Reduced GABA inhibition of sympathetic function  in renal-wrapped hypertensive rats

Martin, Douglas; Haywood, Joseph R.

doi:10.1152/ajpregu.1998.275.5.r1523

Cited by 56 publications

(75 citation statements)

References 35 publications

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“…PVH neuronal activation contributes to the changes in sympathetic tone associated with many physiological or pathophysiological conditions such as water deprivation, hypertension and heart failure (Martin and Haywood, 1998;Allen, 2002;Felder et al, 2003;Ito et al, 2003;Stocker et al, 2004a;. The neural pathway from PVH to spinal sympathetic vasomotor efferents is likely to relay in the RVLM (Allen, 2002;Brooks et al, 2004a), a region of dense projection from the PVH which contains the bulk of the bulbospinal sympathoexcitatory blood-pressure regulating neurons (Schreihofer and Guyenet, 1997;Guyenet et al, 1998;Schreihofer and Guyenet, 2000;Stornetta et al, 2002b).…”

Section: Discussionmentioning

confidence: 99%

Water deprivation activates a glutamatergic projection from the hypothalamic paraventricular nucleus to the rostral ventrolateral medulla

Stocker

Simmons

Stornetta

et al. 2005

J of Comparative Neurology

122

133

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Elevated sympathetic outflow contributes to the maintenance of blood pressure in water-deprived rats. The neural circuitry underlying this response may involve activation of a pathway from the hypothalamic paraventricular nucleus (PVH) to the rostral ventrolateral medulla (RVLM). We sought to determine whether the PVH-RVLM projection activated by water deprivation is glutamatergic and/or contains vasopressin-or oxytocin-neurophysins. Vesicular glutamate transporter2 (VGLUT2) mRNA was detected by in situ hybridization in the majority of PVH neurons retrogradely labeled from the ipsilateral RVLM with cholera-toxin subunit B (CTB; 85% on average with regional differences). Very few RVLM-projecting PVH neurons were immunoreactive for oxytocin-or vasopressin-associated neurophysin. Injection of biotinylated dextran amine (BDA) into the PVH produced clusters of BDA-positive nerve terminals within the ipsilateral RVLM that were immunoreactive (ir) for the VGLUT2 protein. Some of these terminals made close appositions with tyrosine-hydroxylase-ir dendrites (presumptive C1 cells). In waterdeprived rats (n=4), numerous VGLUT2 mRNA-positive PVH neurons retrogradely labeled from the ipsilateral RVLM with CTB were c-Fos-ir (16-40% depending on PVH region). In marked contrast, few glutamatergic, RVLM-projecting PVH neurons were c-Fos-ir in control rats (n=3; 0-3% depending on PVH region). Most (94 ± 4%) RVLM-projecting PVH neurons activated by water deprivation contained VGLUT2 mRNA. In summary, the majority of PVH neurons that innervate the RVLM are glutamatergic and this population includes the neurons that are activated by water deprivation. One mechanism by which water deprivation may increase the sympathetic outflow is the activation of a glutamatergic pathway from the PVH to the RVLM.

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Section: Discussionmentioning

confidence: 99%

Water deprivation activates a glutamatergic projection from the hypothalamic paraventricular nucleus to the rostral ventrolateral medulla

Stocker

Simmons

Stornetta

et al. 2005

J of Comparative Neurology

122

133

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“…These data as well as literature evidence 6,20 raise the possibility that Ang II may act centrally to reduce GABAergic function in the PVN, thereby providing a potential mechanism by which sympathetic activity could become elevated in cardiovascular diseases such as congestive heart failure 6 and arterial hypertension. 20 …”

Section: Discussionmentioning

confidence: 62%

“…Indeed, it has been reported that GABA-mediated control of SNA within the PVN is reduced in rats with salt-sensitive hypertension 20 and heart failure. 6 One interpretation of these data is that elevated plasma Ang II present in both disease models may lead to reduced GABAergic function within the PVN.…”

Section: Discussionmentioning

confidence: 99%

“…4 Although mechanisms of GABA-Ang II interaction within the PVN have not been fully defined, in vitro electrophysiological studies indicate that GABA tonically opposes excitatory actions of Ang II on neurosecretory neurons, 18 and excitation of spinally projecting neurons involves presynaptic actions of Ang II to reduce GABA release. 19 In addition, functional studies in rats with sodium-dependent hypertension 20 and heart failure 6 have suggested that Ang II-induced sympathoexcitation involves reduced GABA-mediated inhibition within the PVN. This conclusion is consistent with evidence that both plasma Ang II and SNA are elevated whereas the sympathetic response to blockade of PVN GABA-A receptors is attenuated in these disease models.…”

mentioning

confidence: 99%

“…This conclusion is consistent with evidence that both plasma Ang II and SNA are elevated whereas the sympathetic response to blockade of PVN GABA-A receptors is attenuated in these disease models. 6,20 The aim of the present study was to determine more directly the effect of elevated plasma Ang II on cardiovascular and renal SNA responses to acute GABA-A receptor blockade in the PVN. This was accomplished by infusing rats intravenously with Ang II at a rate selected to leave plasma volume undisturbed.…”

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Effect of Intravenous Angiotensin II Infusion on Responses to Hypothalamic PVN Injection of Bicuculline

