Cytokines Down-Regulate alpha1-adrenergic Receptor Expression During Endotoxemia

Crit Care Med. 2003 Feb;31(2):566-71. doi: 10.1097/01.CCM.0000048621.36569.69.

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.

Design: Prospective animal trial followed by a controlled cell culture study.

Setting: Laboratory of the Department of Anesthesiology.

Subjects: Male Sprague-Dawley rats weighing 200 to 250 g and a mesangial cell line.

Interventions: 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.

Measurements and main 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / physiology*
  • Down-Regulation*
  • Endotoxemia / immunology*
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha / biosynthesis*

Substances

  • Cytokines
  • Receptors, Adrenergic, alpha