β 2-Adrenoceptor desensitization in cultured human airway smooth muscle

Abstract

1. The mechanisms underlying control of cyclic AMP responses to isoprenaline were studied in primary cultures of human airway smooth muscle cells. In these cells, isoprenaline induced concentration-related cyclic AMP formation via β2-adrenoceptor stimulation. 2. Prior incubation of cells with varying concentrations of isoprenaline (1–16 h), forskolin, prostaglandin E2 or a stable analogue of cyclic AMP all produced concentration-related desensitization of cyclic AMP responses to subsequent challenge with isoprenaline (maximum reduction with 1 μmol/l isoprenaline, 85% after 16 h). The desensitization induced over 2 h (44%) by a concentration of prostaglandin E2 which gave a similar rise in cyclic AMP levels to 1 μmol/l isoprenaline was significantly less (P < 0.05) than the desensitization (62%) induced over 2 h by 1 μmol/l isoprenaline itself. 3. Isoprenaline-induced desensitization of β2-adrenoceptor-induced cyclic AMP formation was insensitive to prior exposure of cells to dexamethasone. 4. These findings suggest that isoprenaline-induced desensitization of β2-adrenoceptor-induced cyclic AMP formation in primary cultures of human airway smooth muscle cells is mediated through both a cyclic AMP-dependent and probably an additional cyclic AMP-independent pathway, and that these pathways are insensitive to inhibition by glucocorticoids.