Impaired cAMP production in human airway smooth muscle cells by bradykinin: role of cyclooxygenase products

Interleukin (IL)-1 beta 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-1 beta, 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) E-2 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 B-2 agonist [Tyr(Me)(8)]BK, the Ca2+ ionophore A-23187, and PGE(2) and prevented by the BS antagonist HOE-140, but anti-IL-1 beta serum was ineffective. The results indicate that BK impairs human ASM cell responses to Iso, and the effect is largely mediated by B-2 receptor-related COX product release via both COX isoforms and is independent of IL-1 beta.