Further Pharmacological Evidence of Nuclear Factor-κB Pathway Involvement in Bradykinin B1 Receptor-Sensitized Responses in Human Umbilical Vein

Bradykinin (BK) B 1 receptors are thought to exert a pivotal role in maintaining and modulating inflammatory processes. They are not normally present under physiological situations but are induced under physiopathological conditions. In isolated human umbilical vein (HUV), a spontaneous BK B 1 receptor up-regulation and sensitization process has been demonstrated. Based on pyrrolidine-dithiocarbamate inhibition, it has been proposed that this phenomenon is dependent on nuclear factor-κB (NF-κB) activation. The aim of this study was to further evaluate the NF-κB pathway involvement on BK B 1 receptor sensitization in isolated HUV, using several pharmacological tools. In 5-h incubated rings, either the I-κB kinase inhibitor 3-(4-methylphenylsulfonyl)-2-propenenitrile (Bay 11–7082) or the proteasome activity inhibitor Z-Leu-Leu-Leu-CHO (MG-132) inhibited the development of the BK B 1 receptor-sensitized contractile responses. Furthermore, pro-inflammatory cytokine interleukin-6 (IL-6) produced a leftward shift of the concentration-response curve to the BK B 1 receptor agonist, whereas anti-inflammatory cytokines interleukin-4 (IL-4) and tumor growth factor-β1 (TGF-β1) produced a rightward shift of the responses to des-Arg 9 -BK in our preparations. Taken together, these results point to NF-κB as a key intermediary in the activation of the expression of BK B 1 receptor-sensitized responses in HUV and support the role of inflammatory mediators in the modulation of this process.