Endothelin-receptor gene-expression in rat endotoxemia

Objective: The reduced vascular response to endothelin-1 has focused interest onto the regulation of the endothelin-receptor subtypes ETA and ETB during severe sepsis. Design and setting: Prospective animal trial followed by a controlled cell culture study in the laboratory of the Department of Anesthesiology. Subjects: Male Sprague-Dawley rats weighing 200–250 g, aortic vascular smooth muscle cell line A7r5. Interventions: Rats were injected with lipopolysaccharide to induce severe experimental endotoxemia. ETA/ETB receptor gene expression was investigated by specific RNase protection assay, and abundance of tumor necrosis factor α was determined in the lung and kidney. Aortic vascular smooth muscle cells were incubated with the proinflammatory cytokines interleukin-1β, tumor necrosis factor α, and interferon γ or with the nitric oxide donor S-nitroso-N-acetylpenicillamine to investigate the regulation of ETA receptor gene expression during severe inflammation. Measurements and results: ETA/ETB receptor gene expression was markedly downregulated in the lung but was unchanged in the kidney during endotoxemia. ETA receptor gene expression was downregulated in aortic vascular smooth muscle cells by tumor necrosis factor α but not by interleukin 1β, interferon γ, or nitric oxide. In vivo there seems to be a correlation between the tissue concentration of tumor necrosis factor α and gene expression of ETA receptors in the lung and kidney. Conclusions: Our data show that sepsis causes downregulation of ETA receptors at the level of gene expression, and provide correlative evidence that this effect can be mediated by tumor necrosis factor α. This downregulation of ETA receptors possibly contributes to the attenuated vascular response to endothelin-1 in the pulmonary circulation.