Long-term high salt intake involves reduced SK Currents and Increased Excitability of PVN Neurons with projections to the rostral ventrolateral medulla in rats

Evidence indicates that high salt (HS) intake activates presympathetic paraventricular nucleus (PVN) neurons, which contributes to sympathoexcitation of salt-sensitive hypertension. The present study determined whether 5 weeks of HS (2% NaCl) intake alters the small conductance Ca2+-activated potassium channel (SK) current in presympathetic PVN neurons and whether this change affects the neuronal excitability. In whole-cell voltage-clamp recordings, HS-treated rats had significantly decreased SK currents compared to rats with normal salt (NS, 0.4% NaCl) intake in PVN neurons. The sensitivity of PVN neuronal excitability in response to current injections was greater in HS group compared to NS controls. The SK channel blocker apamin augmented the neuronal excitability in both groups but had less effect on the sensitivity of the neuronal excitability in HS group compared to NS controls. In the HS group, the interspike interval (ISI) was significantly shorter than that in NS controls. Apamin significantly shortened the ISI in NS controls but had less effect in the HS group. This data suggests that HS intake reduces SK currents, which contributes to increased PVN neuronal excitability at least in part through a decrease in spike frequency adaptation and may be a precursor to the development of salt-sensitive hypertension

High salt intake augments excitability of PVN neurons in rats: Role of the endoplasmic reticulum Ca\u3csup\u3e2+\u3c/sup\u3e store

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 \u3c 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 \u3c 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 \u3c 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

Acetic Acid: An Underestimated Metabolite in Ethanol-Induced Changes in Regulating Cardiovascular Function

Acetic acid is a bioactive short-chain fatty acid produced in large quantities from ethanol metabolism. In this review, we describe how acetic acid/acetate generates oxidative stress, alters the function of pre-sympathetic neurons, and can potentially influence cardiovascular function in both humans and rodents after ethanol consumption. Our recent findings from in vivo and in vitro studies support the notion that administration of acetic acid/acetate generates oxidative stress and increases sympathetic outflow, leading to alterations in arterial blood pressure. Real-time investigation of how ethanol and acetic acid/acetate modulate neural control of cardiovascular function can be conducted by microinjecting compounds into autonomic control centers of the brain and measuring changes in peripheral sympathetic nerve activity and blood pressure in response to these compounds

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

Evidence indicates that high salt (HS) intake activates presympathetic paraventricular nucleus (PVN) neurons, which contributes to sympathoexcitation of salt-sensitive hypertension. The present study determined whether 5 weeks of HS (2% NaCl) intake alters the small conductance Ca2+-activated potassium channel (SK) current in presympathetic PVN neurons and whether this change affects the neuronal excitability. In whole-cell voltage-clamp recordings, HS-treated rats had significantly decreased SK currents compared to rats with normal salt (NS, 0.4% NaCl) intake in PVN neurons. The sensitivity of PVN neuronal excitability in response to current injections was greater in HS group compared to NS controls. The SK channel blocker apamin augmented the neuronal excitability in both groups but had less effect on the sensitivity of the neuronal excitability in HS group compared to NS controls. In the HS group, the interspike interval (ISI) was significantly shorter than that in NS controls. Apamin significantly shortened the ISI in NS controls but had less effect in the HS group. This data suggests that HS intake reduces SK currents, which contributes to increased PVN neuronal excitability at least in part through a decrease in spike frequency adaptation and may be a precursor to the development of salt-sensitive hypertension

Long-Term High Salt Intake Involves Reduced Sk Currents And Increased Excitability Of Pvn Neurons With Projections To The Rostral Ventrolateral Medulla In Rats

Evidence indicates that high salt (HS) intake activates presympathetic paraventricular nucleus (PVN) neurons, which contributes to sympathoexcitation of salt-sensitive hypertension. The present study determined whether 5 weeks of HS (2% NaCl) intake alters the small conductance Ca2+-activated potassium channel (SK) current in presympathetic PVN neurons and whether this change affects the neuronal excitability. In whole-cell voltage-clamp recordings, HS-treated rats had significantly decreased SK currents compared to rats with normal salt (NS, 0.4% NaCl) intake in PVN neurons. The sensitivity of PVN neuronal excitability in response to current injections was greater in HS group compared to NS controls. The SK channel blocker apamin augmented the neuronal excitability in both groups but had less effect on the sensitivity of the neuronal excitability in HS group compared to NS controls. In the HS group, the interspike interval (ISI) was significantly shorter than that in NS controls. Apamin significantly shortened the ISI in NS controls but had less effect in the HS group. This data suggests that HS intake reduces SK currents, which contributes to increased PVN neuronal excitability at least in part through a decrease in spike frequency adaptation and may be a precursor to the development of salt-sensitive hypertension

