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Vol. 301, Issue 3, 975-980, June 2002

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

Sergio Pablo Sardi1, Verónica Rey-Ares2, Virginia Andrea Pujol-Lereis, Santiago Alejo Serrano and Rodolfo Pedro Rothlin

Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina

Bradykinin (BK) B1 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 B1 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-kappa B (NF-kappa B) activation. The aim of this study was to further evaluate the NF-kappa B pathway involvement on BK B1 receptor sensitization in isolated HUV, using several pharmacological tools. In 5-h incubated rings, either the I-kappa B 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 B1 receptor-sensitized contractile responses. Furthermore, pro-inflammatory cytokine interleukin-6 (IL-6) produced a leftward shift of the concentration-response curve to the BK B1 receptor agonist, whereas anti-inflammatory cytokines interleukin-4 (IL-4) and tumor growth factor-beta 1 (TGF-beta 1) produced a rightward shift of the responses to des-Arg9-BK in our preparations. Taken together, these results point to NF-kappa B as a key intermediary in the activation of the expression of BK B1 receptor-sensitized responses in HUV and support the role of inflammatory mediators in the modulation of this process.

1 Current address: Department of Neuroscience, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston. MA. 02115.

2 Current address: Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077-Goettingen, Germany.

0022-3565/02/3013-0975$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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