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A genetically based GPCR‐mediated central molecular mechanism underlying the pathophysiology of salt‐sensitive hypertension
Author(s) -
Wainford Richard David,
Carmichael Casey Yumi,
Kuwabara Jill Toshiko
Publication year - 2013
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.27.1_supplement.955.8
Subject(s) - medicine , endocrinology , homeostasis , chemistry , downregulation and upregulation , sodium , blood pressure , endogeny , norepinephrine , biochemistry , gene , organic chemistry , dopamine
Aim We have demonstrated endogenous up‐regulation of hypothalamic paraventricular nucleus (PVN) Gαi 2 ‐proteins is required to suppress norepinephrine (NE) mediated sodium retention during high salt intake in the Sprague‐Dawley rat. In these studies we examined the role(s) of central Gαi 2 proteins in sodium homeostasis and blood pressure regulation following elevated dietary salt‐intake in Brown Norway (BN), Dahl salt‐resistant (DSR), Dahl salt‐sensitive (DSS) and DSSBN8 congenic rat strains. Methods BN, DSR, DSS or DSSBN8 rats were maintained on a normal (0.4% NaCl) or high (8% NaCl) diet for 21‐days Additional groups of DSR and DSS rats received a 21‐day i.c.v. infusion of a Gαi 2 targeted oligodeoxynucleotide during high salt‐intake. On day‐21 MAP, 24h metabolic balance, plasma NE and PVN Gαi 2 protein levels were determined (N=5/group). Results HS‐intake did not alter MAP, suppressed plasma NE (P<0.05), and evoked a site‐specific increase in PVN Gαi 2 protein levels in salt‐resistant BN and DSR (4.8 and 4.2‐fold respectively, P<0.05), but not hypertensive DSS, rats. Brain Gαi 2 protein downregulation evoked hypertension, sodium retention and elevated plasma NE content in DSR rats (P<0.05) and profoundly exacerbated DSS hypertension (P<0.05). In DSSBN8 rats BN chromosome 8 substitution attenuated hypertension, sodium retention and global sympathoexcitation vs. DSS rats (P<0.05) and restored PVN specific Gαi 2 protein up‐regulation. Conclusion PVN Gαi 2 protein‐gated pathways represent a genetically conserved central molecular mechanism that suppresses NE mediated renal sodium reabsorption to maintain a salt‐resistant phenotype. Owing to SNP's in the GNAI2 gene correlating with hypertension in human subjects our findings have translational implications for human hypertension ‐ HL107330.