Central actions of angiotensin in cardiovascular control: Multiple roles for a single peptide

1992 ◽  
Vol 70 (5) ◽  
pp. 779-785 ◽  
Author(s):  
Alastair V. Ferguson ◽  
Katharine M. Wall
Keyword(s):  
Blood Pressure ◽  
Area Postrema ◽  
Circumventricular Organs ◽  
Subfornical Organ ◽  
Cardiovascular Control ◽  
Multiple Roles ◽  
Ang Ii ◽  
Electrophysiological Studies ◽  
The Central Nervous System ◽  
Central Actions

Angiotensin II (ANG II) acts peripherally as a hormone, with actions on the vasculature, adrenals, and kidney. In addition, certain actions of ANG II in the central nervous system are directed toward cardiovascular control and fluid volume homeostasis. Dense binding sites for ANG II are found at circumventricular organs, which apparently have the ability to relay information to cardiovascular centers via neural circuitry. Microinjection of ANG II into the subfornical organ (SFO) or area postrema (AP) produces site-specific increases in blood pressure. In addition, electrophysiological studies demonstrate profound effects of ANG II, acting at the SFO, on activity of neurohypophysial neurons and release of oxytocin and vasopressin, which can be antagonized by ANG II blockers or attenuated by SFO lesions. Evidence from microinjection, electrophysiological, and lesion studies indicate a complex interaction between central sites involved in mechanisms of cardiovascular control: the SFO, AP, organum vasculosum of the lamina terminalis, and paraventricular and supraoptic nuclei of the hypothalamus. Not only is ANG II a humoral messenger in this central scenario, but evidence suggests it acts as a neurotransmitter or neuroendocrine substance within specific CNS pathways, suggesting multiple roles for this peptide in central cardiovascular control.Key words: blood pressure regulation, circumventricular organs, vasopressin, area postrema, subfornical organ.

scholarly journals Circumventricular organs and ANG II-induced salt appetite: blood pressure and connectivity

2000 ◽  
Vol 279 (6) ◽  
pp. R2277-R2286 ◽  
Author(s):  
Douglas A. Fitts ◽  
Elizabeth M. Starbuck ◽  
Alexandra Ruhf
Keyword(s):  
Blood Pressure ◽  
Water Intake ◽  
Femoral Vein ◽  
Circumventricular Organs ◽  
Subfornical Organ ◽  
Salt Appetite ◽  
Ang Ii ◽  
Sodium Depletion ◽  
Apparent Contradiction ◽  
Organum Vasculosum Laminae Terminalis

A lesion of the subfornical organ (SFO) may reduce sodium depletion-induced salt appetite, which is largely dependent on ANG II, and yet ANG II infusions directly into SFO do not provoke salt appetite. Two experiments were designed to address this apparent contradiction. In experiment 1 sustained infusions of ANG II into SFO did not produce a sustained elevation of blood pressure, and neither a reduction of blood pressure alone with minoxidil and captopril nor a reduction of both blood pressure and volume with furosemide and captopril enhanced salt appetite. Infusions of ANG II in the organum vasculosum laminae terminalis (OVLT) did evoke salt appetite without raising blood pressure. In experiment 2 knife cuts of the afferent and efferent fibers of the rostroventral pole of the SFO abolished water intake during an infusion of ANG II into the femoral vein but failed to reduce salt appetite during an infusion of ANG II into the OVLT. We conclude that 1) hypertension does not account for the failure of infusions of ANG II in the SFO to generate salt appetite and 2) the OVLT does not depend on its connectivity with the SFO to generate salt appetite during ANG II infusions.

RAS in the Central Nervous System: Potential Role in Neuropsychiatric Disorders

2018 ◽  
Vol 25 (28) ◽  
pp. 3333-3352 ◽  
Author(s):  
Natalia Pessoa Rocha ◽  
Ana Cristina Simoes e Silva ◽  
Thiago Ruiz Rodrigues Prestes ◽  
Victor Feracin ◽  
Caroline Amaral Machado ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Central Nervous System ◽  
Nervous System ◽  
Therapeutic Potential ◽  
Neuropsychiatric Disorders ◽  
Extensive Literature ◽  
Ang Ii ◽  
Mas Receptor ◽  
The Central Nervous System ◽  
The Brain

