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 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 mumol/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 mumol/L) or thioperamide (10 mumol/L) or phentolamine (10 mumol/L) did not prevent the inhibitory effect of ketotifen (10 mumol/L). Cetirizine (10 mumol/L), on the other hand, produced no inhibition of the noncholinergic contraction at all. Metitepine (0.1 mumol/L) and methysergide (1 mumol/L), both 5-HT1 antagonists, attenuated the inhibitory effect of ketotifen (10 mumol/L). Ketanserin (a 5-HT2 antagonist, 10 mumol/L) and tropisetron (a 5-HT3 antagonist, 1 mumol/L) had no effect. Ketoifen (100 mumol/L) did not affect the cumulative dose-response relationship to exogenous substance P (0.01 mumol/L to 10 mmol/L).(ABSTRACT TRUNCATED AT 250 WORDS)
Verleden
G M
GM
Laboratory of Pneumology, Catholic University Leuven, Belgium.
Pype
J L
JL
Demedts
M M
MM
D000320:Adrenergic Fibers / Q000187:drug effects; D000818:Animals; D002799:Cholinergic Fibers / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D006633:Histamine Antagonists; D066298:In Vitro Techniques; D007665:Ketotifen / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009469:Neuromuscular Junction / Q000187:drug effects*; D011955:Receptors, Drug / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects* / Q000294:innervation
D006633:Histamine Antagonists; D011955:Receptors, Drug; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D007665:Ketotifen