The effects of airway inflammation induced by chronic antigen exposure on substance P (SP)-induced increases and vasoactive intestinal peptide (VIP)-induced decreases in airway opening pressure (Pao), and the recovery of intact and hydrolyzed radiopeptide were studied in tracheally perfused guinea pig lungs. SP (10(-6) mol/kg) induced a significantly greater increase in Pao in lungs from antigen-exposed (30 +/- 5 cm H2O) than saline-exposed animals (15 +/- 1 cm H2O, P < 0.05). Significantly more intact 3H-SP and significantly less 3H-SP 1-7, a neutral endopeptidase (NEP) hydrolysis product, were recovered from the lung effluent of antigen-exposed than saline-exposed animals (P < 0.05). Injection of VIP (10(-9) mol/kg) induced significantly more pulmonary relaxation in saline-exposed compared with antigen-exposed lungs (62 +/- 4%, P < 0.001). In contrast to effluent from saline-exposed animals, lung effluent from antigen-exposed lungs contained less intact VIP, increased amounts of a tryptic hydrolysis product, and no products consistent with the degradation of VIP by NEP. These data indicate that inflamed lungs are more sensitive to the contractile effects of SP because it is less efficiently degraded by NEP and are less sensitive to the relaxant effects of VIP because it is more efficiently degraded by a tryptic enzyme. Changes in airway protease activity occur with allergic inflammation and may contribute to airway hyperresponsiveness.