5-HYDROXYTRYPTAMINE FACILITATES CHOLINERGIC BRONCHOCONSTRICTION IN HUMAN AND GUINEA-PIG AIRWAYS

5-hydroxytryptamine (5-HT) may not play a major role in controlling hu man airway smooth muscle tone, as it has little direct effect on airwa y caliber. However, its role as a neuromodulator has not been determin ed. We have identified a facilitatory effect of 5-HT on cholinergic ne urotransmission and characterized the 5-HT receptors involved in human and guinea pig trachea. In guinea pig trachea, 5-HT facilitated elect ric field stimulation-induced cholinergic bronchoconstriction in a con centration-dependent manner (EC(50) = 2.6 mu M). The 5-HT3/4 and 5-HT3 antagonists, ICS 205-930 and ondansetron, inhibited the effect of 5-H T competitively (pA(2) values of 7.3 and 7.1, respectively); methiothe pin (5-HT1/2C antagonist), ketanserin (5-HT2A antagonist), and GR 1138 08A (5-HT4 antagonist) had no effect. The rank order of potency of 5-H T agonists was 5-HT > 2-methyl-5-HT (5-HT2 selective) > 5-methoxytrypt amine (5-HT4 selective) > alpha-methyl-5-HT (5-HT2 selective). 5-carbo xamidotryptamine (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 facilitate s cholinergic bronchoconstriction via prejunctional receptors. In huma n bronchi, 5-HT also facilitated cholinergic bronchoconstriction, whic h was inhibited by ICS 205-930. The effects of the 5-HT3 antagonists a nd selective agonists in human and guinea pig airways suggests that th ese facilitatory effects are mediated by 5-HT3 receptors.