Effect of chlorphentermine on the pulmonary disposition of 5-hydroxytryptamine in the isolated perfused rabbit lung.

Abstract

It has been postulated that chlorphentermine (CP), as well as other drugs known to accumulate and to induce morphologic changes in lung tissue, might affect the uptake and metabolism of the endogenous vasopressor amine, 5-hydroxytryptamine (5-HT). The uptake and metabolism of [14C]5-HT was followed in artificially ventilated, isolated perfused rabbit lung preparations using erythrocyte-free perfusate with an initial 5-HT concentration of 5 microgram/100 ml. Samples of the perfusate were analyzed for total radioactivity, metabolites, and the parent compound. Preloading the lungs with 25 or 30 mumoles of CP significantly decreased the formation of 5-hydroxyindolacetic acid (5-HIAA) to 56% and 34% of the control value, respectively. These experiments indicated that decreased pulmonary metabolism of 5-HT by CP might be mediated via a dual effect of hindered uptake and inhibition of metabolism. In experiments designed to examine the effect on uptake by blocking 5-HT metabolism, CP significantly decreased 5-HT uptake by lungs preloaded with pargyline. In other experiments designed to examine the effect of CP on 5-HT metabolism, CP (0.3 mM) significantly inhibited 5-HT metabolism by 60% in in vitro incubations of rabbit lung homogenates. These experiments provided evidence that CP significantly decreases the pulmonary uptake and metabolism of 5-HT. Decreased pulmonary 5-HT clearance may bear a causal relation to the drug-induced pulmonary hypertension observed with chronic CP treatment.