Monoamine oxidase (MAO) is responsible for the pulmonary metabolism of 5-hydroxytryptamine (5-HT) and phenylethylamine (PEA). In the present study the effects of treatment of rats with the tricyclic antidepressant desmethylimipramine (DM) on the disposition of 5-HT and PEA in isolated perfused rat lungs was investigated. DMI accumulation in the lung reached a plateau after 6 days of treatment with mean values of 1.1, 6.1, and 315 nmol/lung at dose levels of 0.67, 6.7, and 33 mumol/kg/day, respectively. During a 10-min perfusion at a concentration of 10(-6) M, both 5-HT and PEA were rapidly taken up and extensively metabolized by lungs from control animals. DMI treatment decreased pulmonary clearance of 5-HT and the extent of its metabolism in a partially dose-related manner. Efflux experiments showed that no unmetabolized 5-HT appeared in the effluent from lungs of either control or DMI-treated rats. These data suggest that DMI decreases both transport of 5-HT across the pulmonary endothelium and MAO activity. PEA clearance in perfused lung was decreased in a dose-related manner by DMI treatment with a corresponding decrease in its metabolism. In efflux experiments, unmetabolized PEA was only found in the perfusate from lungs of DMI-treated rats. It was concluded that PEA clearance after DMI results almost entirely from inhibition of pulmonary MAO. The data also suggest that there may be two discrete pools of MAO in lung, one of which is relatively unaffected by DMI.