Responses to GABA-A receptor blockade in the hypothalamic PVN are attenuated by local AT<sub>1</sub> receptor antagonism

Chen, Qing Hui; Toney, Glenn M.

doi:10.1152/ajpregu.00028.2003

Cited by 60 publications

(73 citation statements)

References 39 publications

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“…In support of this hypothesis, we found that PVN administration of two AT1R antagonists, candesartan and valsartan, significantly decreased arterial BP in water-deprived rats. In contrast, AT1R blockade had little effect in waterreplete animals, in agreement with previous reports (12,49). Interestingly, the depressor response was slowly developing, reaching its nadir only after 15-20 min.…”

Section: Discussionsupporting

confidence: 92%

AT₁ and glutamatergic receptors in paraventricular nucleus support blood pressure during water deprivation

Freeman¹,

Brooks²

2007

American Journal of Physiology-Regulatory, Integrative and Comp

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ter deprivation activates sympathoexcitatory neurons in the paraventricular nucleus (PVN); however, the neurotransmitters that mediate this activation are unknown. To test the hypothesis that ANG II and glutamate are involved, effects on blood pressure (BP) of bilateral PVN microinjections of ANG II type 1 receptor (AT1R) antagonists, candesartan and valsartan, or the ionotropic glutamate receptor antagonist, kynurenate, were determined in urethane-anesthetized waterdeprived and water-replete male rats. Because PVN may activate sympathetic neurons via the rostral ventrolateral medulla (RVLM) and because PVN disinhibition increases sympathetic activity in part via increased drive of AT1R in the RVLM, candesartan was also bilaterally microinjected into the RVLM. Total blockade of the PVN with bilateral microinjections of muscimol, a GABAA agonist, decreased BP more (P Ͻ 0.05) in water-deprived (Ϫ29 Ϯ 8 mmHg) than in water-replete (Ϫ7 Ϯ 2 mmHg) rats, verifying that the PVN is required for BP maintenance during water deprivation. PVN candesartan slowly lowered BP by 7 Ϯ 1 mmHg (P Ͻ 0.05). In waterreplete rats, however, candesartan did not alter BP (1 Ϯ 1 mmHg). Valsartan also produced a slowly developing decrease in arterial pressure (Ϫ6 Ϯ 1 mmHg; P Ͻ 0.05) in water-deprived but not in water-replete (Ϫ1 Ϯ 1 mmHg) rats. In water-deprived rats, PVN kynurenate rapidly decreased BP (Ϫ19 Ϯ 3 mmHg), and the response was greater (P Ͻ 0.05) than in water-replete rats (Ϫ4 Ϯ 1 mmHg). Finally, as in PVN, candesartan in RVLM slowly decreased BP in water-deprived (Ϫ8 Ϯ 1 mmHg; P Ͻ 0.05) but not in water-replete (Ϫ3 Ϯ 1 mmHg) rats. These data suggest that activation of AT 1 and glutamate receptors in PVN, as well as of AT1R in RVLM, contributes to BP maintenance during water deprivation.angiotensin II; rostral ventrolateral medulla; candesartan; valsartan; glutamate WATER DEPRIVATION IS ASSOCIATED with regional activation of sympathetic nerves (8,37,38). Recent studies indicate that sympathoexcitatory neurons in the paraventricular nucleus (PVN) contribute to this activation, since acute blockade of the PVN results in profound decreases in arterial blood pressure (BP) and sympathetic activity (42,43). Moreover, PVN neurons that project to the spinal cord, which houses sympathetic preganglionic neurons, or to the rostral ventrolateral medulla (RVLM), a hindbrain region responsible for the basal activity of many sympathetic nerves, express c-fos after water deprivation (41, 42), indirectly suggesting activation. However, the neurotransmitters that drive PVN sympathoexcitatory neurons during water deprivation have not been identified. Considerable indirect evidence implicates ANG II or a related peptide. First, water deprivation increases circulating ANG II levels, and increased binding of ANG II to type 1 receptors (AT1R) in circumventricular organs, such as the subfornical organ, increases the release and activity of an ANG II-like peptide in PVN (for a review, see Ref. 17). Second, both water deprivation and increases in osmolali...

