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Endothelium dependent expression and underlying mechanisms of des-Arg⁹-bradykinin-induced B₁R-mediated vasoconstriction in rat portal vein.
- Source :
-
Peptides [Peptides] 2012 Oct; Vol. 37 (2), pp. 216-24. Date of Electronic Publication: 2012 Jul 31. - Publication Year :
- 2012
-
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.<br /> (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Bradykinin analogs & derivatives
Dose-Response Relationship, Drug
Male
Portal Vein metabolism
Rats
Rats, Wistar
Receptor, Bradykinin B1 biosynthesis
Structure-Activity Relationship
Bradykinin pharmacology
Endothelium metabolism
Portal Vein drug effects
Receptor, Bradykinin B1 metabolism
Vasoconstriction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1873-5169
- Volume :
- 37
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Peptides
- Publication Type :
- Academic Journal
- Accession number :
- 22868213
- Full Text :
- https://doi.org/10.1016/j.peptides.2012.07.020