ObjectiveThe reduced pressure response to norepinephrine in septic patients has directed our interest to the regulation of &agr;1-adrenergic receptorsin vitroandin vivoduring conditions mimicking acute sepsis.DesignProspective animal trial followed by a controlled cell culture study.SettingLaboratory of the Department of Anesthesiology.SubjectsMale Sprague-Dawley rats weighing 200 to 250 g and a mesangial cell line.InterventionsExperimental endotoxemia was induced in rats with lipopolysaccharide, and blood pressure dose-response studies with norepinephrine were performed. &agr;1-Receptor gene expression was determined in various organs by a specific RNase protection assay, and tissue concentrations of the proinflammatory cytokines interleukin-1&bgr; and tumor necrosis factor-&agr; were measured. Rat renal mesangial cells were incubated with these cytokines or with nitric oxide donors to investigate the regulation of &agr;1-adrenergic receptors during severe inflammation on a cellular level.Measurements and Main ResultsThe pressor effect of norepinephrine was markedly diminished during endotoxemia. The animals showed down-regulated mRNA levels of &agr;1A-, &agr;1B- and &agr;1D-receptors in all organs investigated, and the tissue concentrations of interleukin-1&bgr; and tumor necrosis factor-&agr; were highly increased during experimental endotoxemia. Incubation of cultured rat renal mesangial cells with the cytokines resulted in diminished &agr;1B-receptor gene expression and [H]prazosin binding capacity, whereas incubation of the cells with nitric oxide donors did not affect &agr;1B-receptor expression. In line, blocking of cytokine-induced nitric oxide synthesis by coincubation of mesangial cells withNG-nitro-l-arginine methyl ester did not influence cytokine-induced down-regulation of &agr;1B-receptors.ConclusionsOur data show that endotoxemia causes a systemic down-regulation of &agr;1-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 &agr;1-adrenergic receptors contributes to the attenuated blood pressure response to norepinephrine and, therefore, to septic circulatory failure in patients.