Hydroxylamines potentiated the responses of the canine colonic epithelium to histamine but not to other agonists such as serotonin or carbachol. We tested the hypothesis that an inhibition of histamine catabolism could explain the observed potentiation. A clear structure activity relation was defined, active compounds having the structure NH2-O-R, R being a simple uncharged aliphatic group. Active compounds delayed the disappearance of histamine from the bathing solutions and inhibited colonic diamine oxidase, an effect mimicked by standard inhibitors aminoguanidine and semicarbazide. Histamine agonists that possessed an imidazole nucleus (2- and 4-methylhistamine) were affected, whereas impromidine, 2 pyridylethylamine, and dimaprit were not. Agonist specificity combined with the enzyme data suggest an inhibition of histamine catabolism as a possible mechanism for the potentiating effects observed.