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Natriuretic peptides regulate sympathetic nervous activity independent of mineralocorticoid receptor


Natriuretic peptides (ANP/BNP) increase cGMP and exert cardiovascular protective effects via guanylyl cyclase A (GC-A) receptor, which is distributed in many organs such as the heart, the vasculature and the brain [1]. Sympathetic nervous system (SNS) as well as renin-angiotensin-aldosterone-system contributes to cardiovascular disease. However, the endogenous effect of GC-A signaling on SNS is not investigated. Recent study shows that activated mineralocorticoid receptor (MR) in the hypothalamus induces systemic SNS activation [2], whereas ANP infusion in human inhibited SNS activity in the heart [3]. Notably, it is reported that ANP counteracts the deleterious effects of MR in the heart [4]. Therefore, we hypothesized that ANP suppresses MR activation in the brain and leads to the inhibition of SNS activity.


To investigate whether ANP/GC-A signaling inhibits SNS activity through the suppression of the brain MR, we examined urinary catecholamine secretion in global GC-A receptor KO mice and the effect of intracerebroventricular (ICV) infusion of MR blocker.

Methods and results

We measured blood pressure (BP) and urinary norepinephrine (U-NE) secretion in wild type and global GC-A KO mice. Both BP and U-NE is significantly higher in GC-A KO than in wild type mice, indicating SNS is activated in GC-A KO mice. To study whether SNS activation is caused by the brain MR, we infused Eplerenone (MR blocker) into the ICV with osmotic mini pump for 2 weeks. Contrary to our hypothesis, both BP and U-NE did not change after 2 weeks ICV infusion, suggesting that activated SNS in GC-A KO is independent of MR. Furthermore, high sodium diet (NaCl 6%) for 2 weeks did not increase BP and U-NE in GC-A KO mice. MR protein expression in the hypothalamus was almost similar between GC-A KO and Wild type mice. These data suggest that SNS activity in GC-A KO mice is independent of MR and insensitive to sodium load. Unexpectedly, the most of GC-A KO mice died after ICV infusion of Losartan (AT1 receptor blocker), whereas wild type mice survived.


Natriuretic peptides/GC-A signaling regulates SNS activity independent of both brain MR and sodium load. Brain AT1 receptor might be important in the regulation of cardiovascular system in global GC-A KO mice.


  1. Kuhn M: Structure, regulation, and function of mammalian membrane guanylyl cyclase receptors, with a focus on guanylyl cyclase-A. Circ Res. 2003, 93 (8): 700-709. 10.1161/01.RES.0000094745.28948.4D.

    Article  CAS  PubMed  Google Scholar 

  2. Hamlyn JM, Blaustein MP: Salt sensitivity, endogenous ouabain and hypertension. Curr Opin Nephrol Hypertens. 2013, 22 (1): 51-58.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Kasama S, Toyama T, Kumakura H, Takayama Y, Ishikawa T, Ichikawa S, et al: Effects of intravenous atrial natriuretic peptide on cardiac sympathetic nerve activity in patients with decompensated congestive heart failure. J Nucl Med. 2004, 45 (7): 1108-1113.

    CAS  PubMed  Google Scholar 

  4. Nakagawa H, Oberwinkler H, Nikolaev VO, Gaßner B, Umbenhauer S, Wagner H, et al: Atrial natriuretic peptide locally counteracts the deleterious effects of cardiomyocyte mineralocorticoid receptor activation. Circ Heart Fail. 2014, 7 (5): 814-821. 10.1161/CIRCHEARTFAILURE.113.000885.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Hitoshi Nakagawa.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

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Nakagawa, H., Nakada, Y. & Saito, Y. Natriuretic peptides regulate sympathetic nervous activity independent of mineralocorticoid receptor. BMC Pharmacol Toxicol 16 (Suppl 1), A71 (2015).

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