Aim: We have demonstrated up-regulation of hypothalamic paraventricular nucleus (PVN) Gαi2-proteins is required to suppress norepinephrine (NE) mediated sodium retention during high salt intake in the Sprague-Dawley rat (1, 2). In these studies we examined the role(s) of PVN Gαi2 proteins in the pathophysiology of salt-sensitive hypertension in Brown Norway (BN), Dahl salt-resistant (DSR), Dahl salt-sensitive (DSS) and congenic DSSBN8 (3) rat strains. Methods: BN, DSR, DSS or DSSBN8 rats were maintained on a normal (NS-0.4% NaCl) or high (HS-8% NaCl) diet for 21-days. Additional groups of intact and bilateral renal denervated (RDNX) DSR and DSS rats received a 21-day i.c.v. infusion of a scrambled (S) or a Gαi2 targeted oligodeoxynucleotide during high salt-intake. MAP was continuously recorded by radiotelemetry. 24h sodium balance, plasma NE, Fractional excretion of sodium (FENa) and PVN Gαi2 protein levels were determined after 21-days on a NS or HS diet (N=8/group ± SEM). Results: HS-intake did not alter MAP, increased FENa and suppressed plasma NE in BN, DSR and S infused DSR rats (Δplasma NE [nmol/L]; BN -32±4, DSR -35±3, DSR S -33±5, P<0.05). HS-diet evoked a site-specific increase in PVN Gαi2 protein levels in salt-resistant BN, DSR and S infused DSR rats (4.8, 4.2 and 3.9-fold respectively, P<0.05) but not in hypertensive DSS rats. Oligodeoxynucleotide-mediated CNS Gαi2 protein down-regulation evoked hypertension (MAP [mmHg]; DSR S HS 98±4 vs. DSR Gαi2 HS 124±3, P<0.05), sodium retention and elevated plasma NE content (plasma NE [nmol/L]; DSR S HS 75±8 vs. DSR Gαi2 HS 108±7, P<0.05) in DSR rats and profoundly exacerbated DSS hypertension (MAP [mmHg]; DSS S HS 155±5 vs. DSR Gαi2 HS 178±5, P<0.05). RDNX prevented the development of hypertension (MAP [mmHg]; DSR Sham RDNX HS Gαi2 128±4 vs DSR RDNX HS Gαi2 97±4, P<0.05), sodium retention and sympathoexcitation in DSR rats and prevented the exacerbation of DSS hypertension. BN chromosome 8 substitution restored salt-induced PVN specific Gαi2 protein up-regulation (3.6-fold, P<0.05), attenuated the development of salt-sensitive hypertension (MAP [mmHg]; DSS HS 159±4 vs. DSSBN8 HS 138±3, P<0.05) and global sympathoexcitation (plasma NE [nmol/L]; DSS HS 98±6 vs. DSSBN8 HS 65±6, P<0.05) in DSSBN8 vs. DSS rats. Conclusion: Up-regulation of PVN Gαi2 protein-gated pathways represents a conserved central molecular mechanism that suppresses renal nerve-dependent NE mediated sodium reabsorption to maintain a salt-resistant phenotype. We speculate PVN Gαi2 protein-gated regulation of NE secretion influences renal NCC expression (4) to maintain salt-resistance. SNP’s in the GNAI2 gene correlate with human hypertension (5) suggesting the translational potential of our mechanistic studies.