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 mumol/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-HT3 agonist 2-methyl-5-hydroxytryptamine had no effect on the short-circuit current at concentrations of up to 5 mmol/l. The 5-HT1D agonist sumatriptan had no effect at concentrations below 5 mmol/l and at 5 mmol/l had only a transient effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Graham
A
A
Ion Transport Laboratory, National Heart and Lung Institute, London, U.K.
Alton
E W
EW
Geddes
D M
DM
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D002065:Buspirone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D017294:Ondansetron / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D012756:Sheep / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects*; D014132:Trachea / Q000187:drug effects*
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000584:Amiloride; D002065:Buspirone; D017294:Ondansetron; D011985:Receptors, Serotonin; D012701:Serotonin; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D015222:Sodium Channels; C045918:2-methyl-5-HT