Abstract 323: Impaired PVN Neuronal Activity In Rats Lacking Central Gαi2 Proteins: Implications For The Pathophysiology Of Salt-Sensitive Hypertension
Aim: We have demonstrated downregulation of central Gαi2 proteins produces global sympathoexcitation and elevated MAP in response to acute and chronic high-salt challenge. The current study sought to define whether alterations in PVN neuronal activity in rats lacking brain Gαi2 proteins underlie the sympathoexcitatory and pressor responses observed upon acute and chronic high-salt challenge.
Methods: In acute studies, 24-h ICV scrambled (SCR) or Gαi2 oligodeoxynucleotide (ODN; 25μg/5μl)-pretreated conscious Sprague-Dawley rats were monitored for changes in MAP in response to IV bolus NaCl (3M; 0.14 ml/100g). Rats were sacrificed at control, 10-, 40-, or 100-min post IV NaCl and cFos IHC was performed. In chronic studies, rats receiving an ICV miniosmotic-pump infusion of Gαi2 or SCR ODN (25μg/day) were maintained on a normal (NS; 0.4% NaCl) or high (HS; 8% NaCl) salt diet for 7 days and sacrificed for FosB IHC (N=6/gp).
Results: In response to IV sodium, in SCR rats MAP returned to control levels by 100-min whereas Gαi2 rats remained significantly elevated (MAP 100-min post NaCl [mmHg] SCR: 134±2 vs. Gαi2: 146±3, P<0.05). At 40-min post NaCl, a significant reduction in Fos immunoreactivity was observed in SCR but not Gαi2 rats ([PVN cFos+ cells] SCR control: 168±21 vs. post NaCl: 39±16, p<0.05, Gαi2 control: 155±18 vs. post NaCl: 116±16). Additionally, Gαi2 prevented the Na+ induced decrease of circulating plasma NE at 100-min (Δplasma NE [%control] SCR: -8.46±1.31 vs. Gαi2: +5.13±7.90, P<0.05). In SCR infused rats, a chronic HS diet evoked a significant decrease ([FosB+ cells] NS: 224±13 vs. HS: 133±16, P<0.05) while a HS diet in Gαi2 infused rats induced a significant increase ([FosB+ cells] NS: 212±10 vs. HS: 296±15, P<0.05) in PVN FosB immunoreactivity.
Conclusion: Gαi2 proteins represent a novel CNS mechanism influencing PVN neuronal activity in an acute and chronic setting. Na+ induced decreases in Fos+ PVN cells in SCR rats likely reflect inhibition of neuronal activity to facilitate sympathoinhibition and physiological blood pressure control. In Gαi2 rats, failure to inhibit PVN neuronal activity and sympathetic outflow represents a mechanism by which impairment of Gαi2 signaling may contribute to the pathophysiology of salt-sensitive hypertension.
Author Disclosures: C.Y. Carmichael: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Significant; NIH HL107330, K02HL112718, T32 GM008541. A.C. Carmichael: None. P. Vartanyan: None. R.D. Wainford: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Significant; NIH HL107330, K02HL112718, T32 GM008541.
- © 2014 by American Heart Association, Inc.