Department of Pharmacology, Menarini Ricerche SpA, Florence, Italy.
Br J Pharmacol. 2009 Dec;158(8):1996-2004. doi: 10.1111/j.1476-5381.2009.00511.x.
Bradykinin (BK) and B2 receptors have been implicated in the pathophysiology of osteoarthritis (OA), and synovitis is one of its hallmarks. Here, the selective B2 receptor antagonists MEN16132 and icatibant have been pharmacologically characterized in human synovial cells.
Radioligand and functional studies (inositol phosphate (IP) accumulation, interleukin (IL)-6 and IL-8 release) were performed in cultured synoviocytes.
[3H]-BK saturation studies indicated receptor density (Bmax) 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: pIC50 8.1; IL-8: pIC50 8.4) and icatibant (IL-6: pIC50 6.6; IL-8: pIC50 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-kappaB (BAY-117085) and by the glucocorticoid dexamethasone.
Bradykinin via B2 receptors can participate in inflammatory events in synovitis. MEN16132 is a highly potent B2 receptor antagonist capable of blocking pro-inflammatory responses to BK evoked in human synoviocytes.
缓激肽（BK）和 B2 受体参与骨关节炎（OA）的病理生理学，滑膜炎是其特征之一。在这里，选择性 B2 受体拮抗剂 MEN16132 和 icatibant 已在人滑膜细胞中进行了药理学表征。
在培养的滑膜细胞中进行放射性配体和功能研究（三磷酸肌醇（IP）积累、白细胞介素（IL）-6 和 IL-8 释放）。
[3H]-BK 饱和研究表明，每个细胞的受体密度（Bmax）和 K(d) 值分别为 121,550 个位点和 1.14 nM。在滑膜细胞中，MEN16132（pK(I) 8.9）比 icatibant（pK(I) 8.4）强三倍。两种拮抗剂在 BK 诱导的 IP 测定中均表现出竞争性拮抗作用（对照 EC50 0.45 nM），pK(B) 值分别为 9.9（MEN16132）和 8.1（icatibant）。24 小时孵育 BK 诱导 IL-6（EC50 216 nM）和 IL-8（EC50 53 nM）释放。MEN16132（IL-6：pIC50 8.1；IL-8：pIC50 8.4）和 icatibant（IL-6：pIC50 6.6；IL-8：pIC50 6.7）均可完全阻止这种 BK 诱导的释放。吲哚美辛不影响 BK 诱导的基础或 IL-6/IL-8 释放，而 nordihydroguaiaretic acid 降低了基础释放，尽管 BK 仍增加了 IL-6 和 IL-8 的产生。BK 诱导的 IL-8 释放被磷脂酶 C（U73122）、p38（SB203580）、JNK（SP600125）、ERK 1/2（PD98059）MAPK、磷酸肌醇 3-激酶（LY294002）、NF-κB（BAY-117085）抑制剂和糖皮质激素地塞米松减弱。
缓激肽通过 B2 受体可参与滑膜炎中的炎症事件。MEN16132 是一种高活性 B2 受体拮抗剂，能够阻断人滑膜细胞中 BK 引起的促炎反应。
