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Resistance to endotoxic shock in mice lacking natriuretic peptide receptor‐A
Author(s) -
Panayiotou Catherine Maria,
Stidwill Raymond,
Taylor Valerie,
Singer Mervyn,
Hobbs Adrian J.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1129.15
Subject(s) - septic shock , medicine , natriuretic peptide , endocrinology , lipopolysaccharide , receptor , homeostasis , pharmacology , chemistry , biology , sepsis , heart failure
Natriuretic peptides (NP) play key roles in cardiovascular homeostasis via guanylyl cyclase‐linked NP receptors (NPR). Plasma NP levels are increased in patients with septic (endotoxic) shock and correlate with the cardiac dysfunction observed. Yet, a definitive role for NP in the pathogenesis of septic shock has not been established. NO production by inducible NO synthase (iNOS) occurs in response to infection and aberrant regulation of iNOS underlies several cardiovascular disorders. Herein, we have used NPR‐A knockout (KO) mice to investigate a potential role for NP in regulating iNOS expression/activity and (cardio)vascular dysfunction during endotoxic shock. In vivo lipopolysaccharide (LPS) administration caused a greater suppression of responses to U46619 , ANP, ACh and SPER‐NO in aortae from WT versus NPR‐A KO mice. This differential vascular function was paralleled by reduced iNOS expression (lung: −38.5±6.3%*, aorta: −80.3±10.2%*; * P <0.05 v WT) and activity (plasma [NO x ]: WT 597.7±35.0 μM, NPR‐A KO 387.2±22.4* μM). In accord, LPS‐induced hypotension was enhanced in WT versus NPR‐A KO mice (δ max MABP: WT − 29.7±3.8 mmHg, KO −10.5±6.3 mmHg*). Thus, NPR‐A activation is an important determinant of iNOS expression and (cardio)vascular dysfunction during endotoxic shock and the NP system may represent a novel target in the treatment of this life‐threatening condition. Supported by the Wellcome Trust