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Enhanced aldosterone synthesis and insufficient activation of cyp2c9‐EET pathway in the brain play a pivotal role in salt‐induced sympathetic activation in mice with pressure overload
Author(s) -
Ito Koji,
Hirooka Yoshitaka,
Sunagawa Kenji
Publication year - 2012
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.26.1_supplement.137.2
Subject(s) - aldosterone , endocrinology , medicine , mineralocorticoid receptor , aldosterone synthase , chemistry , mineralocorticoid , excretion , blood pressure , renin–angiotensin system
Background Recently, we demonstrated that high‐salt (HS) intake augments sympathetic drive via brain mineralocorticoid receptor (MR) – epithelial Na channels (ENaCs) pathway activation in mice with pressure‐overload (PO‐mice). In the present study, we determined whether imbalance between aldosterone synthesis and activation of cyp2c9‐EET plays a pivotal role in sympathetic activation in this model. Methods and Results We performed aortic banding to create PO‐mice. Sham operation was performed as control (Sham‐mice). Four weeks after aortic banding, mice were fed with either a HS (8%) diet or a regular‐salt diet for additional 4 weeks. Urinary norepinephrine excretion, a marker of sympathetic activity was significantly increased by HS in PO‐mice, but not in Sham‐mice. The expressions of brain MR and the ratio of phosphorylated/total serum glucocorticoid inducible kinase‐1(sgk‐1), a marker of MR activity increased in PO‐mice. Furthermore, unlike in Sham‐mice, PO‐induced MR activation maintained despite HS loading. Intracerebroventricular (ICV) infusion of aldosterone synthesis inhibitor, FAD 286A (100 μg/kg/day, 4 weeks), decreased brain MR activity with the reduction of sympathetic drive. We also examined the cyp2C9 expression and 11,12‐epoxyeicosatrienoic acids (EET) concentration in the brain, a major pathway to inhibit ENaCs. HS increased cyp2c9 expression and 11,12‐EET concentration in the brain only in Sham‐mice, but not in PO‐mice. Conclusion In PO‐mice, HS increases sympathetic drive via the activation of brain MR‐ENaCs pathway through aldosterone‐dependent MR activation and insufficient activation of cyp2c9‐EET pathway.