The actions of ketotifen on intestinal smooth muscles

Ketotifen is a tricyclic drug with a wide spectrum of pharmacological effects. We studied the actions of ketotifen on the mechanical activity of isolated segments of guinea-pig ileum, guinea-pig colon and mouse colon. In the guinea-pig ileum ketotifen induced small contractions and inhibited the contractions induced by carbachol and by electric field stimulation. Responses to bradykinin (in the absence or in the presence of atropine 1 mu M) were similarly inhibited by ketotifen, with an IC50 of 23 mu M. In the guinea-pig colon ketotifen evoked non-cholinergic contractions with a pD(2) of 4.5, but still it inhibited responses to bradykinin (IC50 = 75 mu M). Ketotifen relaxed the unstimulated mouse colon with a pD(2) of 4.2. This effect persisted in the presence of propranolol and phentolamine (each 10 mu M). Incubation of the mouse colon with the nitric oxide synthase inhibitors N-G-nitro-L-Arginine methyl ester hydrochloride (L-NAME), or L-N-G-nitro-arginine (L-NNA) (100-500 mu M) did not alter the inhibitory action of ketotifen. The histamine H-1 receptor antagonist chlorpheniramine (5 mu M) or the nerve blocker tetrodotoxin (1 mu M) did not alter the inhibitory effects of ketotifen. It is concluded that the actions of ketotifen are mediated by a non-cholinergic, non-histaminergic mechanisms.