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Aldosterone and Vascular Mineralocorticoid Receptors in Murine Endotoxic and Human Septic Shock*

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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-κB 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 α1-adrenoceptor and mineralocorticoid receptor expressions studied in mouse aortas were down-regulated at 6 and 18 hours in endotoxemic mice and restored in aldosterone-treated mice. Furthermore, tumor necrosis factor-α decreased both mineralocorticoid receptor and α1-adrenoceptor expressions within 5 hours in human vascular cells in a nuclear factor-κB 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 α1-adrenoceptor expression in endotoxic shock. Furthermore, blunted vascular mineralocorticoid receptor expression might participate in hemodynamic failure during sepsis.
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Keywords: adrenoceptor; aldosterone; mineralocorticoid receptor; mineralocorticoids; sepsis

Document Type: Research Article

Publication date: September 1, 2017

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