Cerebrospinal Fluid Hypernatremia Elevates Sympathetic Nerve Activity and Blood Pressure via the Rostral Ventrolateral Medulla

Stocker, Sean D.; Lang, Susan M.; Simmonds, Sarah; Wenner, Megan M.; Farquhar, William B.

doi:10.1161/hypertensionaha.115.05936

Cited by 47 publications

(69 citation statements)

References 54 publications

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“…Injection of aCSF into the OVLT did not alter SNA or mean ABP. As previously reported, 13 ICV infusion of NaCl produced concentration-dependent increase in lumbar SNA, adrenal SNA, and ABP (Figure 6). Renal SNA decreased (Figure 6), and splanchnic SNA did not change (data not shown).…”

Section: Resultssupporting

confidence: 89%

“…Intracarotid injection of 0.5M NaCl should increase carotid NaCl concentrations <6–7% (assuming carotid blood flow is 5.5mL/min), whereas ICV infusion of 0.5M or 1.0M NaCl increase CSF [Na + ] by ~3mM (2%) and ~7mM (5%). 13 …”

Section: Methodsmentioning

confidence: 99%

“…7–9 Prior studies suggest the putative NaCl-sensing neurons reside within the anteroventral third ventricular region (AV3V). 10–13 Lesion of AV3V prevents/attenuates the sympathoexcitatory and pressor response to central hypernatremia 12–14 and neurogenic forms of salt-sensitive hypertension. 15–17 AV3V is comprised of several hypothalamic nuclei bordering the rostral third ventricle including the periventricular preoptic, medial preoptic, ventral median preoptic, organum vasculosum of the lamina terminalis (OVLT), and fibers of passage from the subfornical organ (SFO).…”

Section: Introductionmentioning

confidence: 99%

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Organum Vasculosum of the Lamina Terminalis Detects NaCl to Elevate Sympathetic Nerve Activity and Blood Pressure

et al. 2017

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High salt diet elevates NaCl concentrations in the cerebrospinal fluid to increase sympathetic nerve activity (SNA) in salt-sensitive hypertension. The organum vasculosum of the lamina terminalis (OVLT) resides along the rostral wall of the third ventricle, lacks a complete blood-brain-barrier, and plays a pivotal role in body fluid homeostasis. Therefore, the present study used a multi-faceted approach to examine whether OVLT neurons of Sprague Dawley rats are intrinsically sensitive to changes in extracellular NaCl concentrations and mediate the sympathoexcitatory responses to central NaCl loading. Using in vitro whole-cell recordings, step-wise increases in extracellular NaCl concentrations (2.5–10mM) produced concentration-dependent excitation of OVLT neurons. Additionally, these excitatory responses were intrinsic to OVLT neurons as hypertonic NaCl evoked inward currents despite pharmacologic synaptic blockade. In vivo single-unit recordings demonstrate the majority of OVLT neurons (72%, 13/19) display concentration-dependent increases in neuronal discharge to intracarotid (50µL/15s) or intracerebroventricular infusion (5µL/10min) of hypertonic NaCl. Microinjection of hypertonic NaCl (30nL/60s) into the OVLT, but not adjacent areas, increased lumbar SNA, adrenal SNA, and ABP in a concentration-dependent manner. Renal SNA decreased, and splanchnic SNA remained unaffected. Finally, local inhibition of OVLT neurons with the GABAA receptor agonist muscimol (24nL/10s) significantly attenuated the sympathoexcitatory and pressor responses to intracerebroventricular infusion of 0.5M or 1.0M NaCl. Collectively, these findings indicate that OVLT neurons detect changes in extracellular NaCl concentrations to selectively alter SNA and raise ABP.

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Section: Resultssupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Organum Vasculosum of the Lamina Terminalis Detects NaCl to Elevate Sympathetic Nerve Activity and Blood Pressure

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“…In other studies using rats, various injection volumes (5-76 l) and NaCl concentrations (0.3-4.5 M) were used for intracerebroventricular injection (21,22,44,47). Among them, injection of 76 l of hypertonic NaCl aCSF containing 0.3 M NaCl increased [Na ϩ ] in CSF by ϳ19 mM in rats (22), the same level as the present study (ϳ18 mM, Fig.…”

Section: Discussionsupporting

confidence: 75%

Na_x signaling evoked by an increase in [Na⁺] in CSF induces water intake via EET-mediated TRPV4 activation

