Electrical field stimulation (EFS) of guinea-pig airways, in vitro, evokes an excitatory nonadrenergic noncholinergic (eNANC) contraction mediated by release of tachykinins from sensory nerve endings. Epinastine (WAL 801CL) is an anti- histaminic drug with binding affinity at certain other receptors, including α-adren- ergic receptors and various serotonin (5-HT) receptor subtypes. It is used in asthma treatment; however, its mechanism of action remains to be fully defined. We have investigated whether epinastine could modulate the eNANC contraction in guinea-pig airways in vitro, and have tried to elucidate its receptor mechanism. Epinastine (0.1-100 µM) produced a concentration-dependent inhibition of the noncholinergic contraction, with a maximum inhibition of 91±7% at 100 µM. Pretreatment of the tissues with combined 5-HT1/5-HT2 antagonists, methysergide (1 µM) or methiothepin (0.1 µM), significantly attenuated the inhibitory effect of epinastine on the noncholinergic contraction. Pretreatment with tropisetron (1 µM), a 5-HT3 antagonist, ketanserin (10 µM), a 5-HT2 antagonist, thioperamide (10 µM), a histamine H3 antagonist, or phentolamine (10 µM), an α-adrenergic antagonist, however, had no effect. Chlorpheniramine (10 µM), another histamine H1 receptor antagonist without significant 5-HT receptor binding affinity, did not produce any inhibition of the eNANC contraction. Epinastine (100 µM) did not displace the dose- response curve to exogenously applied substance P (0.01-10 µM). These results suggest that epinastine, although identified as a 5-HT antagonist, acts as a 5-HT1 agonist and that it inhibits the noncholinergic contraction in guinea- pig airways through stimulation of a prejunctional 5-HT1-like receptor, located to sensory nerves.