CONCLUSIVE EVIDENCE FOR DISTINCT TRANSPORTERS FOR 5-HYDROXYTRYPTAMINEAND NORADRENALINE IN PULMONARY ENDOTHELIAL-CELLS OF THE RAT

The aims of this study were to obtain conclusive evidence about the ro les of a 5-hydroxytryptamine [5-HT] transporter and uptake(1) in the d issipation of 5-HT in the lungs of the rat and to compare the properti es of the 5-HT transporter In rat lungs with that in other tissues, in cluding brain and platelets. In the first part of the study, the IC50 values of a range of selective inhibitors and substrates of the 5-HT t ransporter or uptake(1) were determined for inhibition of uptake of 5- HT or noradrenaline in intact perfused lungs of rats. Monoamine oxidas e was inhibited and, in experiments with noradrenaline, catechol-O-met hyltransferase was also inhibited. Initial rates of uptake of 5-HT or noradrenaline were measured in lungs perfused with 2 nmol/l H-3-5-HT o r H-3-noradrenaline for 2 min, in the absence or presence of at least three concentrations of paroxetine, citalopram, fluoxetine, 7-methyltr yptamine, tryptamine, nisoxetine, imipramine, 5-HT, desipramine, (+)-o xaprotiline, cocaine or tyramine. The results showed that pharmacologi cally distinct transporters are involved in the uptake of 5-HT and nor adrenaline in rat lungs, since there was no significant correlation be tween the IC50 values for inhibition of 5-HT and noradrenaline uptake in the lungs. However, there were significant correlations between the IC50 values for (a) inhibition of 5-HT uptake in rat lungs and of upt ake by the 5-HT transporter in rat brain and (b) inhibition of noradre naline uptake in rat lungs and of uptake(1) in rat phaeochromocytoma P C-12 cells. The results support the conclusion that 5-HT uptake in rat lungs occurs, at least predominantly, by a 5-HT transporter which is very similar to or the same as that in other tissues, such as the brai n, and provide further evidence for transport of noradrenaline by upta ke(1). Further experiments were carried out to determine whether there is any transport of 5-HT by uptake(1) or of noradrenaline by the 5-HT transporter in rat lungs. Lungs were perfused with 2 nmol/l H-3-5-HT or H-3-noradrenaline for 2 min in the absence or presence of 1 mu mol/ l citalopram, desipramine, or citalopram and desipramine. The results showed that there was no evidence of any transport of 5-HT in the lung s by uptake(1) or of noradrenaline by the 5-HT transporter, in that de sipramine had no effect on 5-HT uptake (in the absence or presence of citalopram) and citalopram had no effect on noradrenaline uptake (in t he absence or presence of desipramine). The final series of experiment s was carried out to determine whether, at high concentrations of the amine, there is any interaction of 5-HT with uptake(1) or of noradrena line with the 5-HT transporter. Noradrenaline, at a concentration of 1 0 mu mol/l, did not affect 5-HT uptake in lungs perfused with 2 nmol/l H-3-5-HT for 2 min (uptak(1) inhibited), but 50 mu mol/l 5-HT inhibit ed noradrenaline uptake by 56% in lungs perfused with 2 nmol/l H-3-nor adrenaline for 2 min (5-HT transporter inhibited). These and the above results show that the 5-HT transporter appears to be exclusively resp onsible for 5-HT uptake in rat lungs, despite the possible interaction of 5-HT at high concentrations with the uptake(1) transporter in the cells. On the other hand, noradrenaline is transported exclusively by uptake(1) in the lungs, and there is no evidence that it interacts wit h the 5-HT transporter, even at high concentrations.