Ketotifen modulates noncholinergic contraction in guinea pig airways in vitro by a prejunctional nonhistamine receptor

Abstract

In guinea pig airways, electrical field stimulation (50 V, 0.5 msec, 8 Hz for 20 seconds) produces a rapid contraction, which is followed by a long-lasting contraction, at least in the lower part of the trachea and in the bronchi. The latter contraction is due to the release of neuropeptides from airway sensory nerves. Ketotifen fumarate has been demonstrated to inhibit the noncholinergic contraction in guinea pig airways in vitro, but no attempt has been made to identify the receptor type. Therefore we have performed an in vitro study to investigate which receptor is responsible for the inhibitory effects of ketotifen on noncholinergic contraction in guinea pig airways. Ketotifen (3 to 100 μmol/L) produced a concentration-dependent inhibition of the noncholinergic contraction, with a maximum inhibition of 74% ± 7% at 8 Hz stimulation (p < 0.001; n = 5). Pretreatment of the tissues with either cimetidine (10 μmol/L) or thioperamide (10 μmol/L) or phentolamine (10 μmol/L) did not prevent the inhibitory effect of ketotifen (10 μmol/L). Cetirizine (10 μmol/L), on the other hand, produced no inhibition of the noncholinergic contraction at all. Metitepine (0.1 μmol/L) and methysergide (1 μmol/L), both 5-HT1 antagonists, attenuated the inhibitory effect of ketotifen (10 μmol/L). Ketanserin (a 5-HT2 antagonist, 10 μmol/L) and tropisetron (a 5-HT3 antagonist, 1 μmol/L) had no effect. Ketotifen (100 μmol/L) did not affect the cumulative dose-response relationship to exogenous substance P (0.01 μmol/L to 10 mmol/L). These results indicate that ketotifen may modulate the release of neuropeptides from airway sensory nerves by a prejunctional mechanism, the exact receptor of which seems to be a nonhistamine receptor, probably a 5-HT1 receptor. (J ALLERGYCLINIMMUNOL1994;94:207-14.)