Cytokines down-regulate α1-adrenergic receptor expression during endotoxemia

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Abstract
The reduced pressure response to norepinephrine in septic patients has directed our interest to the regulation of α1-adrenergic receptors in vitro and in vivo during conditions mimicking acute sepsis. Prospective animal trial followed by a controlled cell culture study. Laboratory of the Department of Anesthesiology. Male Sprague-Dawley rats weighing 200 to 250 g and a mesangial cell line. Experimental endotoxemia was induced in rats with lipopolysaccharide, and blood pressure dose-response studies with norepinephrine were performed. α1-Receptor gene expression was determined in various organs by a specific RNase protection assay, and tissue concentrations of the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α were measured. Rat renal mesangial cells were incubated with these cytokines or with nitric oxide donors to investigate the regulation of α1-adrenergic receptors during severe inflammation on a cellular level. The pressor effect of norepinephrine was markedly diminished during endotoxemia. The animals showed down-regulated mRNA levels of α1A-, α1B- and α1D-receptors in all organs investigated, and the tissue concentrations of interleukin-1β and tumor necrosis factor-α were highly increased during experimental endotoxemia. Incubation of cultured rat renal mesangial cells with the cytokines resulted in diminished α1B-receptor gene expression and [H]prazosin binding capacity, whereas incubation of the cells with nitric oxide donors did not affect α1B-receptor expression. In line, blocking of cytokine-induced nitric oxide synthesis by coincubation of mesangial cells with NG-nitro-l-arginine methyl ester did not influence cytokine-induced down-regulation of α1B-receptors. Our data show that endotoxemia causes a systemic down-regulation of α1-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 α1-adrenergic receptors contributes to the attenuated blood pressure response to norepinephrine and, therefore, to septic circulatory failure in patients.