title: Further pharmacological evidence of nuclear factor-kappa B pathway involvement in bradykinin B1 receptor-sensitized responses in human umbilical vein.
abstract: 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-kappaB (NF-kappaB) activation. The aim of this study was to further evaluate the NF-kappaB pathway involvement on BK B(1) receptor sensitization in isolated HUV, using several pharmacological tools. In 5-h incubated rings, either the I-kappaB 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-beta1 (TGF-beta1) produced a rightward shift of the responses to des-Arg(9)-BK in our preparations. Taken together, these results point to NF-kappaB 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.
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Sergio Pablo
authors.initials: SP
authors.lastname: Sardi
authors.forename: Verónica
authors.initials: V
authors.lastname: Rey-Ares
authors.forename: Virginia Andrea
authors.initials: VA
authors.lastname: Pujol-Lereis
authors.forename: Santiago Alejo
authors.initials: SA
authors.lastname: Serrano
authors.forename: Rodolfo Pedro
authors.initials: RP
authors.lastname: Rothlin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007231:Infant, Newborn; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D016328:NF-kappa B / Q000502:physiology*; D009570:Nitriles; D009930:Organic Chemicals; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013450:Sulfones; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014471:Umbilical Veins / Q000187:drug effects / Q000502:physiology*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D015850:Interleukin-6; D007976:Leupeptins; D016328:NF-kappa B; D009570:Nitriles; D009930:Organic Chemicals; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin; D011994:Recombinant Proteins; D013450:Sulfones; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C024626:bradykinin, des-Arg(9)-; D015847:Interleukin-4; D012701:Serotonin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D001920:Bradykinin