Cardiovascular effects of angiotensin II and glutamate in the PVN of Dahl salt-sensitive rats

Gabor, Alexander; Leenen, Frans H. H.

doi:10.1016/j.brainres.2012.01.060

Cited by 32 publications

(25 citation statements)

References 47 publications

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“…Water intake was also higher in Ang II hypertensive rats, likely from the effects of circulating Ang II on AT 1 receptors in circumventricular organs of the lamina terminalis (LT) that lack a blood-brain barrier, such as the subfornical organ (SFO). 21 In contrast to absent effects in normal rats, [11][12][13] infusion of candesartan or kynurenate in the PVN lowered BP in rats after subcutaneous Ang II for 2 weeks. These findings are consistent with other models of chronic sympathetic hyperactivity 9,11,12 and indicate that increased glutamate and AT 1 -receptor activation in the PVN contributes to the maintenance of elevated BP from a chronic increase in circulating Ang II.…”

Section: Candesartan and Kynurenate In The Pvn Of Rats With Subcutanementioning

confidence: 96%

“…13 In Dahl S rats on a high-salt diet, at the peak BP decrease by a glutamate receptor blocker, an AT 1 -receptor blocker in the PVN does not further decrease BP. 13 These findings suggest that the effects of increased AT 1 -receptor activation in the PVN of hypertensive Dahl S rats are fully mediated by local glutamate release. Consistent with these findings, Ang II increases glutamatergic signaling in the PVN, either by increasing glutamate release from interneurons, 14,15 or by decreasing gamma-amino butyric acid (GABA)-mediated inhibition of the PVN.…”

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confidence: 97%

“…11 Glutamate and AT 1 -receptor blockers in the PVN decrease BP in waterdeprived rats 12 and in Dahl S rats on high-salt diet. 13 In Dahl S rats on a high-salt diet, at the peak BP decrease by a glutamate receptor blocker, an AT 1 -receptor blocker in the PVN does not further decrease BP. 13 These findings suggest that the effects of increased AT 1 -receptor activation in the PVN of hypertensive Dahl S rats are fully mediated by local glutamate release.…”

mentioning

confidence: 97%

“…Infusions were performed intracerebroventricular at 3.8 μL/min and into the PVN at 300 nL/min as in our previous studies. 13,18 Animals were allowed to settle for ≥30 minutes before recording of baseline BP and HR levels for 10 minutes. For multiple infusions into the PVN, at the peak effect of the first drug, cannulas were removed, reloaded with the second drug, and relowered into the PVN within ≈5 minutes of the end of the first infusion.…”

mentioning

confidence: 99%

“…Infusion sites were considered to be inside the lateral ventricle if the dye was confined to the ventricles and not in brain tissue, and inside the PVN if the midpoint of the dye circle was inside the borders of the PVN. 13 Only data from rats with injection sites inside the PVN ( Figure S1 in the online-only Data Supplement) or lateral ventricle were used for analysis. The distribution of the volume infused into the PVN was described previously ( Figure 2B).…”

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Central Mineralocorticoid Receptors and the Role of Angiotensin II and Glutamate in the Paraventricular Nucleus of Rats With Angiotensin II–Induced Hypertension

Gabor

Leenen

2013

Hypertension

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A chronic increase in circulating angiotensin II (Ang II) increases neuronal activation in hypothalamic nuclei, such as the paraventricular nucleus (PVN), 1,2 and causes progressive hypertension, 2,3 presumably by increasing sympathetic activity. [4][5][6] A central neuromodulatory pathway involving aldosterone-endogenous ouabain (EO) seems to play a critical role in these responses to Ang II. 2,7 Chronic subcutaneous infusion of Ang II increases plasma and hypothalamic aldosterone content. 2 Intracerebroventricular infusion of an aldosterone synthase (AS) inhibitor prevents increase in hypothalamic, but not in plasma aldosterone, and intracerebroventricular infusion of an AS inhibitor or a mineralocortoicod receptor (MR) blocker markedly attenuate the neuronal activation in the PVN.2 Intracerebroventricular infusion of an AS inhibitor, 2 MR blocker, 2,7 EO-binding antibody Fab fragments (Digibind), 2 or an angiotensin type 1 (AT 1 )-receptor blocker 8 largely prevents the Ang II-induced hypertension. These findings suggest that a chronic increase in circulating Ang II increases local hypothalamic aldosterone production, and activates an MR-EO pathway in the brain, which is essential for the Ang II-induced hypertension.Several models of chronic sympathetic hyperactivity are associated with an increase in glutamate receptor and AT 1 -receptor activation in the PVN. A glutamate or AT 1 -receptor blocker in the PVN decreases sympathetic nerve activity, blood pressure (BP), and heart rate (HR) in rats with chronic heart failure 9,10 and in spontaneously hypertensive rats. 11 Glutamate and AT 1 -receptor blockers in the PVN decrease BP in waterdeprived rats 12 and in Dahl S rats on high-salt diet. 13 In Dahl S rats on a high-salt diet, at the peak BP decrease by a glutamate receptor blocker, an AT 1 -receptor blocker in the PVN does not further decrease BP. 13 These findings suggest that the effects of increased AT 1 -receptor activation in the PVN of hypertensive Dahl S rats are fully mediated by local glutamate release. Consistent with these findings, Ang II increases glutamatergic signaling in the PVN, either by increasing glutamate release from interneurons, 14,15 or by decreasing gamma-amino butyric acid (GABA)-mediated inhibition of the PVN. 16,17 No studies have yet evaluated the role of the central aldosterone neuromodulatory pathway in Ang II and glutamate receptor activation in the PVN of hypertensive rats. We hypothesized Abstract-A chronic increase in circulating angiotensin II (Ang II) activates an aldosterone-mineralocorticoid receptorouabain neuromodulatory pathway in the brain that increases neuronal activation in hypothalamic nuclei, such as the paraventricular nucleus (PVN) and causes progressive hypertension. Several models of chronic sympathetic hyperactivity are associated with an increase in AT 1 and glutamate receptor activation in the PVN. The current study evaluated whether increased angiotensin type 1 (AT 1 ) and glutamate receptor-dependent signaling in the PVN contributes to the mainten...

