Abstract 501: PVN Gαi2 Proteins are Required to Maintain Fluid and Electrolyte Homeostasis and Long-term Blood Pressure Regulation
Hypothesis: Hypothalamic PVN GPCR-activated Gαi2 protein-gated pathways mediate the natriuretic and diuretic responses evoked by acute volume expansion (VE) and are required for fluid & electrolyte homeostasis and MAP regulation during elevated dietary salt-intake.
METHODS: Male Sprague-Dawley rats received a 7-day bilateral PVN infusion of a scrambled (S) or Gαi2 oligodeoxynucleotide (ODN-300ng/side/day) or a control i.c.v. infusion of a Gαi2 ODN (600ng/day) prior to an acute i.v. isotonic saline VE (5% body weight). Separate rats infused i.c.v. or PVN with a Gαi2 ODN were maintained on a normal 0.4% (NS) or high 8% NaCl (HS) diet for 7-days - MAP, 24h metabolic balance, plasma norepinephrine (NE) and PVN Gαi2 protein levels were then determined (N=6/group).
Results: Bilateral PVN Gαi2 ODN infusion evoked PVN specific down-regulation of Gαi2 proteins; in contrast i.c.v. Gαi2 ODN infusion did not alter brain Gαi2 protein levels. PVN specific Gαi2 protein down-regulation attenuated the natriuretic (peak UNaV [μeq/min] PVN S 30±4, i.c.v Gαi2 34±4 vs. PVN Gαi2 16±3, P<0.05) and diuretic (peak UV [μl/min] PVN S 320±22, i.c.v Gαi2 336±27 vs. PVN Gαi2 175±26, P<0.05) responses to an acute i.v. VE. In chronic studies HS-intake evoked a significant endogenous 3-fold site-specific increase in PVN Gαi2 proteins in i.c.v. Gαi2 ODN infused rats. Following bilateral PVN Gαi2 ODN infusion, rats maintained on HS retained sodium (24h Na+ balance [meq] PVN Gαi2 + NS 0.3±0.2, i.c.v. Gαi2 + HS 0.5±0.2 vs. PVN Gαi2 + HS 2.3±0.4, P<0.05), exhibited global sympathoexcitation (plasma NE [nmol/L] PVN Gαi2 + NS 48±6, i.c.v. Gαi2 + HS 17±4 vs. PVN Gαi2 + HS 75±9, P<0.05) and developed salt-sensitive hypertension (MAP [mmHg] PVN Gαi2 + NS 124±3, i.c.v. Gαi2 + HS 126±3, PVN Gαi2 + HS 141±2, P<0.05).
Conclusion: PVN Gαi2 protein-gated pathways contribute significantly to the diuretic and natriuretic responses to acute VE. Further, dysregulation of sympathetically driven sodium retaining mechanisms occurred following PVN Gαi2 protein down-regulation evoking salt-sensitive hypertension. We conclude PVN Gαi2-subunit protein-gated pathways are required to appropriately regulate renal sodium excretion to facilitate sodium homeostasis and maintain a salt-resistant phenotype.
- © 2012 by American Heart Association, Inc.