The brain renin–angiotensin system: location and physiological roles

McKinley, Michael J.; Albiston, Anthony L.; Allen, Andrew M.; Mathai, Michael L.; May, Clive; McAllen, Robin M.; Oldfield, Brian J.; Mendelsohn, Frederick A.O.; Chai, Siew Yeen

doi:10.1016/s1357-2725(02)00306-0

Cited by 458 publications

(381 citation statements)

References 134 publications

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“…Previously, we and others had shown that centrally administered angiotensin antagonist drugs were capable of blocking water drinking, vasopressin release, and natriuresis in response to intracerebroventricularly injected hypertonic saline, suggesting angiotensin signaling in osmoregulatory pathways (5,18,27,29,36,48). The results we have obtained in AgtϪ/Ϫ mice show that angiotensin peptides are not necessary in the brain (or elsewhere) for central osmoregulatory thirst mechanisms to function adequately.…”

Section: Discussionmentioning

confidence: 98%

“…Centrally administered angiotensin stimulates water drinking, vasopressin secretion, and a brisk natriuresis that promote a positive fluid balance and reduce plasma osmolality (19,29,38). One of the postulated physiological functions of brain angiotensin II is that of a signaling molecule in osmoregulatory neural pathways, probably as a neurotransmitter or modulator (5).…”

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confidence: 99%

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Osmoregulatory fluid intake but not hypovolemic thirst is intact in mice lacking angiotensin

Walker

Alexiou

Allen

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Water intakes in response to hypertonic, hypovolemic, and dehydrational stimuli were investigated in mice lacking angiotensin II as a result of deletion of the angiotensinogen gene (AgtϪ/Ϫ mice), and in C57BL6 wild-type (WT) mice. Baseline daily water intake in AgtϪ/Ϫ mice was approximately threefold that of WT mice because of a renal developmental disorder of the urinary concentrating mechanisms in AgtϪ/Ϫ mice. Intraperitoneal injection of hypertonic saline (0.4 and 0.8 mol/l NaCl) caused a similar dose-dependent increase in water intake in both AgtϪ/Ϫ and WT mice during the hour following injection. As well, AgtϪ/Ϫ mice drank appropriate volumes of water following water deprivation for 7 h. However, AgtϪ/Ϫ mice did not increase water or 0.3 mol/l NaCl intake in the 8 h following administration of a hypovolemic stimulus (30% polyethylene glycol sc), whereas WT mice increased intakes of both solutions during this time. Osmoregulatory regions of the brain [hypothalamic paraventricular and supraoptic nuclei, median preoptic nucleus, organum vasculosum of the lamina terminalis (OVLT), and subfornical organ] showed an increased number of neurons exhibiting Fos-immunoreactivity in response to intraperitoneal hypertonic NaCl in both AgtϪ/Ϫ mice and WT mice. Polyethylene glycol treatment increased Fos-immunoreactivity in the subfornical organ, OVLT, and supraoptic nuclei in WT mice but only increased Fos-immunoreactivity in the supraoptic nucleus in AgtϪ/Ϫ mice. These data show that brain angiotensin is not essential for the adequate functioning of neural pathways mediating osmoregulatory thirst. However, angiotensin II of either peripheral or central origin is probably necessary for thirst and salt appetite that results from hypovolemia.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Osmoregulatory fluid intake but not hypovolemic thirst is intact in mice lacking angiotensin

Walker

Alexiou

Allen

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…6 AT 1 R is rich in the specific brain nuclei that regulate SNS activation, such as the anteroventral third ventricle, paraventricular nucleus of the hypothalamus, nucleus tractus solitarii and RVLM. [48][49][50] Moreover, a high density of AT 1 R is present in the brain regions involved in the regulation of SNS activation, such as the circumventricular organs outside of the bloodbrain barrier, where peripherally administered ARBs are able to effect change without consideration of the blood-brain barrier, as well as inside of the blood-brain barrier. 50 The reduction of oxidative stress via inhibition of AT 1 R caused by orally administered TLM may not be a phenomenon unique to the RVLM.…”

Section: Discussionmentioning

confidence: 99%

Sympathoinhibition caused by orally administered telmisartan through inhibition of the AT1 receptor in the rostral ventrolateral medulla of hypertensive rats