Sakuta

Nishihara

Hiyama

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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-Water-intake behavior is under the control of brain systems that sense body fluid conditions at sensory circumventricular organs (sCVOs); however, the underlying mechanisms have not yet been elucidated in detail. Na x is a sodium (Na ϩ ) level sensor in the brain, and the transient receptor potential vanilloid (TRPV) channels TRPV1 and TRPV4 have been proposed to function as osmosensors. We herein investigated voluntary water intake immediately induced after an intracerebroventricular administration of a hypertonic NaCl solution in TRPV1-, TRPV4-, Na x-, and their doublegene knockout (KO) mice. The induction of water intake by TRPV1-KO mice was normal, whereas intake by TRPV4-KO and Na x-KO mice was significantly less than that by WT mice. Water intake by Nax/TRPV4-double KO mice was similar to that by the respective single KO mice. When TRPV4 activity was blocked with a specific antagonist HC-067047, water intake by WT mice was significantly reduced, whereas intake by TRPV4-KO and Na x-KO mice was not. Similar results were obtained with the administration of miconazole, which inhibits the biosynthesis of epoxyeicosatrienoic acids (EETs), endogenous agonists for TRPV4, from arachidonic acid (AA). Intracerebroventricular injection of hypertonic NaCl with AA or 5,6-EET restored water intake by Nax-KO mice to the wild-type level but not that by TRPV4-KO mice. These results suggest that the Na ϩ signal generated in Nax-positive glial cells leads to the activation of TRPV4-positive neurons in sCVOs to stimulate water intake by using EETs as gliotransmitters. Intracerebroventricular injection of equiosmolar hypertonic sorbitol solution induced small but significant water intake equally in all the genotypes, suggesting the presence of an unknown osmosensor in the brain. TRPV1; TRPV4; Nax; water intake; epoxyeicosatrienoic acid MAMMALS possess a set of homeostatic mechanisms that function together to maintain body fluid osmolality at approximately 300 mosmol/kg H 2 O by controlling the intake and excretion of water and salt (4, 5). This homeostatic osmoregulation is vital because changes in cell volume due to severe hypertonicity or hypotonicity cause irreversible damage to organs and lethal neurological trauma (6,8,46). Animals exhibit prominent and effective responses to dehydration, including behavioral responses, such as water intake and salt aversion, and vasopressin (VP)-induced reductions in urine volume (39). Central and peripheral sensing systems for body fluid conditions have been shown to contribute to body fluid homeostasis (10).The Na ϩ ion is the main determinant of osmolality in vivo. When animals are dehydrated, osmolality in body fluids increases along with elevations in the concentration of Na McKinley et al. (33,35) previously reported that the injection of a hypertonic NaCl solution into the third ventricle of conscious sheep induced stronger antidiuretic and drinking responses than that of an equiosmolar hypertonic sucrose solution. Therefore, they speculated that a Na ϩ sensor other than osmosenso...

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“…Mice received an SFO injection of rAAV2-CaMKII-HA-hM3D(Gq)-IRES-mCitrine at least 3 wk before experiments. In vivo single-unit recordings of SFO neurons were then performed in mice anesthetized with isoflurane with glass electrodes (10 -30 M⍀) angled 86°from the midsagittal sinus and filled with 4% Neurobiotin dissolved in 0.5 M sodium acetate (pH 7.4) (Stocker et al 2015;Stocker and Toney 2005). A multibarrel glass pipette was lowered into the lateral ventricle to test SFO neuronal responsiveness to 0.5 M NaCl (100 nl over 5 s) or ANG II (20 ng in 100 nl over 5 s).…”

Section: Methodsmentioning

confidence: 99%

DREADD-induced activation of subfornical organ neurons stimulates thirst and salt appetite

Nation

Nicoleau

Kinsman

et al. 2016

Journal of Neurophysiology

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Nation HL, Nicoleau M, Kinsman BJ, Browning KN, Stocker SD. DREADD-induced activation of subfornical organ neurons stimulates thirst and salt appetite. J Neurophysiol 115: 3123-3129, 2016. First published March 30, 2016 doi:10.1152/jn.00149.2016.-The subfornical organ (SFO) plays a pivotal role in body fluid homeostasis through its ability to integrate neurohumoral signals and subsequently alter behavior, neuroendocrine function, and autonomic outflow. The purpose of the present study was to evaluate whether selective activation of SFO neurons using virally mediated expression of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) stimulated thirst and salt appetite. Male C57BL/6 mice (12-15 wk) received an injection of rAAV2-CaMKII-HAhM3D(Gq)-IRES-mCitrine targeted at the SFO. Two weeks later, acute injection of clozapine N-oxide (CNO) produced dose-dependent increases in water intake of mice with DREADD expression in the SFO. CNO also stimulated the ingestion of 0.3 M NaCl. Acute injection of CNO significantly increased the number of Fos-positive nuclei in the SFO of mice with robust DREADD expression. Furthermore, in vivo single-unit recordings demonstrate that CNO significantly increases the discharge frequency of both ANG II-and NaCl-responsive neurons. In vitro current-clamp recordings confirm that bath application of CNO produces a significant membrane depolarization and increase in action potential frequency. In a final set of experiments, chronic administration of CNO approximately doubled 24-h water intake without an effect on salt appetite. These findings demonstrate that DREADD-induced activation of SFO neurons stimulates thirst and that DREADDs are a useful tool to acutely or chronically manipulate neuronal circuits influencing body fluid homeostasis.

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Cerebrospinal Fluid Hypernatremia Elevates Sympathetic Nerve Activity and Blood Pressure via the Rostral Ventrolateral Medulla

Cited by 47 publications

References 54 publications

Organum Vasculosum of the Lamina Terminalis Detects NaCl to Elevate Sympathetic Nerve Activity and Blood Pressure

Organum Vasculosum of the Lamina Terminalis Detects NaCl to Elevate Sympathetic Nerve Activity and Blood Pressure

Na_x signaling evoked by an increase in [Na⁺] in CSF induces water intake via EET-mediated TRPV4 activation

DREADD-induced activation of subfornical organ neurons stimulates thirst and salt appetite

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Cerebrospinal Fluid Hypernatremia Elevates Sympathetic Nerve Activity and Blood Pressure via the Rostral Ventrolateral Medulla

Cited by 47 publications

References 54 publications

Organum Vasculosum of the Lamina Terminalis Detects NaCl to Elevate Sympathetic Nerve Activity and Blood Pressure

Organum Vasculosum of the Lamina Terminalis Detects NaCl to Elevate Sympathetic Nerve Activity and Blood Pressure

Nax signaling evoked by an increase in [Na+] in CSF induces water intake via EET-mediated TRPV4 activation

DREADD-induced activation of subfornical organ neurons stimulates thirst and salt appetite

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Na_x signaling evoked by an increase in [Na⁺] in CSF induces water intake via EET-mediated TRPV4 activation