2003

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Abstract-The hypothalamic paraventricular nucleus (PVN) plays an important role in the sympathoexcitatory response to elevated plasma angiotensin II (Ang II). However, the mechanism by which Ang II influences sympathetic activity is not fully understood.In this study, we tested the hypothesis that GABA(␥-aminobutyric acid)-ergic function in the PVN is reduced by peripheral infusion of Ang II. To accomplish this, rats received either intravenous Ang II (12 ng/kg per minute) or vehicle (D5W) for 7 days, and renal sympathetic nerve activity (SNA), mean arterial pressure (MAP), and heart rate (HR) responses were recorded after unilateral PVN microinjection of the GABA-A receptor antagonist bicuculline methiodide (BMI, 0.1 nmol). Results indicate that in contrast to a significant increase in renal SNA, MAP, and HR observed in vehicle-infused rats (PϽ0.05), BMI injection into the PVN of Ang II-infused animals was without effect on all recorded variables. In a separate groups of animals, ganglionic blockade produced a significantly greater fall in MAP (PϽ0.01) in Ang II-infused rats than in vehicle-infused control rats, indicating that the contribution of SNA to the maintenance of blood pressure was elevated in the Ang II-infused group. Overall, these data indicate that cardiovascular and sympathoexcitatory responses to acute GABA-A receptor antagonism in the PVN are significantly blunted in rats after 7 days of intravenous infusion of Ang II. We conclude that an Ang II-induced reduction in GABAergic inhibition within the PVN may contribute to elevated SNA observed in this study. Key Words: angiotensin II Ⅲ hypothalamus Ⅲ sympathetic nervous system Ⅲ hypertension, arterial A s the dominant inhibitory neurotransmitter in the mammalian brain, ␥-aminobutyric acid (GABA) 1 plays an important role in regulating cardiovascular function. 2,3 In brain regions such as the nucleus tractus solitarius 2 and rostral ventrolateral medulla 2,3 that control sympathetic nerve activity (SNA), GABA tonically suppresses neuronal activity and excitability. In the hypothalamic paraventricular nucleus (PVN), neuronal activity is also regulated by GABA 4 -6 and by a number of excitatory neurotransmitters as well. 7,8 Among the latter is the peptide angiotensin II (Ang II). Ang II-containing fibers arise from Ang II-sensitive regions of the forebrain known as circumventricular organs (CVO), which lack a complete blood-brain barrier. 9,10 Neurons in two forebrain CVOs, the subfornical organ and organum vasculosum of the lamina terminalis, express Ang II AT 1 receptors in high density 11 and appear to sense and respond to circulating Ang II. 9,12-15 Although Ang II increases SNA through these and other central actions, 16,17 the mechanism by which circulating Ang II enhances PVN neuronal excitability is not fully understood.On the basis of literature evidence, it is clear that GABA 4 -6 and Ang II 13-15 can each act individually within the PVN to influence cardiovascular function. More recently, it has been shown that local GABA-Ang II interacti...

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Altered balance of γ‐aminobutyric acidergic and glutamatergic afferent inputs in rostral ventrolateral medulla‐projecting neurons in the paraventricular nucleus of the hypothalamus of renovascular hypertensive rats

Biancardi

Campos

Stern

2009

J of Comparative Neurology

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An imbalance of excitatory and inhibitory functions has been shown to contribute to numerous pathological disorders. Accumulating evidence supports the idea that a change in hypothalamic γ-aminobutyric acid (GABA)-ergic inhibitory and glutamatergic excitatory synaptic functions contributes to exacerbated neurohumoral drive in prevalent cardiovascular disorders, including hypertension. However, the precise underlying mechanisms and neuronal substrates are still not fully elucidated. In the present study, we combined quantitative immunohistochemistry with neuronal tract tracing to determine whether plastic remodeling of afferent GABAergic and glutamatergic inputs into identified RVLM-projecting neurons of the hypothalamic paraventricular nucleus (PVN-RVLM) contributes to an imbalanced excitatory/inhibitory function in reno-vascular hypertensive rats (RVH). Our results indicate that both GABAergic and glutamatergic innervation densities increased in oxytocin-positive, PVN-RVLM (OT-PVN-RVLM) neurons in RVH rats. Despite this concomitant increase, time-dependent and compartment-specific differences in the reorganization of these inputs resulted in an altered balance of excitatory/inhibitory inputs in somatic and dendritic compartments. A net predominance of excitatory over inhibitory inputs was found in OT-PVN-RVLM proximal dendrites. Our results indicate that, along with previously described changes in neurotransmitter release probability and postsynaptic receptor function, remodeling of GABAergic and glutamatergic afferent inputs contributes as an underlying mechanism to the altered excitatory/ inhibitory balance in the PVN of hypertensive rats.

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Reduced GABA inhibition of sympathetic function in renal-wrapped hypertensive rats

Cited by 56 publications

References 35 publications

Water deprivation activates a glutamatergic projection from the hypothalamic paraventricular nucleus to the rostral ventrolateral medulla

Water deprivation activates a glutamatergic projection from the hypothalamic paraventricular nucleus to the rostral ventrolateral medulla

Effect of Intravenous Angiotensin II Infusion on Responses to Hypothalamic PVN Injection of Bicuculline

Altered balance of γ‐aminobutyric acidergic and glutamatergic afferent inputs in rostral ventrolateral medulla‐projecting neurons in the paraventricular nucleus of the hypothalamus of renovascular hypertensive rats

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