Effects of 5-hydroxytryptamine and 5-hydroxytryptamine receptor agonists on ion transport across mammalian airway epithelia.

1. 5-Hydroxytryptamine has been suggested as a candidate for an endogenous inhibitor of airway sodium transport. Amiloride, an inhibitor of epithelial sodium channels, has therapeutic potential in disorders of airway ion transport such as cystic fibrosis, but its duration of action in vivo is short. 5-Hydroxytryptamine and related compounds have been studied to investigate whether any might be a useful alternative to amiloride for clinical use, and to further assess the possible physiological role of 5-hydroxytryptamine in the regulation of airway ion transport. 2. Sheep tracheal epithelium was mounted in Ussing chambers under short-circuit conditions. Mucosal application of 5-hydroxytryptamine resulted in an immediate, reversible, concentration-related decrease in the short-circuit current, maximal with 38% inhibition of the short-circuit current at 25 mmol/l. This response was completely inhibited by pretreatment of tissues with mucosal amiloride (100 μmol/l). These features are consistent with a direct effect of 5-hydroxytryptamine on amiloride-sensitive sodium channels. Similar results were obtained in a limited number of studies using human bronchial epithelium. 3. The effects of mucosal addition of a range of 5-hydroxytryptamine agonists were studied to determine if any was a more potent blocker of amiloride-sensitive sodium transport than 5-hydroxytryptamine. The 5-HT 3 agonist 2-methyl-5-hydroxytryptamine had no effect on the short-circuit current at concentrations of up to 5 mmol/l. The 5-HT 1D agonist sumatriptan had no effect at concentrations below 5 mmol/l and at 5 mmol/l had only a transient effect. The 5-HT 1A agonists buspirone and 8-hydroxy-2-(di-n-propylamino)tetralin and the 5-HT 2 agonist α-methyl-5-hydroxytryptamine were all more potent inhibitors of the short-circuit current than 5-hydroxytryptamine, but, although their effects were reduced by pretreatment of tissues with mucosal amiloride (100 μmol/l), none had a specific effect on the amiloride-sensitive sodium current. The effect of buspirone on the short-circuit current was also studied after mucosal sodium substitution, and although its effect was again reduced, significant inhibition of the short-circuit current still occurred, indicating that ion transport processes other than sodium absorption were being affected. 4. Mucosal application of ondansetron, an antagonist at the 5-HT 3 receptor (an ion channel), also produced a dose-related inhibition of the short-circuit current that was not mediated via the amiloride-sensitive sodium current. Pretreatment of tissues with ordansetron had no effect on the subsequent response to 5-hydroxytryptamine. 5. We conclude that mucosally applied 5-hydroxytryptamine specifically inhibits amiloride-sensitive sodium transport in airway epithelia, but with a median inhibitory concentration too high for it to be therapeutically useful. The high median inhibitory concentration also indicates that 5-hydroxytryptamine is unlikely to be a physiological regulator of sodium channels. Screening a number of 5-hydroxytryptamine receptor agonists has failed to identify a more potent inhibitor of sodium transport which may have had therapeutic potential.