Clonidine-displacing substance, thought to be the endogenous ligand for imidazoline receptors, has been identified recently as agmatine (1-amino-4-guanidinobutane). The similarity of this compound's structure to that of the diamine oxidase (DAO) inhibitor, aminoguanidine, led us to investigate the possibility that agmatine might be a substrate for this enzyme. The metabolism of agmatine by purified porcine kidney DAO was measured by a peroxidase-linked colorimetric assay. Agmatine was a substrate for this enzyme and, under the experimental conditions used here, was metabolised at a rate of 0.8 mumol agmatine h-1 (unit DAO activity)-1. In contrast, agmatine was a substrate neither for rat brain monoamine oxidase (MAO) -A or -B, nor for rat brown adipose tissue semicarbazide-sensitive amine oxidase (SSAO). The metabolism of agmatine by DAO was inhibited by aminoguanidine (IC50 14.9 nM) and by the antidepressant, phenelzine (IC50 1.95 microM). These results suggest that administration of DAO inhibitors may increase endogenous agmatine levels and thus alter imidazoline receptor densities. A review of the literature documenting ligand affinities for idazoxan-preferring (I2) imidazoline binding site subtypes and drug affinities for DAO enzymes indicates that some of the I2 sites described elsewhere may correspond to DAO and not to an imidazoline receptor.