KETOTIFEN MODULATES NONCHOLINERGIC CONTRACTION IN GUINEA-PIG AIRWAYS IN-VITRO BY A PREJUNCTIONAL NONHISTAMINE RECEPTOR

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 n europeptides from airway sensory nerves. Ketotifen fumarate has been d emonstrated to inhibit the noncholinergic contraction in guinea pig ai rways in vitro, but no attempt has been made to identify the receptor type. Therefore we have performed an in vitro study to investigate whi ch receptor is responsible for the inhibitory effects of ketotifen on noncholinergic contraction in guinea pig airways. Ketotifen (3 to 100 mu mol/L) produced a concentration-dependent inhibition of the nonchol inergic contraction, with a maximum inhibition of 74% +/- 7% at 8 Hz s timulation (p < 0.001; n = 5). Pretreatment of the tissues with either cimetidine (10 mu mol/L) or thioperamide (10 mu mol/L) or phentolamin e (10 mu mol/L) did not prevent the inhibitory effect of ketotifen (10 mu mol/L). Cetirizine (10 mu mol/L), on the other hand, produced no i nhibition of the noncholinergic contraction at all. Metitepine (0.1 mu mol/L) and methysergide (1 mu mol/L) both 5-HT1 antagonists, attenuat ed the inhibitory effect of ketotifen (10 mu mol/L). Ketanserin (a 5-H T2 antagonist, 10 mu mol/L) and tropisetron (a 5-HT3 antagonist 1 mu m ol/L) had no effect Ketotifen (100 mu mol/L) did not affect the cumula tive dose-response relationship to exogenous substance P (0.01 mu mol/ L to 10 mmol/L). These results indicate that ketotifen may modulate th e release of neuropeptides from airway sensory nerves by a prejunction al mechanism, the exact receptor of which seems to be a nonhistamine r eceptor, probably a 5-HT1 receptor.