5-Hydroxytryptamine facilitates cholinergic bronchoconstriction in human and guinea pig airways.
5-hydroxytryptamine (5-HT) may not play a major role in controlling human airway smooth muscle tone, as it has little direct effect on airway caliber. However, its role as a neuromodulator has not been determined. We have identified a facilitatory effect of 5-HT on cholinergic neurotransmission and characterized the 5-HT receptors involved in human and guinea pig trachea. In guinea pig trachea, 5-HT facilitated electric field stimulation-induced cholinergic bronchoconstriction in a concentration-dependent manner (EC50 = 2.6 microM). The 5-HT3/4 and 5-HT3 antagonists, ICS 205-930 and ondansetron, inhibited the effect of 5-HT competitively (pA2 values of 7.3 and 7.1, respectively); methiothepin (5-HT1/2C antagonist), ketanserin (5-HT2A antagonist), and GR 113808A (5-HT4 antagonist) had no effect. The rank order of potency of 5-HT agonists was 5-HT > 2-methyl-5-HT (5-HT3 selective) > 5-methoxytryptamine (5-HT4 selective) > alpha-methyl-5-HT (5-HT2 selective). 5-carboxamidotryptamine (5-HT1A/B/D) and sumatriptan (5-HT1D selective) were essentially inactive. 5-Hydroxytryptamine had no effect on contractile responses to exogenous acetylcholine, suggesting that 5-HT facilitates cholinergic bronchoconstriction via prejunctional receptors. In human bronchi, 5-HT also facilitated cholinergic bronchoconstriction, which was inhibited by ICS 205-930. The effects of the 5-HT3 antagonists and selective agonists in human and guinea pig airways suggests that these facilitatory effects are mediated by 5-HT3 receptors.
Takahashi
T
T
Department of Thoracic Medicine, National Heart and Lung Institute, London, United Kingdom.
Ward
J K
JK
Tadjkarimi
S
S
Yacoub
M H
MH
Barnes
P J
PJ
Belvisi
M G
MG
D000328:Adult; D000818:Animals; D001980:Bronchi / Q000294:innervation; D016084:Bronchoconstriction / Q000502:physiology*; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D018377:Neurotransmitter Agents / Q000502:physiology*; D011985:Receptors, Serotonin / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000502:physiology; D014132:Trachea / Q000294:innervation
D018377:Neurotransmitter Agents; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin