Journal
CRITICAL CARE MEDICINE
Volume 45, Issue 9, Pages E954-E962Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CCM.0000000000002462
Keywords
adrenoceptor; aldosterone; mineralocorticoids; mineralocorticoid receptor; sepsis
Categories
Funding
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Centre de Recherche Industrielle et Technique (CRIT)
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Objectives: Vascular mineralocorticoid receptors play a role in vascular tone and blood pressure regulation, might participate in the pathophysiology of circulatory failure during sepsis, and represent a potential therapeutic target in this disease. We aimed to study the effects of mineralocorticoids and the involvement of vascular mineralocorticoid receptors in murine endotoxic and human septic shock. Design: Experimental study. Setting: Translational investigation including animal research and in vitro experiments using human vascular cells and plasma from septic patients. Subjects: Adult male C57Black 6 mice, adult patients with septic shock. Interventions: Mice were injected with lipopolysaccharide and/or aldosterone. Human endothelial and smooth muscle cells were treated with pro-inflammatory cytokines with or without aldosterone, nuclear factor-kappa B inhibitor BAY 11-7082, or plasma from septic patients. Measurements and Main Results: Aldosterone improved 5-day survival, invasive arterial pressure, and in vivo and ex vivo arterial response to phenylephrine at 18 hours after induction of murine endotoxic shock. Both alpha 1-adrenoceptor and mineralocorticoid receptor expressions studied in mouse aortas were down-regulated at 6 and 18 hours in endotoxemic mice and restored in aldosteronetreated mice. Furthermore, tumor necrosis factor-a decreased both mineralocorticoid receptor and alpha 1-adrenoceptor expressions within 5 hours in human vascular cells in a nuclear factor-kappa B pathway-dependent manner. Mineralocorticoid receptor expression was also blunted in human cells treated with plasma from septic patients. Conclusion: We found a beneficial effect of mineralocorticoids on survival, blood pressure, and vascular reactivity, associated with a restoration of alpha 1-adrenoceptor expression in endotoxic shock. Furthermore, blunted vascular mineralocorticoid receptor expression might participate in hemodynamic failure during sepsis.
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