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NPR-A gene deletion reverses vascular dysfunction associated with sepsis
© Panayiotou and Hobbs; licensee BioMed Central Ltd. 2007
Published: 25 July 2007
Natriuretic peptides are a family of hormone/paracrine factors that play important roles in cardiovascular homeostasis. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), produced in the heart, bind to the particulate quanylate cyclase (pGC) linked natriuretic peptide receptor A (NPR-A) and generate the intracellular messenger cyclic guanosine 3',5'-monophosphate (cGMP). Via this receptor, ANP/BNP cause vasodilatation and natriuresis, and are important in the regulation of blood pressure; mice lacking NPR-A exhibit hypertension and cardiac hypertrophy . Since many cardiovascular disorders, including atherosclerosis and septic shock, are now accepted as inflammatory diseases of the vessel wall, elucidating potential roles for natriuretic peptides in regulating vascular inflammation could assist in the prevention and treatment of cardiovascular disease.
Materials and methods
Male NPR-A knockout (KO) or wild type (WT; C57BL6) mice (25–30 g) were treated with 12.5 mg/kg i.v. Salmonella typhimurium lipopolysaccharide (LPS) or vehicle. After 16 h tissues (lung, aorta) were snap frozen and analysed for iNOS expression by western blot; plasma NOx was measured by chemiluminescence. Endothelial and vascular (dys)function were assessed in isolated aortic rings using organ bath pharmacology. Vessels were pre-contracted with an ~EC80 concentration of U46619 and concentration-response curves constructed to spermine NONOate (SPER-NO; 10-9–10-4 M), ANP (10-11–10-6 M), and acetylcholine (ACh; 10-9–10-5 M).
Deletion of NPR-A in vivo results in reduced iNOS expression and vascular dysfunction associated with endotoxaemia. These data suggest that NPR-A activation (by ANP and/or BNP) can function as a pro-inflammatory mechanism that might assist in facilitating host defence in response to infection.
This work was supported by The Wellcome Trust.
This article is published under license to BioMed Central Ltd.