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© 1982 Oxford University Press

research-article

Effect of Chlorphentermine Pretreatment on 5-Hydroxytryptamine Disposition in the Isolated Perfused Rat Lungu1,2

LINDA S. ANGEVINE3 and HARIHARA M. MEHENDALE

Department of Pharmacology and Toxicology, University of Mississippi Medical Center Jackson, MS 39216

Effect of Chlorphentermine Pretreatment on 5-Hydroxy-tryptamine Disposition in the Isolated Perfused Rat Lung. Angevine, L.S. and Mehendale, H.M. (1982). Fundam. Appl. Toxicol. 2:306-312. 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 µM). 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 µmol 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 µmol 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 µmol) 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.


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