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

Abstract

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.

• Authors: Fouad Fadel, Gwennan André-Grégoire, Basile Gravez, Brigitte Bauvois, Sandrine Bouchet, Catalina Sierra-Ramos, Andrea Polito, Arnaud Mansart, Diego Alvarez de la Rosa, Djillali Annane, Frédéric Jaisser
• Journal: Critical care medicine (Crit Care Med) Vol. 45 Issue 9 Pg. e954-e962 (Sep 2017) ISSN: 1530-0293 [Electronic] United States
• PMID: 28445239 (Publication Type: Journal Article)

Chemical References

• 3-(4-methylphenylsulfonyl)-2-propenenitrile
• Cytokines
• Endotoxins
• Inflammation Mediators
• Lipopolysaccharides
• NF-kappa B
• Nitriles
• Receptors, Mineralocorticoid
• Sulfones
• Aldosterone

Topics

• Aldosterone (pharmacology)
• Animals
• Blood Pressure
• Cytokines (pharmacology)
• Disease Models, Animal
• Down-Regulation
• Endotoxins
• Humans
• Inflammation Mediators (pharmacology)
• Lipopolysaccharides
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (antagonists & inhibitors)
• Nitriles (pharmacology)
• Receptors, Mineralocorticoid (biosynthesis)
• Shock, Septic (drug therapy, mortality, physiopathology)
• Sulfones (pharmacology)