2012

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In patients and animals with hypertension, sympathetic nervous system (SNS) activation is present. We have demonstrated that angiotensin II type 1 receptor (AT 1 R)-induced oxidative stress in the rostral ventrolateral medulla (RVLM), a vasomotor center in the brainstem, causes SNS activation in hypertensive rats. The aim of the present study was to determine whether orally administered AT 1 R blockers (ARBs) inhibit SNS activation through an anti-oxidant effect via inhibition of AT 1 R in the RVLM of hypertensive rats and, if so, whether the benefits are class effects of ARBs. Stroke-prone spontaneously hypertensive rats (SHRSPs), a hypertensive model with sympathoexcitation, were divided into four groups: SHRSPs treated with telmisartan (TLM), candesartan (CAN), or hydralazine (HYD) and a vehicle group (VEH). Although systolic blood pressure was reduced in the TLM, CAN and HYD groups to the same level, heart rate, SNS activation and oxidative stress in the RVLM were significantly lower in the TLM group only. The pressor effect caused by the microinjection of angiotensin II into the RVLM and the depressor effect caused by the microinjection of tempol, a superoxide dismutase mimetic, into the RVLM were both significantly smaller in TLM, but not in CAN or HYD. These results suggest that orally administered TLM inhibits SNS activation through an anti-oxidant effect via inhibition of AT 1 R in the RVLM of SHRSPs; these results are also independent of depressor effects and are not class effects of ARBs. Keywords: angiotensin II; brain; oxidative stress; sympathetic nervous system INTRODUCTION Sympathetic nervous system (SNS) activation is a main cause of the development and progression of hypertension. 1-4 SNS activation is mainly regulated by the brain, 5-7 and we have demonstrated in rat models with hypertension or heart failure that direct interventions to the brain have beneficial effects because of sympathoinhibition. [8][9][10][11][12][13][14] Particularly in the brain, SNS activation is mainly regulated by the rostral ventrolateral medulla (RVLM) in the brainstem, and the functional integrity of the RVLM is essential for the maintenance of basal vasomotor tone. 5,6 We have demonstrated that oxidative stress in the RVLM produced by the angiotensin II type 1 receptor (AT 1 R) causes SNS activation. 11,14-17 Upregulation of the central AT 1 R is important in the pathophysiology of hypertension. 6,7 Microinjection of AT 1 R blockers (ARBs) into the RVLM or intracerebroventricular infusion of ARBs inhibits SNS activation in hypertensive rats. 15,[18][19][20] However, AT 1 R or oxidative stress in the RVLM have not been targets for the treatment of hypertensive patients because we do not have suitable oral agents to inhibit AT 1 R or oxidative stress in the RVLM of hypertensive patients.

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“…Angiotensin II (AngII) is the principal peptide involved in vascular homeostasis in the brain RAS (McKinley et al 2003). The hemodynamic mechanisms of AngII are primarily mediated through activation of the type 1 angiotensin receptor (AT 1 ; Saavedra 2005) localized to brain regions involved in autonomic function (Ando et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Impact of the AGTR1 A1166C polymorphism on subcortical hyperintensities and cognition in healthy older adults

Salminen

Schofield

Pierce

et al. 2014

AGE

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Vascular aging consists of complex and multifaceted processes that may be influenced by genetic polymorphisms of the renin-angiotensin system. A polymorphism in the angiotensin II type 1 receptor gene (AGTR1/rs5186) has been associated with an increased risk for arterial stiffness, hypertension, and ischemic stroke. Despite these identified relationships, the impact of AGTR1 A1166C on white matter integrity and cognition is less clear in a healthy aging population. The present study utilized indices of neuroimaging and neuropsychological assessment to examine the impact of the A1166C polymorphism on subcortical hyperintensities (SH) and cognition in 49 healthy adults between ages 51-85. Using a dominant statistical model (CC + CA (risk) vs. AA), results revealed significantly larger SH volume for individuals with the C1166 variant (p<0.05, partial eta 2 = 0.117) compared with those with the AA genotype. Post hoc analyses indicated that increased SH volume in C allele carriers could not be explained by vascular factors such as pulse pressure or body mass index. In addition, cognitive performance did not differ significantly between groups and was not significantly associated with SH in this cohort. Results suggest that presence of the C1166 variant may serve as a biomarker of risk for suboptimal brain integrity in otherwise healthy older adults prior to changes in cognition.

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The brain renin–angiotensin system: location and physiological roles

Cited by 458 publications

References 134 publications

Osmoregulatory fluid intake but not hypovolemic thirst is intact in mice lacking angiotensin

Osmoregulatory fluid intake but not hypovolemic thirst is intact in mice lacking angiotensin

Sympathoinhibition caused by orally administered telmisartan through inhibition of the AT1 receptor in the rostral ventrolateral medulla of hypertensive rats

Impact of the AGTR1 A1166C polymorphism on subcortical hyperintensities and cognition in healthy older adults

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