Abstract 106: Hypothalamic PVN GαI2 Protein-mediated Renal Nerve Dependent Sympathoinhibition Facilitates Suppression of NCC Activity and a Salt-resistant Phenotype

Abstract

Aim: We hypothesize hypothalamic paraventricular (PVN) specific Gαi2 proteins, which are up-regulated in the PVN during increased sodium intake, mediate global and renal sympathoinhibition to facilitate suppression of the activity of the sodium chloride cotransporter (NCC) and salt-resistance in the Sprague Dawley rat. Methods: Groups of intact or bilateral renal denervated (RDNX) salt-resistant Sprague-Dawley rats received a bilateral PVN infusion of a scrambled (SCR) or Gαi2 oligodeoxynucleotide (ODN-300ng/side/day) and a normal 0.4% (NS) or high 8% NaCl (HS) diet for 7-days. On day-7 24h Na+ balance was assessed - in sub-groups MAP, plasma norepinephrine (NE) content, kidney NE content and NCC activity (peak natriuresis to iv bolus hydrochlorothiazide (HCTZ)) was assessed (N=6/gp/study). Results: In SCR ODN infused rats HS-intake evoked a significant 3-fold site-specific increase in PVN Gαi2 proteins and suppressed plasma NE content (plasma NE [nmol/L] SCR NS 72±4 vs HS 40±5, P<0.05), endogenous kidney NE content (NE [pg/m] SCR NS 586±36 vs HS 496±41, P<0.05) and NCC activity (peak ΔUNaV to HCTZ [μeq/min] SCR NS 10.6±0.8 vs HS 7±1, P<0.05) without impacting sodium homeostasis or MAP. ODN-mediated PVN Gαi2 down-regulation caused renal nerve-dependent hypertension (MAP [mmHg] Gαi2 NS 126±2, Gαi2 HS 147±2, Gαi2 HS + RDNX 131±3 P<0.05) sodium retention (24h Na+ balance [meq] Gαi2 NS 0.6±0.3, Gαi2 HS 2.3±0.4, Gαi2 HS + RDNX 0.8±0.3 P<0.05), global and renal sympathoexcitation (plasma NE [nmol/L] Gαi2 NS 67±7, Gαi2 HS 105±11, Gαi2 HS + RDNX 74±6 P<0.05; kidney NE content [pg/mg] Gαi2 NS 614±48 vs HS 823±59, P<0.05) and a failure to suppress NCC activity (peak ΔUNaV to HCTZ [μeq/min] Gαi2 NS 10.2±2, Gαi2 HS 14.7±2, Gαi2 HS + RDNX 7.6±2, P<0.05). Conclusion: PVN Gαi2 protein-gated pathways represent a sodium sensitive CNS mechanism acting to regulate renal nerve-dependent sodium excretion via, in part, actions upon the activity of the NCC. Based on recent studies by other groups we speculate the regulation of NCC in this setting is mediated by the actions of NE released from efferent renal nerves on renal adrenoceptors to impact the signal transduction network that regulates NCC expression.