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Section: Discussionsupporting

confidence: 92%

AT₁ and glutamatergic receptors in paraventricular nucleus support blood pressure during water deprivation

Freeman¹,

Brooks²

2007

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Similar to previous studies, 4,5,6,22 our data show that BMI microinjected into the PVN in rats infused with vehicle for 7 days significantly increases renal SNA, MAP, and HR. In contrast, rats infused with Ang II had significantly blunted responses.…”

Section: Discussionsupporting

confidence: 91%

“…Standard methods were used to record renal SNA. 4,17 Renal SNA responses to intravenous sodium nitroprusside and phenylephrine were used to assess the signal-to-noise ratio of each recording. Hematocrit was measured from venous blood.…”

Section: Methodsmentioning

confidence: 99%

“…More recently, it has been shown that local GABA-Ang II interactions may be key to regulating PVN neuronal excitability and sympathetic outflow. 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.…”

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confidence: 99%

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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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“…In spite of receiving strong tonic inhibitory input (Chen and Toney 2003b;Chen et al 2003;Kenney et al 2003;Li et al 2006;Martin et al 1991), PVN neurons nevertheless do contribute to ongoing SNA. In anesthetized rats, for example, studies have shown that acute inhibition of PVN neuronal activity or blockade of excitatory inputs reduces ongoing renal SNA (RSNA) (Akine et al 2003;Allen 2002;Stocker et al 2004b, lumbar SNA , and ABP (Akine et al 2003;Allen 2002;Freeman and Brooks 2007;Stocker et al 2004b.…”

Section: Introductionmentioning

confidence: 99%

In Vivo Discharge Properties of Hypothalamic Paraventricular Nucleus Neurons With Axonal Projections to the Rostral Ventrolateral Medulla

Chen

Toney

2010

Journal of Neurophysiology

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Chen Q-H, Toney GM. In vivo discharge properties of hypothalamic paraventricular nucleus neurons with axonal projections to the rostral ventrolateral medulla. J Neurophysiol 103: 4 -15, 2010. First published November 4, 2009 doi:10.1152/jn.00094.2009. The hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) are key components of a neural network that generates and regulates sympathetic nerve activity (SNA). Although each region has been extensively studied, little is presently known about the in vivo discharge properties of individual PVN neurons that directly innervate the RVLM. Here extracellular recording was performed in anesthetized rats, and antidromic stimulation was used to identify single PVN neurons with axonal projections to the RVLM (n ϭ 94). Neurons were divided into two groups that had either unbranched axons terminating in the RVLM (i.e., PVN-RVLM neurons, n ϭ 65) or collateralized axons targeting both the RVLM and spinal cord [i.e., PVN-RVLM/ intermediolateral cell column (IML) neurons, n ϭ 29]. Many PVN-RVLM (32/65, 49%) and PVN-RVLM/IML (17/29, 59%) neurons were spontaneously active. The average firing frequency was not different across groups. Spike-triggered averaging revealed that spontaneous discharge of most neurons was temporally correlated with renal SNA (PVN-RVLM: 12/21, 57%; PVN-RVLM/IML: 6/9, 67%). Time histograms triggered by the electrocardiogram (ECG) R-wave indicated that discharge of most cells was also cardiac rhythmic (PVN-RVLM: 25/32, 78%; PVN-RVLM/IML: 10/17, 59%). Raising and lowering arterial blood pressure to increase and decrease arterial baroreceptor input caused a corresponding decrease and increase in firing frequency among cells of both groups (PVN-RVLM: 9/13, 69%; PVN-RVLM/IML: 4/4, 100%). These results indicate that PVN-RVLM and PVN-RVLM/IML neurons are both capable of contributing to basal sympathetic activity and its baroreflex modulation.

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Responses to GABA-A receptor blockade in the hypothalamic PVN are attenuated by local AT₁ receptor antagonism

Cited by 60 publications

References 39 publications

AT₁ and glutamatergic receptors in paraventricular nucleus support blood pressure during water deprivation

AT₁ and glutamatergic receptors in paraventricular nucleus support blood pressure during water deprivation

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

In Vivo Discharge Properties of Hypothalamic Paraventricular Nucleus Neurons With Axonal Projections to the Rostral Ventrolateral Medulla

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Responses to GABA-A receptor blockade in the hypothalamic PVN are attenuated by local AT1 receptor antagonism

Cited by 60 publications

References 39 publications

AT1 and glutamatergic receptors in paraventricular nucleus support blood pressure during water deprivation

AT1 and glutamatergic receptors in paraventricular nucleus support blood pressure during water deprivation

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

In Vivo Discharge Properties of Hypothalamic Paraventricular Nucleus Neurons With Axonal Projections to the Rostral Ventrolateral Medulla

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Responses to GABA-A receptor blockade in the hypothalamic PVN are attenuated by local AT₁ receptor antagonism

AT₁ and glutamatergic receptors in paraventricular nucleus support blood pressure during water deprivation

AT₁ and glutamatergic receptors in paraventricular nucleus support blood pressure during water deprivation