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Resistance to endotoxic shock in mice lacking natriuretic peptide receptor-A.

Abstract：

BACKGROUND AND PURPOSE:Excessive production of nitric oxide (NO) by inducible NO synthase (iNOS) is thought to underlie the vascular dysfunction, systemic hypotension and organ failure that characterize endotoxic shock. Plasma levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) are raised in animal models and humans with endotoxic shock and correlate with the associated cardiovascular dysfunction. Since both NO and natriuretic peptides play important roles in cardiovascular homeostasis via activation of guanylate cyclase-linked receptors, we used mice lacking natriuretic peptide receptor (NPR)-A (NPR1) to establish if natriuretic peptides contribute to the cardiovascular dysfunction present in endotoxic shock. EXPERIMENTAL APPROACH:Wild-type (WT) and NPR-A knockout (KO) mice were exposed to lipopolysaccharide (LPS) and vascular dysfunction (in vitro and in vivo), production of pro-inflammatory cytokines, and iNOS expression and activity were evaluated. KEY RESULTS:LPS-treated WT animals exhibited a marked fall in mean arterial blood pressure (MABP) whereas NPR-A KO mice maintained MABP throughout. LPS administration caused a greater suppression of vascular responses to the thromboxane-mimetic U46619, ANP, acetylcholine and the NO-donor spermine-NONOate in WT versus NPR-A KO mice. This differential effect on vascular function was paralleled by reduced pro-inflammatory cytokine production, iNOS expression and activity (plasma [NO(x)] and cyclic GMP). CONCLUSIONS AND IMPLICATIONS:These observations suggest that NPR-A activation by natriuretic peptides facilitates iNOS expression and contributes to the vascular dysfunction characteristic of endotoxic shock. Pharmacological interventions that target the natriuretic peptide system may represent a novel approach to treat this life-threatening condition.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Panayiotou CM,Baliga R,Stidwill R,Taylor V,Singer M,Hobbs AJ

doi

10.1111/j.1476-5381.2010.00830.x

subject

Has Abstract

pub_date

2010-08-01 00:00:00

pages

2045-54

issue

eissn

0007-1188

issn

1476-5381

pii

BPH830

journal_volume

160

pub_type

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Resistance to endotoxic shock in mice lacking natriuretic peptide receptor-A.