neurokinin-a and azelastine

The influence of epithelial removal on the antihistaminic activity of azelastine in the guinea-pig isolated cervical trachea and main bronchus was examined. In both preparations with an intact epithelium, histamine produced a concentration-dependent contraction, but its potency (pD2) and contractility (Emax) were significantly higher in the main bronchus than in the cervical trachea. Epithelial removal from these preparations significantly increased the pD2 values in both tracheal and bronchial preparation, while the Emax value was significantly increased only in the cervical trachea. When these preparations were pretreated with azelastine (20 or 200 nM), concentration-response curves for histamine shifted downward, but were not influenced by the presence of an intact epithelium. Neither concentration of azelastine significantly modified the contractile responsiveness of tracheal and bronchial preparations to carbachol or neurokinin A. These results indicate that azelastine selectively antagonizes the histamine-induced contraction of the guinea-pig airway smooth muscles with or without an intact epithelium.

Topics: Animals; Bronchi; Carbachol; Epithelium; Guinea Pigs; Histamine; Histamine H1 Antagonists; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth; Neurokinin A; Phthalazines; Trachea

Recently, mast cell stabilizers, so called antiallergic drugs, that also have blocking effects on receptors for chemical mediators (CM) have been developed. The present study investigated the effects of a new antiallergic drug, epinastine (3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazol [1,5-a]azepine hydrochloride, WAL 810 CL; CAS 80012-43-7) on the in vivo bronchoconstriction (BC) induced by several CM as compared with those of other antiallergic drugs such as ketotifen, azelastine and oxatomide. Male Hartley guinea pigs were used. The BC was measured with a modified Konzett-Rössler method and expressed as a change in ventilation overflow (VO) under anesthesia. Antiallergic drugs were given orally 1 h before i.v. administration of CM. I.v. administrations of histamine (His), U-46619 (thromboxane A2 mimetic), leukotriene D4 (LTD4), prostaglandin D2 (PGD2), substance P (SP), neurokinin A (NKA), bradykinin (BK) and endothelin-1 (ET-1) increased VO in a dose dependent manner. The potency was as follows; ET-1 greater than LTD4 greater than NKA much greater than U-46619 greater than SP greater than His greater than BK much greater than PGD2. All the antiallergic drugs used markedly inhibited the His-induced BC. Epinastine, ketotifen and azelastine also significantly inhibited the BK-induced BC; epinastine had the strongest anti-BK effect among them. On the other hand, the four antiallergic drugs did not inhibit the BC induced by the other CM except for His and BK. Based on the above results, it is suggested that epinastine possesses anti-His and BK effects, and therefore could be promising as a new antiallergic drug without sedative effect.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bradykinin; Bronchoconstriction; Dibenzazepines; Guinea Pigs; Histamine; Histamine H1 Antagonists; Imidazoles; Ketotifen; Male; Neurokinin A; Phthalazines; Piperazines; Prostaglandin D2; Prostaglandin Endoperoxides, Synthetic; SRS-A; Substance P