CYPROHEPTADINE-INDUCED ATTENUATION OF TYPE-I IMMEDIATE-HYPERSENSITIVITY REACTIONS OF AIRWAY SMOOTH-MUSCLE FROM IMMUNE-SENSITIZED CATS

We assessed the effect of serotonergic inhibition by cyproheptadine on the responsiveness of tracheal smooth muscle (TSM) strips and epithel ium-intact third-generation bronchial rings from immune-sensitized (As caris suum) cats after exposure to antigen. Cats were sensitized by IM administration of antigen and adjuvant twice over a 4-week period. Se nsitization was confirmed in vivo by skin testing with antigen and by physiologic airway responses after exposure to nebulized antigen. Tiss ues were tethered isometrically to force transducers and were actively equilibrated by exposures to KCl-substituted perfusate. Maximal respo nse after exposure to antigen (expressed as percentage of maximal cont raction of each tissue to 63 mM KCl (%KCl) was 169 +/- 18% KCl for sen sitized TSM and 43 +/- 18% KCl for sensitized TSM pretreated with cypr oheptadine (P < 0.001). Similarly, maximal response to antigen was 81 +/- 27% KCl for sensitized bronchial rings, compared with 16 +/- 14% K Cl for sensitized bronchial rings pretreated with cyproheptadine (P = 0.05 vs control). Blockade of leukotriene synthesis by 10(-6) to 10(-4 )M A-64077, a selective 5-lipoxygenase inhibitor, had no significant e ffect on peak response for either TSM (193 +/- 13% KCl vs 169 +/- 18% KCl for sensitized untreated TSM) or bronchial rings (79 +/- 20% KCl v s 81 +/- 27% KCl for sensitized untreated bronchial rings). Release of serotonin from airway tissues was confirmed by the presence of seroto nin in the perfusate of 8 sensitized TSM preparations after, but not b efore, antigen challenge. Our data indicate that airways from immune-s ensitized cats have typical immediate-type hypersensitivity responses when exposed to antigen and that these responses are inhibited by sero tonin-receptor blockade, but not by blockade of 5-lipoxygenase. These data implicate serotonin as an important mediator in the immediate-typ e hypersensitivity reaction in the immune-sensitized airways of cats a nd suggest a potential role for serotonin antagonists in the clinical treatment of asthma in this species.