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

LaGrange, Lila P.; Toney, Glenn M.; Bishop, Vernon S.

doi:10.1161/01.hyp.0000102181.83892.04

Cited by 24 publications

(21 citation statements)

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“…Indeed, pregnancy appears to increase the relative contribution of PVN ANG II type 1 receptors to the support of arterial pressure and renal sympathetic nerve activity (16). Third, acute and chronic increases in ANG II decrease GABAergic function in PVN, possibly by presynaptic inhibition of GABA release (17,19,20).…”

Section: Discussionmentioning

confidence: 99%

“…Yet, indirect evidence suggests that any PVN GABAergic suppressive influence on baroreflex function is lessened, thus counteracting the more primary inhibitory effect of pregnancy. First, pregnancy activates the renin-angiotensin system (3, 30), which has been shown to decrease PVN GABAergic inhibition of sympathetic activity and heart rate (17,19,20). Second, a recent study by Kvochina et al (16) demonstrated that the increases in renal sympathetic nerve activity, HR, and arterial pressure following blockade of PVN GABA A receptors were less in anesthetized rats studied near term compared with nonpregnant animals.…”

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confidence: 99%

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GABA in the paraventricular nucleus tonically suppresses baroreflex function: alterations during pregnancy

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Cassaglia

Brooks

2011

American Journal of Physiology-Regulatory, Integrative and Comp

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It is well established that GABAergic inputs to the paraventricular nucleus of the hypothalamus (PVN) tonically suppress heart rate and the activity of several sympathetic nerves. However, whether GABA similarly inhibits PVN control of baroreflex function has not been previously investigated. To test this hypothesis, it was determined whether microinjection of the GABA A antagonist, bicuculline, into the PVN enhances the baroreflex in anesthetized female virgin rats. In addition, because GABAergic inhibition of PVN preautonomic neurons is decreased during pregnancy, it was also determined whether the effects of PVN bicuculline administration on baroreflex function were less in pregnant animals. In virgin rats, PVN microinjection of bicuculline increased (P Ͻ 0.05) baroreflex gain and maximum levels of heart rate (gain, from 1.6 Ϯ 0.6 to 3.8 Ϯ 1.3 bpm/mmHg; maximum, from 406 Ϯ 18 to 475 Ϯ 14 bpm) and of lumbar sympathetic nerve activity (gain from 2.6 Ϯ 0.7 to 4.8 Ϯ 1.6%/ mmHg; maximum, 149 Ϯ 32 to 273 Ϯ 48%), indicating that PVN GABA normally suppresses baroreflex function. Pregnancy decreased heart rate baroreflex gain (pregnant, 0.9 Ϯ 0.3 bpm/mmHg; virgin, 1.9 Ϯ 0.2 bpm/mmHg; P Ͻ 0.05). Following PVN bicuculline administration in pregnant rats, smaller (P Ͻ 0.01) increments in baroreflex gain (pregnant, 0.6 Ϯ 0.1 bpm/mmHg; virgin, 2.4 Ϯ 0.9 bpm/mmHg) and maximum (pregnant, 33 Ϯ 7 bpm; virgin, 75 Ϯ 12 bpm; P Ͻ 0.05) were produced. Collectively, these data suggest that the PVN normally inhibits the baroreflex via tonic GABAergic inputs and that this inhibition is less during pregnancy. heart rate; baroreceptor reflex; lumbar sympathetic nervous system; ␥-aminobutyric acid THE PARAVENTRICULAR NUCLEUS (PVN) of the hypothalamus integrates multiple forebrain and brain stem inputs to regulate the autonomic nervous system via outputs that ultimately converge with focal brain stem nuclei, such as the rostral ventrolateral medulla, as well as preganglionic sympathetic neurons in the spinal cord (7,27,29,32). While the contribution of the PVN and its connections to basal sympathetic tone at rest in normal animals is minimal, it appears to drive increased sympathetic activity in such pathophysiological states as hypertension, heart failure, and water deprivation (7,27). Moreover, the PVN mediates, in part, autonomic responses to diverse homeostatic challenges, such as changes in food intake, blood volume, stress, and body temperature (29). However, whether and how the PVN can also influence the regulation of the baroreceptor reflex is currently unclear.Of the PVN neurotransmitters and neuromodulators that effect these many functions, the tonically active inhibitory GABAergic inputs to preautonomic neurons are dominant (10, 28). Indeed, local pharmacological blockade of PVN GABA A receptors elicits profound increases in arterial pressure, heart rate (HR), and sympathetic activity and excites neurons that project to the brain stem or spinal cord (15,18,20,22). Therefore, one aim of the present study was to test the hypothes...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

GABA in the paraventricular nucleus tonically suppresses baroreflex function: alterations during pregnancy

Page

Cassaglia

Brooks

2011

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Conversely, sympathetic or cardiovascular effects seen after microinjection of higher doses of BMI into nearby regions may well be a consequence of exciting neurons in the DMH (see DeNovellis et al, 1995). This would be particularly true in reports that have targeted the PVN with microinjections ranging from 50 pmol to as much as 2 nmol of BMI and assumed that sympathoexcitatory or cardiovascular effects noted were a consequence of disinhibiting neurons in the latter region (Martin et al, 1991;Reynolds et al, 1996;Zhang and Patel, 1998;Kenney et al, 2003;LaGrange et al, 2003;Reddy et al, 2005;Martin et al, 2006). The extent of the region activated by microinjection of 10 pmoles of BMI in this study make it highly plausible that at least some of the changes elicited by microinjection of these larger doses into the nearby PVN may be a consequence of spread or diffusion to the DMH.…”

Section: Discussionmentioning

confidence: 99%

Induction of Fos-immunoreactivity in the rat brain following disinhibition of the dorsomedial hypothalamus

et al. 2008

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Activation of neurons in the dorsomedial hypothalamus (DMH) appears to play an important role in signaling the excitation of brain regions responsible for experimental fever and for many of the physiological and behavioral changes seen in experimental stress or anxiety in rats. Here, we examined the effect of disinhibition of the DMH by unilateral microinjection of bicuculline methiodide (BMI) on Fos expression in selected regions of the brain that have been implicated in anxiety and responses to stress and fever in rats. Disinhibition of the DMH resulted in dramatic increases in local Fos expression and also increased the numbers of Fos-positive neurons in the lateral septal nucleus and in both the parvocellular and magnocellular subdivisions of the paraventricular nucleus, with greater increases ipsilateral to the injection site in the DMH. However, microinjection of BMI had no significant effect on Fos expression in the bed nucleus of the stria terminalis, another forebrain area implicated in stress and anxiety. In the brainstem, disinhibition of the DMH increased Fos expression in the nucleus tractus solitarius and the ventrolateral medulla bilaterally with greater increases again ipsilateral to the site of the microinjection, and also in the midline rostral raphe pallidus. Thus, disinhibition of neurons in the DMH in conscious rats results in increases in Fos expression in selected forebrain and brainstem regions that have been implicated in stress-induced physiological changes, anxiety, and experimental fever.

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“…[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.…”

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confidence: 99%

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

Cited by 24 publications

References 40 publications

GABA in the paraventricular nucleus tonically suppresses baroreflex function: alterations during pregnancy

GABA in the paraventricular nucleus tonically suppresses baroreflex function: alterations during pregnancy

Induction of Fos-immunoreactivity in the rat brain following disinhibition of the dorsomedial hypothalamus

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

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