Chlorphentermine (CP) is known to be highly accumulated by the lung, to cause pulmonary phospholipidosis and has been suspect in causing
pulmonary hypertension possibly by inhibiting the clearance of
5-hydroxytryptamine (5-HT). It was of interest to determine if subacute CP treatment might inhibit
5-HT clearance by the lung. Animals were treated with CP (50 mg/kg/day po in saline) for 7 days while controls received the vehicle only. Artificially ventilated isolated rat lungs were perfused with a constituted medium. In recirculation perfusion experiments, lungs from CP treated animals exhibited both decreased uptake and metabolism of 14C-5-HT (0.02 microM). In order to distinguish between CP-induced morphological effects and the effect of CP itself, CP was added at an initial perfusate concentration of 0.5 or 5 mumol to the perfusate of lung from untreated animals. A dose-dependent inhibition of
5-HT uptake and metabolism was observed, such that lungs receiving 5 mumol of CP inhibited
5-HT metabolism similarly to that observed in treated lungs. In order to distinguish the effect of CP on
5-HT uptake from its effect on metabolism, pulmonary disposition of
5-HT was studied in the presence of
pargyline, a
monoamine oxidase (
MAO) inhibitor known to block the metabolism of
5-HT. In the presence of 1 mM
pargyline, CP (5 mumol) significantly decreased
5-HT uptake by the lung. CP was also noted to inhibit the metabolism of 14C-5-HT by in vitro incubations of 700 g lung supernatent fractions. In conclusion, subacute treatment with CP results in obtunded clearance of
5-HT by the rat lung, supporting the proposal that CP-induced
pulmonary hypertension may be mediated by decreased pulmonary clearance of
5-HT.