EFFECTS OF NZ-107 ON BRONCHOCONSTRICTION IN GUINEA-PIGS

The effect of 4-bromo-5-(3-ethoxy-4-methoxybenzylamino)-3(2H)-pyridazinone (NZ-107) on bronchoconstriction in guinea pigs was studied (1). The antigen-induced bronchoconstriction was studied in guinea pigs which had been passively sensitized by intravenous injection of antiserum containing anti-benzylpenicilloyl bovine-gamma-globulin IgE antibody. The sensitized guinea pigs were divided into two groups; one group was pretreated with metyrapone (11-beta-hydroxylase inhibitor in glucocorticoid metabolism) and the other with saline. The antigen-induced bronchoconstriction in the metyrapone-treated animals was more severe than that in the saline-treated animals. The asthmatic respiratory changes, in terms of prolongation of the ratio between expiration and inspiration, was also dramatically increased. NZ-107 at doses of 25 and 50 mg/kg significantly inhibited antigen-induced bronchoconstriction in both the saline- and metyrapone-treated animals. NZ-107 showed a tendency to Inhibit accelerated severe asthmatic respiration more strongly in metyrapone-treated animals than in those treated with saline. Salbutamol inhibited antigen-induced bronchoconstriction in saline-treated animals, but its efficacy decreased in metyrapone-treated animals. Unlike salbutamol, prednisolone and hydrocortisone showed the reverse effect, inhibiting bronchoconstriction in metyrapone- but not in saline-treated animals. Sodium cromoglycate inhibited antigen-induced bronchoconstriction in both saline- and metyrapone-treated animals (2). When a subthrehold dose of platelet-activating factor was injected into guinea pigs, airway responsiveness against histamine was clearly increased. NZ-107 at a dose of 0.2 mg/kg i.v. inhibited PAF-induced airway hyperreactivity. These data suggest that NZ-107 inhibited antigen-induced bronchoconstriction in guinea pigs pretreated with both saline and metyrapone, as well as platelet-activating factor induced airway hyperreactivity.