REGULATION OF HISTAMINE H-1 RECEPTOR COUPLING BY DEXAMETHASONE IN HUMAN CULTURED AIRWAY SMOOTH-MUSCLE

1 The regulation of histamine-induced [H-3]-inositol phosphate and int racellular calcium responses in human cultured airway smooth muscle ce lls was studied.2 Histamine induced concentration-dependent [H-3]-inos itol phosphate formation (EC(50) 4 mu M). This response was inhibited by a range of selective H-1 receptor antagonists but not by the H-2-se lective antagonist, tiotidone or the H-3 receptor-selective antagonist , thioperamide, indicating that an H-1 receptor is involved in this re sponse in human cultured airway smooth muscle cells. 3 Preincubation o f human cultured airway smooth muscle cells with concentrations of dex amethasone >10 nM for 22 h produced concentration-dependent inhibition of histamine-induced inositol phosphate formation. The maximum inhibi tion observed was 45% of the response in control cells. The inhibitory effect of dexamethasone was itself reversed by prior exposure to the glucocorticoid receptor antagonist, RU38486 (10 mu M). Preincubation f or 22 h with 1 mu M dexamethasone produced inhibition of the inositol phosphate response to histamine at all concentrations of histamine ind ucing significant inositol phosphate formation in these cells. In cont rast, the response to the G protein activator, NaF (0.1-20 mM) was una ltered by preincubation with dexamethasone. 4 Preincubation of human a irway smooth muscle cells with 1 mu M dexamethasone for time periods o f <6 h failed to inhibit histamine-induced inositol phosphate formatio n in human airway smooth muscle cells. 5 Histamine also induced concen tration-dependent elevation of intracellular calcium levels in Fura 2- loaded human airway smooth muscle cells. This response was inhibited b y preincubation with 1 mu M dexamethasone. 6 We conclude that signal t ransduction through the H-1 receptor in human airway smooth muscle is subject to regulation by dexamethasone and that this may in part accou nt for the protective effect of dexamethasone against spasmogen-induce d contractile responses in the airways.