Background: The Renin-Angiotensin System (RAS) is a key regulator of cardiovascular and renal homeostasis, but also plays important roles in mediating physiological functions in the central nervous system (CNS). The effects of the RAS were classically described as mediated by angiotensin (Ang) II via angiotensin type 1 (AT1) receptors. However, another arm of the RAS formed by the angiotensin converting enzyme 2 (ACE2), Ang-(1-7) and the Mas receptor has been a matter of investigation due to its important physiological roles, usually counterbalancing the classical effects exerted by Ang II. Objective: We aim to provide an overview of effects elicited by the RAS, especially Ang-(1-7), in the brain. We also aim to discuss the therapeutic potential for neuropsychiatric disorders for the modulation of RAS. Method: We carried out an extensive literature search in PubMed central. Results: Within the brain, Ang-(1-7) contributes to the regulation of blood pressure by acting at regions that control cardiovascular functions. In contrast with Ang II, Ang-(1-7) improves baroreflex sensitivity and plays an inhibitory role in hypothalamic noradrenergic neurotransmission. Ang-(1-7) not only exerts effects related to blood pressure regulation, but also acts as a neuroprotective component of the RAS, for instance, by reducing cerebral infarct size, inflammation, oxidative stress and neuronal apoptosis. Conclusion: Pre-clinical evidence supports a relevant role for ACE2/Ang-(1-7)/Mas receptor axis in several neuropsychiatric conditions, including stress-related and mood disorders, cerebrovascular ischemic and hemorrhagic lesions and neurodegenerative diseases. However, very few data are available regarding the ACE2/Ang-(1-7)/Mas receptor axis in human CNS.

Subfornical organ efferents to paraventricular nucleus utilize angiotensin as a neurotransmitter

1993 ◽  
Vol 265 (2) ◽  
pp. R302-R309 ◽  
Author(s):  
Z. Li ◽  
A. V. Ferguson
Keyword(s):  
Electrical Stimulation ◽  
Paraventricular Nucleus ◽  
Response Times ◽  
Subfornical Organ ◽  
Ang Ii ◽  
Neural Responses ◽  
Local Pressure ◽  
Electrophysiological Studies ◽  
Excitatory Responses ◽  
Control Stimulation

In this study, we have utilized electrophysiological single unit recordings to evaluate the effects of nonpeptidergic angiotensin II (ANG II) antagonists on neural responses of hypothalamic paraventricular nucleus (PVN) neurons to either electrical stimulation in subfornical organ (SFO) or direct application of ANG II. Electrical stimulation (200-400 microA; 0.1 ms) in the SFO resulted in excitatory responses in 36 of 50 PVN neurons tested. Peristimulus histogram analysis of such excitatory effects demonstrated latencies of < 30 ms and variability of response times of approximately 50 ms in 14 of these 36 neurons. In view of previous anatomic and electrophysiological studies such inputs were therefore considered to be monosynaptically mediated by direct neural inputs from the SFO. The remaining 22 cells excited by such SFO stimulation showed responses of longer latency and duration suggestive of a different underlying synaptic mechanism. Local pressure ejection of ANG II into the PVN resulted in increased neural activity in 50% (9 of 18) of the neurons tested. After systemic (3 mg/kg iv) or local (2 x 10(-2) M; 1-25 s; 2-40 psi) microinjection of the nonpeptidergic angiotensin II1 (AT1) receptor antagonist losartan, SFO excitations were attenuated in 63.9% (23 of 36) of the PVN neurons tested, such pharmacologically blocked excitatory responses being reduced by 68.3 +/- 5.2% from control stimulation effects (P < 0.001). Similar losartan-induced attenuations of both short latency (presumed monosynaptic) (50.0%) and longer latency (72.7%) responses were observed. In addition, losartan also abolished the excitatory effects of local administration of ANG II on 77.8% (7 of 9) of ANG II-sensitive neurons in PVN tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Enalapril decreases angiotensin II receptors in subfornical organ of SHR

1989 ◽  
Vol 256 (6) ◽  
pp. H1609-H1614 ◽  
Author(s):  
A. J. Nazarali ◽  
J. S. Gutkind ◽  
F. M. Correa ◽  
J. M. Saavedra
Keyword(s):  
Angiotensin Ii ◽  
Angiotensin Converting Enzyme ◽  
Enzyme Inhibitor ◽  
Area Postrema ◽  
Subfornical Organ ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors ◽  
Wky Rats ◽  
Enalapril Treatment

We studied brain angiotensin II (ANG II) receptors by quantitative autoradiography in adult normotensive Wistar-Kyoto (WKY) rats and in spontaneously hypertensive rats (SHR) after treating the rats with the converting-enzyme inhibitor enalapril, 25 mg/kg, po daily for 14 days. Enalapril treatment decreased blood pressure in only SHR, inhibited plasma angiotensin-converting enzyme activity by 85%, and increased plasma ANG I concentration and renin activity in both WKY and SHR. In the untreated SHR animals, ANG II receptor concentrations were higher in the subfornical organ, the area postrema, the nucleus of the solitary tract, and the inferior olive when compared with the untreated WKY rats. Enalapril treatment produced a large decrease in only subfornical organ ANG II receptors of SHR. The selective reversal of the alteration in subfornical organ ANG II receptors in SHR may indicate a decreased central response to ANG II and may be related to the mode of action of angiotensin-converting enzyme inhibitors in this model.

