title: Effect of chlorphentermine pretreatment on 5-hydroxytryptamine disposition in the isolated perfused rat lung.
abstract: 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.
mesh_terms: D000818:Animals; D002745:Chlorphentermine / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010293:Pargyline / Q000494:pharmacology; D010645:Phentermine / Q000031:analogs & derivatives*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism*; D013997:Time Factors
chemical_list: D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D010293:Pargyline; D010645:Phentermine; D002745:Chlorphentermine