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Section: Candesartan and Kynurenate In The Pvn Of Rats With Subcutanementioning

confidence: 96%

mentioning

confidence: 97%

mentioning

confidence: 97%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Central Mineralocorticoid Receptors and the Role of Angiotensin II and Glutamate in the Paraventricular Nucleus of Rats With Angiotensin II–Induced Hypertension

Gabor

Leenen

2013

Hypertension

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Female protection from slow‐pressor effects of angiotensin II involves prevention of ROS production independent of NMDA receptor trafficking in hypothalamic neurons expressing angiotensin 1A receptors

Marques-Lopes

Lynch

Kempen

et al. 2015

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Renin-angiotensin system over-activity, up-regulation of post-synaptic NMDA receptor function, and increased reactive oxygen species (ROS) production in the hypothalamic paraventricular nucleus (PVN) are hallmarks of angiotensin II (AngII)-induced hypertension, which is far more common in young males than in young females. We hypothesize that the sex differences in hypertension are related to differential AngII-induced changes in post-synaptic trafficking of the essential NMDA receptor GluN1 subunit and ROS production in PVN cells expressing angiotensin type 1a receptor (AT1aR). We tested this hypothesis using slow-pressor (14 day) infusion of AngII (600ng/kg/min) in mice, which elicits hypertension in males but not in young females. Two month-old male and female transgenic mice expressing enhanced green fluorescent protein (EGFP) in AT1aR-containing cells were used. In males, but not females, AngII increased blood pressure and ROS production in AT1aR-EGFP PVN cells at baseline and following NMDA treatment. Electron microscopy showed that AngII increased cytoplasmic and total GluN1-silver-intensified immunogold (SIG) densities, and induced a trend towards an increase in near plasmalemmal GluN1-SIG density in AT1aR-EGFP dendrites of males and females. Moreover, AngII decreased dendritic area and diameter in males, but increased dendritic area of small (<1μm) dendrites and decreased diameter of large (>1μm) dendrites in females. Fluorescence microscopy revealed that AT1aR and estrogen receptor β do not co-localize suggesting that, if estrogen is involved, its effect is indirect. The data suggest that the sexual dimorphism in AngII-induced hypertension is associated with sex differences in ROS production in AT1aR-containing PVN cells, but not with post-synaptic NMDA receptor trafficking.

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Glutamatergic Regulation of Hypothalamic Presympathetic Neurons in Hypertension

Pan

2017

Curr Hypertens Rep

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Elevated sympathetic vasomotor tone emanating from the brain is a major mechanism involved in the development of hypertension. Increased glutamatergic excitatory input to presympathetic neurons in the paraventricular nucleus (PVN) of the hypothalamus leads to increased sympathetic outflow in various animal models of hypertension. Recent studies have revealed molecular and cellular mechanisms underlying enhanced glutamatergic synaptic input to PVN presympathetic neurons in hypertension. In this review article, we summarize recent findings on changes in inotropic and metabotropic glutamate receptors, at both presynaptic and postsynaptic sites, responsible for increased glutamatergic input to PVN presympathetic neurons in hypertension. Particular emphasis is placed on the role of protein kinases and phosphatases in the potentiated activity of synaptic NMDA receptors in the PVN in hypertension. New findings about glutamatergic synaptic plasticity in the PVN not only improve the understanding of molecular mechanisms involved in heightened activity of the sympathetic nervous system but also suggest new therapeutic targets for treating drug-resistant, neurogenic hypertension.

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Cardiovascular effects of angiotensin II and glutamate in the PVN of Dahl salt-sensitive rats

Cited by 32 publications

References 47 publications

Central Mineralocorticoid Receptors and the Role of Angiotensin II and Glutamate in the Paraventricular Nucleus of Rats With Angiotensin II–Induced Hypertension

Central Mineralocorticoid Receptors and the Role of Angiotensin II and Glutamate in the Paraventricular Nucleus of Rats With Angiotensin II–Induced Hypertension

Female protection from slow‐pressor effects of angiotensin II involves prevention of ROS production independent of NMDA receptor trafficking in hypothalamic neurons expressing angiotensin 1A receptors

Glutamatergic Regulation of Hypothalamic Presympathetic Neurons in Hypertension

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