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.