scholarly journals Hypertension Induced by Angiotensin II and a High Salt Diet Involves Reduced SK Current and Increased Excitability of RVLM Projecting PVN Neurons

2010 ◽  
Vol 104 (5) ◽  
pp. 2329-2337 ◽  
Author(s):  
Qing-Hui Chen ◽  
Mary Ann Andrade ◽  
Alfredo S. Calderon ◽  
Glenn M. Toney
Keyword(s):  
Angiotensin Ii ◽  
Input Resistance ◽  
High Salt ◽  
Ventrolateral Medulla ◽  
Sk Channels ◽  
Hypertensive Rats ◽  
Cellular Mechanisms ◽  
Hypertensive Group ◽  
Whole Cell Patch Clamp ◽  
The Impact

Although evidence indicates that activation of presympathetic paraventricular nucleus (PVN) neurons contributes to the pathogenesis of salt-sensitive hypertension, the underlying cellular mechanisms are not fully understood. Recent evidence indicates that small conductance Ca2+-activated K+ (SK) channels play a significant role in regulating the excitability of a key group of sympathetic regulatory PVN neurons, those with axonal projections to the rostral ventrolateral medulla (RVLM; i.e., PVN-RVLM neurons). In the present study, rats consuming a high salt (2% NaCl) diet were made hypertensive by systemic infusion of angiotensin II (AngII), and whole cell patch-clamp recordings were made in brain slice from retrogradely labeled PVN-RVLM neurons. To determine if the amplitude of SK current was altered in neurons from hypertensive rats, voltage-clamp recordings were performed to isolate SK current. Results indicate that SK current amplitude ( P < 0.05) and density ( P < 0.01) were significantly smaller in the hypertensive group. To investigate the impact of this on intrinsic excitability, current-clamp recordings were performed in separate groups of PVN-RVLM neurons. Results indicate that the frequency of spikes evoked by current injection was significantly higher in the hypertensive group ( P < 0.05–0.01). Whereas bath application of the SK channel blocker apamin significantly increased discharge of neurons from normotensive rats ( P < 0.05–0.01), no effect was observed in the hypertensive group. In response to ramp current injections, subthreshold depolarizing input resistance was greater in the hypertensive group compared with the normotensive group ( P < 0.05). Blockade of SK channels increased depolarizing input resistance in normotensive controls ( P < 0.05) but had no effect in the hypertensive group. On termination of current pulses, a medium afterhyperpolarization potential (mAHP) was observed in most neurons of the normotensive group. In the hypertensive group, the mAHP was either small or absent. In the latter case, an afterdepolarization potential (ADP) was observed that was unaffected by apamin. Apamin treatment in the normotensive group blocked the mAHP and revealed an ADP resembling that seen in the hypertensive group. We conclude that diminished SK current likely underlies the absence of mAHPs in PVN-RVLM neurons from hypertensive rats. Both the ADP and greater depolarizing input resistance likely contribute to increased excitability of PVN-RVLM neurons from rats with AngII-Salt hypertension.

scholarly journals Synaptic and extrasynaptic transmission of kidney-related neurons in the rostral ventrolateral medulla

2013 ◽  
Vol 110 (11) ◽  
pp. 2637-2647 ◽  
Author(s):  
Hong Gao ◽  
Andrei V. Derbenev
Keyword(s):  
Large Scale ◽  
Critical Role ◽  
Input Resistance ◽  
Rostral Ventrolateral Medulla ◽  
Kainate Receptors ◽  
Ventrolateral Medulla ◽  
Resting Membrane Potential ◽  
Arterial Blood ◽  
Whole Cell Patch Clamp ◽  
Tonic Current

The rostral ventrolateral medulla (RVLM) is a critical component of the sympathetic nervous system regulating homeostatic functions including arterial blood pressure. Using the transsynaptic retrograde viral tracer PRV-152, we identified kidney-related neurons in the RVLM. We found that PRV-152-labeled RVLM neurons displayed an unusually large persistent, tonic current to both glutamate, via N-methyl-d-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA)/kainate receptors, and to γ-aminobutyric acid (GABA), via GABAAreceptors, in the absence of large-scale phasic neurotransmission with whole cell patch-clamp recordings. A cocktail of potent NMDA and AMPA/kainate ionotropic glutamate receptor antagonists AP-5 (50 μM) and CNQX (10 μM) revealed a two-component somatic tonic excitatory current with an overall amplitude of 42.6 ± 13.4 pA. Moreover, application of the GABAAreceptor blockers gabazine (15 μM) and bicuculline (30 μM) revealed a robust somatic tonic inhibitory current with an average amplitude of 196.3 ± 39.3 pA. These findings suggest that the tonic current plays a role in determining the resting membrane potential, input resistance, and firing rate of RVLM neurons. The magnitude of the tonic inhibitory current demonstrates that GABAergic inhibition plays a critical role in regulation of kidney-related RVLM neurons. Our results indicate that the GABAergic tonic current may determine the basal tone of firing activity in kidney-related RVLM neurons.

