High Salt Intake Augments Excitability of PVN Neurons in Rats: Role of the Endoplasmic Reticulum Ca2+ Store

Abstract

High salt (HS) intake sensitizes central autonomic circuitry leading to sympathoexcitation. However, its underlying mechanisms are not fully understood. We hypothesized that inhibition of PVN endoplasmic reticulum (ER) Ca2+ store function would augment PVN neuronal excitability and sympathetic nerve activity (SNA). We further hypothesized that a 2% (NaCl) HS diet for 5 weeks would reduce ER Ca2+ store function and increase excitability of PVN neurons with axon projections to the rostral ventrolateral medulla (PVN-RVLM) identified by retrograde label. PVN microinjection of the ER Ca2+ ATPase inhibitor thapsigargin (TG) increased SNA and mean arterial pressure (MAP) in a dose-dependent manner in rats with a normal salt (NS) diet (0.4%NaCl). In contrast, sympathoexcitatory responses to PVN TG were significantly (p < 0.05) blunted in HS treated rats compared to NS treatment. In whole cell current-clamp recordings from PVN-RVLM neurons, graded current injections evoked graded increases in spike frequency. Maximum discharge was significantly augmented (p < 0.05) by HS diet compared to NS group. Bath application of TG (0.5 μM) increased excitability of PVN-RVLM neurons in NS (p < 0.05), yet had no significant effect in HS rats. Our data indicate that HS intake augments excitability of PVN-RVLM neurons. Inhibition of the ER Ca2+-ATPase and depletion of Ca2+ store likely plays a role in increasing PVN neuronal excitability, which may underlie the mechanisms of sympathoexcitation in rats with chronic HS intake.

Long-Term High Salt Intake Involves Reduced SK Currents and Increased Excitability of PVN Neurons with Projections to the Rostral Ventrolateral Medulla in Rats

“…Graded current injections evoked graded increases in firing frequency and reached saturation at +200 pA current in NS neurons. This data confirms our previous findings regarding PVN-RVLM neuronal excitability between NS and HS-treated rats [ 24 ]. Apamin, a potent SK channel blocker, significantly increased neuronal firing frequency in NS neurons compared to NS neurons without apamin (+200 pA, 49.4 ± 3.2 versus 18.5 ± 2.5 Hz, P < 0.05).…”

“…It has been demonstrated that the SK channels also play an important role in controlling the in vitro excitability of presympathetic PVN-RVLM neurons and in vivo sympathetic outflow in rats [ 3 , 23 ]. Moreover, we have reported that downregulation of SK channel function among the PVN neurons contributed to the sympathoexcitation in rats with chronic HS intake (5 weeks of 2% NaCl) [ 24 ]. Furthermore, our recent study indicates that depletion of endoplasmic reticulum (ER) Ca 2+ store likely plays a role in increasing PVN-RVLM neuronal excitability, which may underlie the mechanisms of sympathoexcitation in rats with HS intake [ 24 ].…”

“…Moreover, we have reported that downregulation of SK channel function among the PVN neurons contributed to the sympathoexcitation in rats with chronic HS intake (5 weeks of 2% NaCl) [ 24 ]. Furthermore, our recent study indicates that depletion of endoplasmic reticulum (ER) Ca 2+ store likely plays a role in increasing PVN-RVLM neuronal excitability, which may underlie the mechanisms of sympathoexcitation in rats with HS intake [ 24 ]. Due to the fact that Ca 2+ release from the ER is a prominent activator of SK channels to mediate neuronal excitability [ 25 ], we hypothesize that reduced SK currents may contribute to the increased excitability of PVN-RVLM neurons in rats with HS intake, which may underlie the neural mechanism of sympathoexcitation.…”

High-Salt Diet Impairs the Neurons Plasticity and the Neurotransmitters-Related Biological Processes

“…The increase in action potential in excitable tissues is the result of a large and rapid Na + influx [32]. It has been reported that high salt intake increases the excitability of some neurons in rodents [33,34]. We therefore assumed that HSD might disrupt morning anticipation behavior by increasing excitability in PDF neurons, and the GAL4-UAS system is the appropriate tool to test this assumption [35].…”

Local Metabolism of Ethanol to Acetic Acid/Acetate in the Central Nucleus of Amygdala Elicits Sympathoexcitatory Responses through Activation of NMDAR in Sprague Dawley Rats

“…While we cannot rule out acetate induced modulation of other voltage-gated K + channels or small conductance calcium activated K + channels (SK-channels), SK-channel involvement is highly unlikely as SK-channel loss of function has been demonstrated to increase neuronal excitability. 44,65,66…”