Abstract 075: Impaired Hypothalamic PVN G-alpha i 2 Signal Transduction Attenuates Endogenous Sympathoinhibitory PVN GABAergic Tone to Evoke the Development of Salt-sensitive Hypertension

Abstract

Aim: We hypothesize hypothalamic PVN Gαi 2 proteins, which are up regulated during high salt intake, facilitate sympathoinhibition and blood pressure regulation via mediating GABA B receptor signal transduction to maintain salt-resistance in the Sprague Dawley (SD) rat. Methods: Groups of male salt-resistant SD rats received a bilateral PVN infusion of a scrambled (SCR) or Gαi 2 oligodeoxynucleotide (ODN-300ng/side/day) and a normal 0.6% (NS) or high 4% NaCl (HS) diet for 7-days. On day-7 24h Na + balance was assessed - in sub-groups MAP, plasma norepinephrine (NE) content, PVN GAD67 [marker of GABAergic expression] and vGLUT2 [marker of glutamatergic expression] immunoreactivity, and the cardiovascular responses to bilateral administration of the GABA B receptor antagonist (CGP52432; 3nmol/side) and the ionotropic glutamate receptor antagonist (kynurenate; 1.4 μg/side) was assessed (N=4/gp/study). Results: In control SCR ODN PVN infused SD rats HS intake suppressed plasma NE (plasma NE [nmol/L] SCR NS 76±7 vs HS 43±6, P<0.05) and evoked increased GAD67, but not vGLUT2, immunoreactivity (Medial Parvocellluar (MP) GAD67 [relative fold change (normalized to DAPI) 8.4±1.1) in all PVN parvocellular sub-regions without impacting MAP or sodium balance. Following ODN-mediated PVN Gαi 2 down-regulation HS intake caused salt-sensitive hypertension (MAP [mmHg] Gαi 2 ODN NS 128±3, HS 148±4, P<0.05), failed to increase GAD67 expression and increased PVN vGLUT2 immunoreactivity in multiple PVN parvocellular sub-regions (MP vGLUT2 [relative fold change (normalized to DAPI) 3.2±0.8). In separate groups of rats bilateral PVN GABA B antagonism increased MAP in control SCR but not Gαi 2 ODN infused rats maintained on a HS intake (peak ΔMAP [mmHg] SCR ODN HS +17±3, Gαi 2 ODN HS +2±2). In contrast, bilateral PVN glutamate antagonism did not alter MAP in control SCR ODN infused rats but decreased MAP in hypertensive Gαi 2 ODN infused SD rats on a HS intake (peak ΔMAP [mmHg] SCR HS +3±3, Gαi 2 ODN HS -13±2). Conclusion: These data suggest impaired Gαi 2 signaling attenuates sympathoinhibitory PVN GPCR-mediated GABAergic tone (i.e., modulates GPCR coupled GABA B responses) and enhances sympathoexcitatory glutamatergic tone to evoke salt-sensitive hypertension in the SD rat.