title: Endothelium dependent expression and underlying mechanisms of des-Arg⁹-bradykinin-induced B₁R-mediated vasoconstriction in rat portal vein.
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.
authors.affiliation: Departamento de Farmacologia, Universidade Federal de Santa Catarina, Santa Catarina, Brazil.
authors.forename: Fernanda L
authors.initials: FL
authors.lastname: Basei
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Cabrini
authors.forename: Cláudia P
authors.initials: CP
authors.lastname: Figueiredo
authors.forename: Stefânia
authors.initials: S
authors.lastname: Forner
authors.forename: Daniela B
authors.initials: DB
authors.lastname: Hara
authors.forename: Andrey F Z
authors.initials: AF
authors.lastname: Nascimento
authors.forename: Graziela S
authors.initials: GS
authors.lastname: Ceravolo
authors.forename: Maria Helena C
authors.initials: MH
authors.lastname: Carvalho
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Medeiros
authors.forename: João B
authors.initials: JB
authors.lastname: Calixto
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000378:metabolism*; D008297:Male; D011169:Portal Vein / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1 / Q000096:biosynthesis / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D043783:Receptor, Bradykinin B1; D001920:Bradykinin