scholarly journals Discharge of RVLM vasomotor neurons is not increased in anesthetized angiotensin II-salt hypertensive rats

2013 ◽  
Vol 305 (12) ◽  
pp. H1781-H1789 ◽  
Author(s):  
Gustavo R. Pedrino ◽  
Alfredo S. Calderon ◽  
Mary Ann Andrade ◽  
Sergio L. Cravo ◽  
Glenn M. Toney
Keyword(s):  
Sympathetic Nerve Activity ◽  
High Salt ◽  
Ventrolateral Medulla ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Nerve Activity ◽  
High Salt Diet ◽  
Salt Diet ◽  
Salt Hypertension ◽  
Single Unit Recordings

Neurons of the rostral ventrolateral medulla (RVLM) are critical for generating and regulating sympathetic nerve activity (SNA). Systemic administration of ANG II combined with a high-salt diet induces hypertension that is postulated to involve elevated SNA. However, a functional role for RVLM vasomotor neurons in ANG II-salt hypertension has not been established. Here we tested the hypothesis that RVLM vasomotor neurons have exaggerated resting discharge in rats with ANG II-salt hypertension. Rats in the hypertensive (HT) group consumed a high-salt (2% NaCl) diet and received an infusion of ANG II (150 ng·kg−1·min−1 sc) for 14 days. Rats in the normotensive (NT) group consumed a normal salt (0.4% NaCl) diet and were infused with normal saline. Telemetric recordings in conscious rats revealed that mean arterial pressure (MAP) was significantly increased in HT compared with NT rats ( P < 0.001). Under anesthesia (urethane/chloralose), MAP remained elevated in HT compared with NT rats ( P < 0.01). Extracellular single unit recordings in HT ( n = 28) and NT ( n = 22) rats revealed that barosensitive RVLM neurons in both groups (HT, 23 cells; NT, 34 cells) had similar cardiac rhythmicity and resting discharge. However, a greater ( P < 0.01) increase of MAP was needed to silence discharge of neurons in HT (17 cells, 44 ± 5 mmHg) than in NT (28 cells, 29 ± 3 mmHg) rats. Maximum firing rates during arterial baroreceptor unloading were similar across groups. We conclude that heightened resting discharge of sympathoexcitatory RVLM neurons is not required for maintenance of neurogenic ANG II-salt hypertension.

Brain stem oxidative stress and its associated signaling in the regulation of sympathetic vasomotor tone

2012 ◽  
Vol 113 (12) ◽  
pp. 1921-1928 ◽  
Author(s):  
Samuel H. H. Chan ◽  
Julie Y. H. Chan
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Brain Stem ◽  
Ventrolateral Medulla ◽  
Future Research ◽  
Vasomotor Tone ◽  
Cellular Mechanisms ◽  
Neurogenic Hypertension ◽  
The Impact ◽  
Sympathetic Vasomotor Tone

There is now compelling evidence from studies in humans and animals that overexcitation of the sympathetic nervous system plays an important role in the pathogenesis of cardiovascular diseases. An excellent example is neurogenic hypertension, in which central sympathetic overactivation is involved in the development, staging, and progression of the disease, and one of the underlying mechanisms involves oxidative stress in key brain stem sites that are engaged in the regulation of sympathetic vasomotor tone. Using the rostral ventrolateral medulla (RVLM) and nucleus tractus solitarii (NTS) as two illustrative brain stem neural substrates, this article provides an overview of the impact of reactive oxygen species and antioxidants on RVLM and NTS in the pathogenesis of neurogenic hypertension. This is followed by a discussion of the redox-sensitive signaling pathways, including several kinases, ion channels, and transcription factors that underpin the augmentation in sympathetic vasomotor tone. In addition, the emerging view that brain stem oxidative stress is also causally related to a reduction in sympathetic vasomotor tone and hypotension during brain stem death, methamphetamine intoxication, and temporal lobe status epilepticus will be presented, along with the causal contribution of the oxidant peroxynitrite formed by a reaction between nitric oxide synthase II (NOS II)-derived nitric oxide and superoxide. Also discussed as a reasonable future research direction is dissection of the cellular mechanisms and signaling cascades that may underlie the contributory role of nitric oxide generated by different NOS isoforms in the differential effects of oxidative stress in the RVLM or NTS on sympathetic vasomotor tone.

scholarly journals Role of Endogenous Angiotensin II on Glutamatergic Actions in the Rostral Ventrolateral Medulla in Goldblatt Hypertensive Rats

