HISTAMINE H-2 RECEPTOR-MEDIATED AIRWAY GOBLET CELL SECRETION AND ITS MODULATION BY HISTAMINE-DEGRADING ENZYMES

Background: Airway goblet cell hypersecretion may contribute to the pa thophysiology of asthma. However, it is unknown whether histamine affe cts goblet cell secretion and, if so, which subtype of histamine recep tor is involved and whether endogenous histamine-degrading enzymes mod ulate these actions. Methods: We morphometrically assessed goblet cell secretion in the guinea pig trachea stained with alcian blue and peri odic acid Schiff stains by measuring the mucus score, which wash inver sely related to the degree of mucus glycoprotein discharge. Results: I nhalation of histamine caused a dose-dependent decrease in mucus score , an affect that was inhibited by pretreatment with the H-2-receptor a ntagonist cimetidine but not with the H-1-receptor antagonist mepyrami ne or the H-3-receptor antagonist thioperamide. Inhaled Dimaprit, a se lective H-2-receptor agonist, likewise decreased mucus score; whereas stimulation of H-1- and H-3-receptors with 2-methylhistamine and (R)-a lpha-methylhistamine, respectively, had no effect. Pretreatment with t he histamine N-methyltransferase inhibitor SKF 91488, but not the diam ine oxidase inhibitor aminoguanidine, potentiated the dose-dependent e ffect of histamine on goblet cell secretion, causing a decrease in the concentration of inhaled histamine required to produce a half-maximal effect from 0.80 +/- 0.12 to 0.48 +/- 0.09 mg/ml (p < 0.01). The hist amine methyltransferase activity in the tracheal mucosa was 29 times h igher than diamine oxidase activity. Conclusion: These findings sugges t that histamine stimulates airway goblet cell secretion through H-2-r eceptors and that this effect may be modulate principally by endogenou s histamine methyltransferase through a degradation of histamine.