Tannin, isolated from cotton bracts and implicated in the pathogenesis of byssinosis, inhibits isoproterenol-stimulated cAMP release from airway cells in part by decreasing cell surface -adrenergic receptor number and uncoupling the -adrenergic receptor from its stimulatory G-protein (Gs). We have hypothesized that tannin, because of its long polymer length and unusual monoflavanoid composition, interacts with the hydrophobic plasma membrane surface of the -adrenergic receptor and alters receptor binding and Gs coupling. In these studies, we demonstrate that decreased polymer length blocks tannin's inhibitory effects on chloride secretion, on cell surface -adrenergic receptor number and on isoproterenol-stimulated cAMP release. We also demonstrate that pretreatment with N-acetylcysteine, which interacts with cysteine residues, inhibits tannin's effects on isoproterenol-stimulated cAMP release. We conclude that polymer length and cysteine residues are essential for tannin's inhibitory effects on the airway epithelium.