Cytokines down-regulate α1-adrenergic receptor expression during endotoxemia

Objective: The reduced pressure response to norepinephrine in septic patients has directed our interest to the regulation of alpha(1)-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. alpha(1)-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 alpha(1)-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 alpha(1A)-, alpha(1B)- and alpha(1D)-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(1B)-receptor gene expression and [H-3]prazosin binding capacity, whereas incubation of the cells with nitric oxide donors did not affect alpha(1B)-receptor expression. In line, blocking of cytokine-induced nitric oxide synthesis by coincubation of mesangial cells with N-6-nitro-L-arginine methyl ester did not influence cytokine-induced down-regulation of alpha(1B)-receptors. Conclusions: Our data show that endotoxemia causes a systemic down-regulation of alpha(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 alpha(1)-adrenergic receptors contributes to the attenuated blood pressure response to norepinephrine and, therefore, to septic circulatory failure in patients.