Hypertension ◽  
2003 ◽  
Vol 42 (4) ◽  
pp. 707-712 ◽  
Author(s):  
Taís Helena F. Carvalho ◽  
Cássia T. Bergamaschi ◽  
Oswaldo U. Lopes ◽  
Ruy R. Campos
Keyword(s):  
Angiotensin Ii ◽  
Rostral Ventrolateral Medulla ◽  
Ventrolateral Medulla ◽  
Hypertensive Rats

Abstract 438: Rapid Inhibition of Pre-sympathetic Kidney-related Neurons in the Rostral Ventrolateral Medulla by Leptin

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Hong Gao ◽  
Maria J Barnes ◽  
D.S. Safwan Majid ◽  
Andrei V Derbenev
Keyword(s):  
Energy Homeostasis ◽  
Input Resistance ◽  
Vital Role ◽  
Rostral Ventrolateral Medulla ◽  
Synaptic Activity ◽  
Ventrolateral Medulla ◽  
Membrane Hyperpolarization ◽  
Postsynaptic Currents ◽  
Whole Cell Patch Clamp ◽  
Critical Components

The adipocyte-derived hormone leptin regulates satiety and plays a vital role in energy homeostasis. Several lines of evidence suggest that obesity is associated with increased prevalence of hypertension and accountable at least in part for the elevation of sympathetic nerve activity. Neurons in the rostral ventrolateral medulla (RVLM) are critical components of both the sympathetic nervous system and cardiovascular regulation. By using whole-cell patch-clamp recordings in brainstem slices we tested the hypothesis that leptin suppresses activity in pre-sympathetic kidney-related RVLM neurons. Application of leptin caused a rapid membrane hyperpolarization in 43% of recorded kidney-related RVLM neurons. Out of 14 neurons, leptin (500nM) hyperpolarized 6 neurons (from -53.3±3.5 mV to -57.0± 3.2 mV; P<0.05) and had no effects on the rest of the neurons. The input resistance was significantly increased by leptin in 6 out of 14 RVLM kidney-related neurons from 276±92 MΩ to 336±97 MΩ (P<0.05). Moreover, leptin (500nM) reduced the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) from 7.9±2.1 Hz to 5.5±2.3 Hz (P<0.05; n=5) with an average of 36% decrease without changing sEPSCs amplitude. The frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) was not affected by administration of leptin. Our study demonstrates that leptin directly hyperpolarized the kidney-related RVLM neurons and indirectly suppressed excitatory synaptic activity to pre-sympathetic kidney-related RVLM neurons. This work was supported by P30GM103337.

scholarly journals Exercise Training Attenuates Proinflammatory Cytokines, Oxidative Stress and Modulates Neurotransmitters in the Rostral Ventrolateral Medulla of Salt-Induced Hypertensive Rats

2018 ◽  
Vol 48 (3) ◽  
pp. 1369-1381 ◽  
Author(s):  
Hong-Bao Li ◽  
Chan-Juan Huo ◽  
Qing Su ◽  
Xiang Li ◽  
Juan Bai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Exercise Training ◽  
Sympathetic Nerve Activity ◽  
High Salt ◽  
Ventrolateral Medulla ◽  
Gamma Aminobutyric Acid ◽  
Hypertensive Rats ◽  
Nerve Activity ◽  
High Salt Diet ◽  
Salt Diet

Background/Aims: Exercise training (ExT) was associated with cardiovascular diseases including hypertension. The rostral ventrolateral medulla (RVLM) is a key region for central control of blood pressure and sympathetic nerve activity. Therefore, this study aimed to investigate the mechanisms within RVLM that can influence exercise training induced effects in salt-induced hypertension. Methods: Male Wistar rats were fed with a normal salt (0.3%) (NS) or a high salt (8%) (HS) diet for 12 weeks to induce hypertension. Then these rats were given moderate-intensity ExT for a period of 12 weeks. RVLM was used to determine glutamate and gamma-aminobutyric acid (HPLC), phosphorylated IKKβ, Fra-LI, 67-kDa isoform of glutamate decarboxylase (GAD67), proinflammatory cytokines (PIC) and NADPH-oxidase (NOX) subunits expression (Immunohistochemistry and Immunofluorescence, Western blotting). PIC and NF-κB p65 activity in the plasma were evaluated by ELISA studies. Renal sympathetic nerve activity (RSNA) was recorded and analyzed using the PowerLab system. Results: High salt diet resulted in increased mean arterial pressure and cardiac hypertrophy. These high salt diet rats had higher RVLM levels of glutamate, PIC, phosphorylated IKKβ, NF-κB p65 activity, Fra-LI, superoxide, NOX-2 (gp91phox) and 4, and lower RVLM levels of gamma-aminobutyric acid and GAD67, and higher plasma levels of PIC, norepinephrine, and higher RSNA. ExT attenuated these changes in salt-induced hypertensive rats. Conclusions: These findings suggest that high salt diet increases the activity of NF-κB and the levels of PIC and oxidative stress, and induces an imbalance between excitatory and inhibitory neurotransmitters in the RVLM. ExT attenuates hypertension and cardiac hypertrophy partially mediated by attenuating oxidative stress and modulating neurotransmitters in the RVLM.

