animals were also evaluated. The ferret did not demonstrate a compliance change in response to histamine as was seen for methacholine, suggesting that resistance changes precede compliance changes, or that the ferret airways are particularly resistant to histamine. Despite a lesser contractile response, the ferret has the advantage of a relatively large lung and long trachea that allow study in several preparations obtained from a single animal. It should prove a useful animal model for study of pulmonary pharmacology.