Beta 2-adrenoceptor desensitization in cultured human airway smooth muscle.
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 beta 2-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 mumol/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 mumol/l isoprenaline was significantly less (P < 0.05) than the desensitization (62%) induced over 2 h by 1 mumol/l isoprenaline itself. 3. Isoprenaline-induced desensitization of beta 2-adrenoceptor-induced cyclic AMP formation was insensitive to prior exposure of cells to dexamethasone. 4. These findings suggest that isoprenaline-induced desensitization of beta 2-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.
Hall
I P
IP
Department of Therapeutics, University Hospital, Queen's Medical Centre, Nottingham, U.K.
Daykin
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K
Widdop
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D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013997:Time Factors
D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D003907:Dexamethasone; D000242:Cyclic AMP; D015232:Dinoprostone; D007545:Isoproterenol