EPINASTINE (WAL 801CL) MODULATES THE NONCHOLINERGIC CONTRACTION IN GUINEA-PIG AIRWAYS IN-VITRO BY A PREJUNCTIONAL 5-HT1-LIKE RECEPTOR

Electrical field stimulation (EFS) of guinea-pig airways, in vitro, ev okes an excitatory nonadrenergic noncholinergic (eNANC) contraction me diated by release of tachykinins from sensory nerve endings. Epinastin e (WAL 801CL) is an antihistaminic drug with binding affinity at certa in other receptors, including alpha-adrenergic receptors and various s erotonin (5-HT) receptor subtypes, It is used in asthma treatment; how ever, its mechanism of action remains to be fully defined. We have inv estigated whether epinastine could modulate the eNANC contraction in g uinea-pig airways in vitro, and have tried to elucidate its receptor m echanism. Epinastine (0.1-100 mu M) produced a concentration-dependent inhibition of the noncholinergic contraction, with a maximum inhibiti on of 91+/-7% at 100 mu M. Pretreatment of the tissues with combined 5 -HT1/5-HT2 antagonists, methysergide (1 mu M) or methiothepin (0.1 mu M), significantly attenuated the inhibitory effect of epinastine on th e noncholinergic contraction. Pretreatment with tropisetron (1 mu M), a 5-HT3 antagonist, ketanserin (10 mu M), a 5-HT2 antagonist, thiopera mide (10 mu M), a histamine H-3 antagonist, or phentolamine (10 mu M), an alpha-adrenergic antagonist, however, had no effect, Chlorpheniram ine (10 mu M), another histamine H-1 receptor antagonist without signi ficant 5-HT receptor binding affinity, did not produce any inhibition of the eNANC contraction. Epinastine (100 mu M) did not displace the d ose-response curve to exogenously applied substance P (0.01-10 mu M). These results suggest that epinastine, although identified as a 5-HT a ntagonist, acts as a 5-HT1 agonist and that it inhibits the noncholine rgic contraction in guineapig airways through stimulation of a prejunc tional 5-HT1-like receptor, located to sensory nerves.