Role of nuclear factor-κB-dependent induction of cytokines in the regulation of vasopressin V1A-receptors during cecal ligation and puncture-induced circulatory failure*

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Here we characterize the impact of nuclear factor-kappaB and cytokines on cecal ligation and puncture-induced circulatory failure and regulation of vasopressin V1A-receptors during inflammation. Prospective animal trial. Laboratory of the Department of Anesthesiology. Male C57/BL6 mice. The effects of cecal ligation and puncture on hemodynamic parameters and V1A-receptor expression were measured in cytokine knock-out mice, in mice with/without treatment with glucocorticoids or NF-kappaB-inhibitors, in mice pretreated with small interfering RNA silencing NF-kappaB and in mice treated with V1 receptor agonists. Furthermore, the effects of cytokines on V1A-receptor expression were determined. Cecal ligation and puncture resulted in a hyperdynamic circulatory failure with diminished blood pressor dose response to V1 receptor agonists and down-regulation of V1A-receptors. Dexamethasone inhibited proinflammatory cytokine production and attenuated cecal ligation and puncture-induced cardiovascular failure in parallel with attenuated down-regulation of V1A-receptor expression. Tumor necrosis factor-alpha, interleukin-1beta, interferon-gamma or interleukin-6 dose-dependently decreased V1A-receptor expression, whereas cecal ligation and puncture-induced down-regulation of V1A-receptors was not affected in cytokine knock-out mice. In contrast, inhibition of NF-kappaB strongly reduced induction of cytokines, prevented septic circulatory failure and down-regulation of V1A-receptor gene expression and improved survival of septic animals. Our data demonstrate that down-regulation of V1A-receptor expression during sepsis may be due to proinflammatory cytokines. Our findings explain the failure of therapeutic strategies targeting single cytokines as well as the success of glucocorticoid therapy and define a critical role for NF-kappaB in the pathogenesis of septic shock.