Epithelium removal and peptidase inhibition enhance relaxation of human airways to vasoactive intestinal peptide.

In this study we evaluated the role of epithelial versus subepithelial peptidases in the responses of isolated peripheral and central human airways to VIP. Human airways were obtained at thoracotomies (n = 8) and studied in organ baths. Intact or epithelium-denuded strips of central and peripheral airways were incubated with or without a cocktail of peptidase inhibitors containing phosphoramidon (2.5 micrograms/ml), leupeptin, aprotinin, captopril, soybean trypsin inhibitor (all 20 micrograms/ml), and bestatin (2.8 micrograms/ml). After precontraction with histamine (5 x 10(-6) M), cumulative concentration-response curves to VIP (10(-10) to 10(-7) M) were obtained. Both intact central and peripheral airways showed only minor relaxations to VIP irrespective of the precontraction level. Removal of the epithelium and addition of peptidase inhibitors additively increased the sensitivity (> 20-fold) and maximal response to VIP in both central and peripheral airways. We conclude that (1) VIP relaxes both central and peripheral human airways but only in the absence of epithelium and/or the presence of peptidase inhibitors, and (2) both epithelial and subepithelial peptidases are important in the inactivation of VIP in human airways.