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Endothelium dependent expression and underlying mechanisms of des-Arg(9)-bradykinin-induced B(1)R-mediated vasoconstriction in rat portal vein

Item Type:Article
Title:Endothelium dependent expression and underlying mechanisms of des-Arg(9)-bradykinin-induced B(1)R-mediated vasoconstriction in rat portal vein
Creators Name:Basei, F.L. and Cabrini, D.A. and Figueiredo, C.P. and Forner, S. and Hara, D.B. and Nascimento, A.F.Z. and Ceravolo, G.S. and Carvalho, M.H.C. and Bader, M. and Medeiros, R. and Calixto, J.B.
Abstract:Endothelial dysfunction has been implicated in portal vein obstruction, a condition responsible for major complications in chronic portal hypertension. Increased vascular tone due to disruption of endothelial function has been associated with an imbalance in the equilibrium between endothelium-derived relaxing and contracting factors. Herein, we assessed underlying mechanisms by which expression of bradykinin B(1) receptor (B(1)R) is induced in the endothelium and how its stimulation triggers vasoconstriction in the rat portal vein. Prolonged in vitro incubation of portal vein resulted in time- and endothelium-dependent expression of B(1)R and cyclooxygenase-2 (COX-2). Inhibition of protein kinase C (PKC) or phosphatidylinositol 3-kinase (PI3K) significantly reduced expression of B(1)R through the regulation of transcription factors, activator protein-1 (AP-1) and cAMP response element-binding protein (CREB). Moreover, pharmacological studies showed that B(1)R-mediated portal vein contraction was reduced by COX-2, but not COX-1, inhibitors. Notably, activation of endothelial B(1)R increased phospholipase A(2)/COX-2-derived thromboxane A(2) (TXA(2)) levels, which in turn mediated portal vein contraction through binding to TXA(2) receptors expressed in vascular smooth muscle cells. These results provide novel molecular mechanisms involved in the regulation of B(1)R expression and identify a critical role for the endothelial B(1)R in the modulation of portal vein vascular tone. Our study suggests a potential role for B(1)R antagonists as therapeutic tools for diseases where portal hypertension may be involved.
Keywords:Bradykinin, Drug Dose-Response Relationship, Endothelium, Portal Vein, Bradykinin B1 Receptor, Structure-Activity Relationship, Vasoconstriction, Animals, Rats
Source:Peptides
ISSN:0196-9781
Publisher:Elsevier (U.S.A.)
Volume:37
Number:2
Page Range:216-224
Date:October 2012
Official Publication:https://doi.org/10.1016/j.peptides.2012.07.020
PubMed:View item in PubMed

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