Effect of chlorphentermine on the pulmonary clearance of 5-hydroxytryptamine in rabbits in vivo.

Previous studies from this laboratory demonstrated that the pulmonary clearance of 5-hydroxytryptamine (5-HT) is perturbed by pulmonary accumulation of chlorphentermine (CP) by isolated perfused lung preparations. This observation raises the possibility that depressed 5-HT clearance may be one factor contributing to CP-induced pulmonary hypertension. The primary objective of the present studies was to determine if the effect of CP could be demonstrated in vivo during single-pass circulation through the lungs. Pulmonary extraction and metabolism of [14C]-5-HT during single pulmonary passage were examined using the reference indicator radioisotope dilution technique in male New Zealand albino rabbits. In control or saline vehicle injected animals, it was established that 81% of administered [14C]-5-HT was extracted by the lung and 25% of total radioactivity in the blood stream was recovered as 5-hydroxyindoleacetic acid (5-HIAA) during single passage through the lungs. Appropriate control incubations of 5-HT with blood and simulated pulmonary circulation through the extracorporeal circulation system yielded only 2 and 5% metabolism, respectively. These results indicate that significant pulmonary metabolism of 5-HT followed by efflux of 5-HIAA into venous output occurs during single-pass circulation. Preadministration of CP (0.5, 1 and 3 mg/kg single dose, i.v.) caused a dose-related inhibition of pulmonary extraction of 5-HT. This effect was also accompanied by a dose-related suppression of the appearance of the metabolite of 5-HT. These results provide in vivo evidence for impairment of pulmonary extraction and deactivation of 5-HT as a result of prior pulmonary accumulation of CP.