Abstract 323: Impaired PVN Neuronal Activity In Rats Lacking Central Gαi2 Proteins: Implications For The Pathophysiology Of Salt-Sensitive Hypertension

Abstract

Aim: We have demonstrated downregulation of central Gαi 2 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 Gαi 2 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 Gαi 2 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 Gαi 2 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 Gαi 2 rats remained significantly elevated (MAP 100-min post NaCl [mmHg] SCR: 134±2 vs. Gαi 2 : 146±3, P<0.05). At 40-min post NaCl, a significant reduction in Fos immunoreactivity was observed in SCR but not Gαi 2 rats ([PVN cFos + cells] SCR control: 168±21 vs . post NaCl: 39±16, p<0.05, Gαi 2 control: 155±18 vs . post NaCl: 116±16). Additionally, Gαi 2 prevented the Na + induced decrease of circulating plasma NE at 100-min (Δplasma NE [%control] SCR: -8.46±1.31 vs. Gαi 2 : +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 Gαi 2 infused rats induced a significant increase ([FosB + cells] NS: 212±10 vs. HS: 296±15, P<0.05) in PVN FosB immunoreactivity. Conclusion: Gαi 2 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 Gαi 2 rats, failure to inhibit PVN neuronal activity and sympathetic outflow represents a mechanism by which impairment of Gαi 2 signaling may contribute to the pathophysiology of salt-sensitive hypertension.