title: Cytokines down-regulate alpha1-adrenergic receptor expression during endotoxemia.
abstract: OBJECTIVE
  The reduced pressure response to norepinephrine in septic patients has directed our interest to the regulation of alpha1-adrenergic receptors in vitro and in vivo during conditions mimicking acute sepsis.
  
  
  METHODS
  Prospective animal trial followed by a controlled cell culture study.
  
  
  METHODS
  Laboratory of the Department of Anesthesiology.
  
  
  METHODS
  Male Sprague-Dawley rats weighing 200 to 250 g and a mesangial cell line.
  
  
  METHODS
  Experimental endotoxemia was induced in rats with lipopolysaccharide, and blood pressure dose-response studies with norepinephrine were performed. Alpha1-receptor gene expression was determined in various organs by a specific RNase protection assay, and tissue concentrations of the proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha were measured. Rat renal mesangial cells were incubated with these cytokines or with nitric oxide donors to investigate the regulation of alpha1-adrenergic receptors during severe inflammation on a cellular level.
  
  
  RESULTS
  The pressor effect of norepinephrine was markedly diminished during endotoxemia. The animals showed down-regulated mRNA levels of alpha1A-, alpha1B- and alpha1D-receptors in all organs investigated, and the tissue concentrations of interleukin-1beta and tumor necrosis factor-alpha were highly increased during experimental endotoxemia. Incubation of cultured rat renal mesangial cells with the cytokines resulted in diminished alpha -receptor gene expression and [3H]prazosin binding capacity, whereas incubation of the cells with nitric oxide donors did not affect alpha1B-receptor expression. In line, blocking of cytokine-induced nitric oxide synthesis by coincubation of mesangial cells with N(G)-nitro-L-arginine methyl ester did not influence cytokine-induced down-regulation of alpha1B-receptors.
  
  
  CONCLUSIONS
  Our data show that endotoxemia causes a systemic down-regulation of alpha1-receptors on the level of gene expression and suggest that this effect is likely mediated by proinflammatory cytokines in a synergistic but nitric oxide-independent fashion. We propose that this down-regulation of alpha1-adrenergic receptors contributes to the attenuated blood pressure response to norepinephrine and, therefore, to septic circulatory failure in patients.
authors.affiliation: Department of Anesthesiology, University of Regensburg, Germany. michael.bucher@klinik.uni-regensburg.de
authors.forename: Michael
authors.initials: M
authors.lastname: Bucher
authors.forename: Frieder
authors.initials: F
authors.lastname: Kees
authors.forename: Kai
authors.initials: K
authors.lastname: Taeger
authors.forename: Armin
authors.initials: A
authors.lastname: Kurtz
mesh_terms: D000818:Animals; D016207:Cytokines / Q000502:physiology*; D015536:Down-Regulation; D019446:Endotoxemia / Q000276:immunology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000096:biosynthesis*
chemical_list: D016207:Cytokines; D011942:Receptors, Adrenergic, alpha