High Salt Intake Augments Excitability Of Pvn Neurons In Rats: Role Of The Endoplasmic Reticulum Ca\u3csup\u3e2+\u3c/sup\u3e Store

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 \u3c 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 \u3c 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 \u3c 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

Microbial Derived Short Chain Fatty-Acids and Autonomic Regulation of Cardiovascular Function

Elevated sympathetic outflow is an important contributor to the salt-sensitive hypertension (SSH). It’s been established that the paraventricular nucleus (PVN) of the hypothalamus regulates autonomic control of cardiovascular function, and increased PVN activity contributes to the elevated sympathetic nerve activity (SNA) in SSH. Accumulating evidence indicates a correlation between gut microbial composition and hypertension. Interestingly, data also suggests there is an increased neural communication between the gastrointestinal (GI) tract and PVN neurons in hypertensive animals. Moreover, it’s been reported high salt diet significantly increased the production of short chain fatty-acids (SCFAs), microbiota-derived metabolites. We have shown microinjection of acetate, a SCFA, into the central nucleus of amygdala, significantly increased SNA and arterial blood pressure (ABP). The objective is to determine the role of microbiota-produced SCFAs, acetate and lactate in the PVN, in regulating SNA and ABP. In anesthetized rats, microinjection with acetate or lactate (0.2 μmol/100nl, n=3~4) into the PVN produced significant increases in splanchnic SNA and ABP (p \u3c0.05~0.01), respectively. Also, pre-treatment of kynurenic acid (KYN, 7.2 nmole/100 nl), an ionotropic EAA receptor antagonist, significantly (p \u3c0.05) attenuated the sympathoexcitatory responses evoked by either acetate or lactate. These data suggested that activation of glutamate receptors in the PVN contribute to sympathoexcitatory and pressor responses elicited by SCFAs. Alterations microbiota communities’ impact human host physiology and pathophysiology but a clear cause/effect relationship has yet to be established. Often researchers use fecal matter to determine a subject microbiome profile to make health inferences. While the mucosa associated bacterial communities may be more informative regarding the impact on the host, little investigation into differences between fecal and mucosal bacterial communities has occurred. Gathering information about the microbiome from feces and making inferences to the host’s health may not be an optimal method. Our next aim is to test the hypothesis that shifts in mucosa associated bacteria induce changes in SCFAs concentrations in circulation which may underlie the neural mechanisms of increased sympathetic outflow in hypertension. We extracted feces and mucosa tissue from the small intestine (SI), the location within the GI where absorption occurs. Bacterial composition was determined using 16S rRNA sequencing. Analysis of rat mucosal tissue from the SI (n=6) and feces (n=6) confirmed the bacterial community composition was significantly different (p =5.4×10−5) between the two locations. Collectively, this data supports the continuation into the investigation of mucosa bacteria-derived SCFA involvement in the increase in sympathetic outflow and SSH

Measurement of cations, anions, and acetate in serum, urine, cerebrospinal fluid, and tissue by ion chromatography

© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. Accurate quantification of cations and anions remains a major diagnostic tool in understanding diseased states. The current technologies used for these analyses are either unable to quantify all ions due to sample size/volume, instrument setup/method, or are only able to measure ion concentrations from one physiological sample (liquid or solid). Herein, we adapted a common analytical chemistry technique, ion chromatography and applied it to measure the concentration of cations; sodium, potassium, calcium, and magnesium (Na + , K + , Ca 2+ , and Mg 2+ ) and anions; chloride, and acetate (Cl − , − OAc) from physiological samples. Specifically, cations and anions were measured in liquid samples: serum, urine, and cerebrospinal fluid, as well as tissue samples: liver, cortex, hypothalamus, and amygdala. Serum concentrations of Na + , K + , Ca 2+ , Mg 2+ , Cl − , and − OAc (mmol/L): 138.8 ± 4.56, 4.05 ± 0.21, 4.07 ± 0.26, 0.98 ± 0.05, 97.7 ± 3.42, and 0.23 ± 0.04, respectively. Cerebrospinal fluid concentrations of Na + , K + , Ca 2+ , Mg 2+ , Cl − , and − OAc (mmol/L): 145.1 ± 2.81, 2.41 ± 0.26, 2.18 ± 0.38, 1.04 ± 0.11, 120.2 ± 3.75, 0.21 ± 0.05, respectively. Tissue Na + , K + , Ca 2+ , Mg 2+ , Cl − , and − OAc were also measured. Validation of the ion chromatography method was established by comparing chloride concentration between ion chromatography with a known method using an ion selective chloride electrode. These results indicate that ion chromatography is a suitable method for the measurement of cations and anions, including acetate from various physiological samples