Tannin, isolated from cotton bracts, inhibits chloride (Cl-) secretion and secondary water transport in airway epithelium. The mechanism for this inhibition was examined using bovine tracheal epithelial cells and 3H-dihydroalprenolol. Tannin (25 µg/ml) exposure rapidly desensitized airway cells to isoproterenol-stimulated cAMP release. This desensitization was due in part to tannin-induced decreases in ß-adrenergic receptor number at the cell surface and to uncoupling of the ß-adrenergic receptor from its stimulatory G protein. Long-term tannin exposure (24 hr) further desensitized the airway epithelium to isoproterenol and forskolin suggesting downregulation of the ß-adrenergic receptor/cAMP pathway by tannin. These studies provide further evidence for the role of tannin in the occupational lung disease, byssinosis.