Impaired cAMP production in human airway smooth muscle cells by bradykinin: role of cyclooxygenase products.
Interleukin (IL)-1beta impairs human airway smooth muscle (ASM) cell cAMP responses to isoproterenol (Iso). We investigated if bradykinin (BK) could cause a similar effect and the role of cyclooxygenase (COX) products in this event, since we have recently reported that BK, like IL-1beta, also causes COX-2 induction and prostanoid release in human ASM cells. BK pretreatment significantly attenuated Iso-induced cAMP generation in a time- and concentration-dependent manner. cAMP generation by prostaglandin (PG) E2 but not by forskolin was also impaired. The COX inhibitor indomethacin completely prevented the impairment, whereas the selective COX-2 inhibitors NS-398 and nimesulide, protein synthesis inhibitors cycloheximide and actinomycin D, and steroid dexamethasone were all partially effective. The impairment was mimicked by the B2 agonist [Tyr(Me)8]BK, the Ca2+ ionophore A-23187, and PGE2 and prevented by the B2 antagonist HOE-140, but anti-IL-1beta serum was ineffective. The results indicate that BK impairs human ASM cell responses to Iso, and the effect is largely mediated by B2 receptor-related COX product release via both COX isoforms and is independent of IL-1beta.
Division of Respiratory Medicine, City Hospital, University of Nottingham, Nottingham NG5 1PB, United Kingdom.
L
L
Pang
E
E
Holland
A J
AJ
Knox
D000328:Adult; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis*; D003513:Cycloheximide / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000819:agonists; D013449:Sulfonamides / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000378:metabolism*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D013449:Sulfonamides; C114203:bradykinin, Tyr(Me)8-; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D003609:Dactinomycin; D000001:Calcimycin; D003907:Dexamethasone; D003513:Cycloheximide; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007545:Isoproterenol; D001920:Bradykinin; C012655:nimesulide; D007213:Indomethacin