Novel effects mediated by bradykinin and pharmacological characterization of bradykinin B-2 receptor antagonism in human synovial fibroblasts

作者：Bellucci F; Cucchi P; Catalani C; Giuliani S; Meini S^*; Maggi C A

来源：British Journal of Pharmacology, 2009, 158(8): 1996-2004.

DOI：10.1111/j.1476-5381.2009.00511.x

• MEN16132
• icatibant
• osteoarthritis
• knee
• synovium
• interleukin-6
• interleukin-8
• cyclooxygenase
• lipoxygenase

Background and purpose:
Bradykinin (BK) and B-2 receptors have been implicated in the pathophysiology of osteoarthritis (OA), and synovitis is one of its hallmarks. Here, the selective B-2 receptor antagonists MEN16132 and icatibant have been pharmacologically characterized in human synovial cells.
Experimental approach:
Radioligand and functional studies (inositol phosphate (IP) accumulation, interleukin (IL)-6 and IL-8 release) were performed in cultured synoviocytes.
Key results:
[3H]-BK saturation studies indicated receptor density (B-max) and K-d values of 121 550 sites per cell and 1.14 nM respectively. In synoviocytes, MEN16132 (pK(i) 8.9) was threefold more potent than icatibant (pK(i) 8.4). Both antagonists showed competitive antagonism in the BK-induced IP assay (control EC50 0.45 nM), with pK(B) values of 9.9 (MEN16132) and 8.1 (icatibant). 24h incubation with BK induced IL-6 (EC50 216 nM) and IL-8 (EC50 53 nM) release. Both MEN16132 (IL-6: pIC(50) 8.1; IL-8: pIC(50) 8.4) and icatibant (IL-6: pIC(50) 6.6; IL-8: pIC(50) 6.7) completely prevented this BK-induced release. Indomethacin did not affect the basal or the IL-6/IL-8 release induced by BK, whereas nordihydroguaiaretic acid decreased the basal release, although BK still increased IL-6 and IL-8 production. BK-induced IL-8 release was attenuated by inhibitors of phospholipase C (U73122), p38 (SB203580), JNK (SP600125), ERK 1/2 (PD98059) MAPKs, phosphoinositide 3-kinase (LY294002), NF-kappa b (BAY-117085) and by the glucocorticoid dexamethasone.
Conclusions and implications:
Bradykinin via B-2 receptors can participate in inflammatory events in synovitis. MEN16132 is a highly potent B-2 receptor antagonist capable of blocking pro-inflammatory responses to BK evoked in human synoviocytes.

• 出版日期2009-12