Effect of angiotensin II in ventrolateral medulla of spontaneously hypertensive rats

1991 ◽  
Vol 260 (5) ◽  
pp. R977-R984 ◽  
Author(s):  
H. Muratani ◽  
D. B. Averill ◽  
C. M. Ferrario
Keyword(s):  
Angiotensin Ii ◽  
Spontaneously Hypertensive Rat ◽  
Cardiovascular Response ◽  
Ventrolateral Medulla ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Pressor Responses ◽  
Wistar Kyoto ◽  
Dose Dependent

The spontaneously hypertensive rat (SHR) exhibits an enhanced activity of the peripheral sympathetic and brain renin-angiotensin systems. In the present experiments, we evaluated the cardiovascular response of angiotensin II (ANG II) microinjected in the rostral (RVLM) and the caudal (CVLM) ventrolateral medulla of age-matched (14-16 wk old) SHR and Wistar-Kyoto (WKY) rats. Responses of mean arterial pressure (MAP) and heart rate (HR) to microinjection of ANG II (5, 20 and 100 pmol) into histologically verified sites of the RVLM and CVLM were compared with those obtained by injections of the excitatory agent L-glutamate (2 nmol) at the same site. In both strains, ANG II elicited dose-dependent pressor responses in the RVLM and depressor responses in the CVLM, both of which peaked at a dose of 20 pmol. The magnitude of the fall in MAP produced by injections of ANG II into the CVLM were significantly (P less than 0.01) greater in SHR than in WKY group. In contrast, peak pressor responses elicited by injection of ANG II into the RVLM were of similar magnitude in the two groups. When compared with the MAP response produced by L-glutamate injections, responses to ANG II microinjection were slower in onset, and the latency to the peak response was longer. Ganglionic blockade with hexamethonium bromide prevented the effect of ANG II injection in the RVLM. This study provides evidence that ANG II acts as an excitatory agent at sites within the ventrolateral medulla that determine the vasomotor control of blood pressure in both normotensive and hypertensive rats.

scholarly journals ATP stimulates rat hypothalamic sympathetic neurons by enhancing AMPA receptor-mediated currents

2015 ◽  
Vol 114 (1) ◽  
pp. 159-169 ◽  
Author(s):  
Hildebrando Candido Ferreira-Neto ◽  
Vagner R. Antunes ◽  
Javier E. Stern
Keyword(s):  
Ampa Receptor ◽  
Ampa Receptors ◽  
Kynurenic Acid ◽  
Sympathetic Neurons ◽  
Synaptic Function ◽  
Ventrolateral Medulla ◽  
Cellular Mechanisms ◽  
Receptor Coupling ◽  
Whole Cell Patch Clamp ◽  
Intracellular Ca

We have previously shown that ATP within the paraventricular nucleus (PVN) induces an increase in sympathetic activity, an effect attenuated by the antagonism of P2 and/or glutamatergic receptors. Here, we evaluated precise cellular mechanisms underlying the ATP-glutamate interaction in the PVN and assessed whether this receptor coupling contributed to osmotically driven sympathetic PVN neuronal activity. Whole-cell patch-clamp recordings obtained from PVN-rostral ventrolateral medulla neurons showed that ATP (100 μM, 1 min, bath applied) induced an increase in firing rate (89%), an effect blocked by kynurenic acid (1 mM) or 4-[[4-Formyl-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]-2-pyridinyl]azo]-1,3-benzenedisulfonic acid tetrasodium salt (PPADS) (10 μM). Whereas ATP did not affect glutamate synaptic function, α-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptor-mediated currents evoked by focal application of AMPA (50 μM, n = 13) were increased in magnitude by ATP (AMPA amplitude: 33%, AMPA area: 52%). ATP potentiation of AMPA currents was blocked by PPADS ( n = 12) and by chelation of intracellular Ca2+ (BAPTA, n = 10). Finally, a hyperosmotic stimulus (mannitol 1%, +55 mosM, n = 8) potentiated evoked AMPA currents (53%), an effect blocked by PPADS ( n = 6). Taken together, our data support a functional stimulatory coupling between P2 and AMPA receptors (likely of extrasynaptic location) in PVN sympathetic neurons, which is engaged in response to an acute hyperosmotic stimulus, which might contribute in turn to osmotically driven sympathoexcitatory responses by the PVN.

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