Chlorphentermine (CP) has been noted to cause primary pulmonary hypertension both clinically and experimentally. It was postulated that CP might affect the pulmonary clearance of endogenous vasoactive substances such as norepinephrine (NE). The uptake and metabolism of 14C-NE were followed in artificially ventilated isolated perfused rabbit lung preparations using a constituted perfusate with initial NE concentration of 5 micrograms/100 ml. Perfusate samples were analyzed for total radioactivity, metabolites, and parent compound. Preloading the lungs with 0.25 mM CP significantly increased the concentrations of total radioactivity, deaminated products, and decreased the concentration of normetanephrine in the perfusate. In addition, the accumulation of total radioactivity in the lung tissue after 60 min of perfusion was significantly decreased in CP-treated lungs. The proportion of deaminated metabolites in the lung tissue was slightly decreased while the percent of normetanephrine, and parent compound were significantly increased by the CP treatment. CP (0.1 mM) also inhibited the in vitro metabolism of NE by 79%. These results provide experimental evidence in support of a hindered pulmonary clearance of circulating NE by CP.