Further pharmacological evidence of nuclear factor-kappa B 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-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.
Sardi
Sergio Pablo
SP
Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
Rey-Ares
Verónica
V
Pujol-Lereis
Virginia Andrea
VA
Serrano
Santiago Alejo
SA
Rothlin
Rodolfo Pedro
RP
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*
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