17β-Estradiol inhibits angiotensin II activation of area postrema neurons

2003 ◽  
Vol 285 (4) ◽  
pp. H1515-H1520 ◽  
Author(s):  
Jaya Pamidimukkala ◽  
Meredith Hay
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Area Postrema ◽  
Ang Ii ◽  
Circumventricular Organ ◽  
Ici 182,780 ◽  
Central Neurons ◽  
Total Inhibition ◽  
17Β Estradiol ◽  
Vasoactive Peptide

It is well established that the area postrema, as a circumventricular organ, is susceptible to modulation by circulating hormones and peptides. Furthermore, activation of the area postrema has been shown to modulate central neurons involved in the regulation of cardiovascular function and blood pressure. In particular, the vasoactive peptide angiotensin II (ANG II) has been shown to inhibit baroreflex regulation of heart rate and increase sympathetic outflow and blood pressure via activation of area postrema neurons. Estrogen is thought to protect against hypertension in both humans and animal models and has been shown in a number of systems to alter the effects of ANG II. The purpose of the present study was to determine the effects of estrogen on ANG II activation of area postrema neurons. In this study, the effects of ANG II and KCl on fura 2-measured cytosolic Ca2+ concentration ([Ca2+]i) responses in cultured area postrema neurons in the presence and absence of 12-h exposure to 100 nM 17β-estradiol (E2) were evaluated. In neurons incubated in control vehicle media, 50 nM ANG II increased [Ca2+]i by 92 ± 12%. In neurons preincubated with 100 nM E2, ANG II increased [Ca2+]i by only 68 ± 11%, for a total inhibition of the ANG II-evoked response of 24%. Coapplication of the estrogen receptor antagonist ICI-182,780 did not inhibit the effects of E2. In the same cells in which the effects of E2 on ANG II-evoked responses were tested, the effects of incubation in E on the depolarization-induced increased [Ca2+2]i due to 60 mM KCl were also tested. Incubation of the cells with 100 nM E increased the KCl-evoked [Ca2+2]i response, and this response was blocked by ICI-182,780. These results suggest that in the area postrema, estrogen may utilize multiple pathways to modulate neural activity and responses to ANG II.

scholarly journals Role of neurons and glia in the CNS actions of the renin-angiotensin system in cardiovascular control

2015 ◽  
Vol 309 (5) ◽  
pp. R444-R458 ◽  
Author(s):  
Annette D. de Kloet ◽  
Meng Liu ◽  
Vermalí Rodríguez ◽  
Eric G. Krause ◽  
Colin Sumners
Keyword(s):  
Blood Pressure ◽  
Glial Cell ◽  
Renin Angiotensin System ◽  
Cardiovascular Control ◽  
Health Concern ◽  
Ang Ii ◽  
Ongoing Research ◽  
Angiotensin System ◽  
Renin Angiotensin

Despite tremendous research efforts, hypertension remains an epidemic health concern, leading often to the development of cardiovascular disease. It is well established that in many instances, the brain plays an important role in the onset and progression of hypertension via activation of the sympathetic nervous system. Further, the activity of the renin-angiotensin system (RAS) and of glial cell-mediated proinflammatory processes have independently been linked to this neural control and are, as a consequence, both attractive targets for the development of antihypertensive therapeutics. Although it is clear that the predominant effector peptide of the RAS, ANG II, activates its type-1 receptor on neurons to mediate some of its hypertensive actions, additional nuances of this brain RAS control of blood pressure are constantly being uncovered. One of these complexities is that the RAS is now thought to impact cardiovascular control, in part, via facilitating a glial cell-dependent proinflammatory milieu within cardiovascular control centers. Another complexity is that the newly characterized antihypertensive limbs of the RAS are now recognized to, in many cases, antagonize the prohypertensive ANG II type 1 receptor (AT1R)-mediated effects. That being said, the mechanism by which the RAS, glia, and neurons interact to regulate blood pressure is an active area of ongoing research. Here, we review the current understanding of these interactions and present a hypothetical model of how these exchanges may ultimately regulate cardiovascular function.

Subfornical organ and cardiovascular influences on identified septal neurons

1988 ◽  
Vol 254 (3) ◽  
pp. R544-R551 ◽  
Author(s):  
S. D. Donevan ◽  
A. V. Ferguson
Keyword(s):  
Blood Pressure ◽  
Medial Septum ◽  
Subfornical Organ ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Diagonal Band ◽  
Sprague Dawley Rats ◽  
Relay Neuron ◽  
Afferent Information ◽  
Septal Neurons

We have identified, in urethan-anesthetized male Sprague-Dawley rats, a polysynaptic pathway connecting the subfornical organ (SFO) with the paraventricular nucleus (PVN) with a relay neuron in the medial septum-diagonal band of Broca (MS-DBB). Extracellular recordings were obtained from 136 MS-DBB neurons antidromically identified as projecting to the PVN. SFO stimulation orthodromically activated 79% of these cells (mean latency, 21.2 +/- 0.6 ms; mean duration, 6.0 +/- 0.2 ms), whereas stimulation in the fornix or hippocampal commissure had no effect. Of 35 identified MS-DBB neurons tested with systemic angiotensin II (ANG II), eight showed increases and six decreases in excitability that coincided with the ANG II-induced increase in blood pressure. To determine whether such changes were blood pressure related, 23 of the 35 identified MS-DBB neurons tested with ANG II were tested with systemic epinephrine. In every case the effect of epinephrine was similar to that of ANG II. These findings suggest that neurons in the MS-DBB receive afferent information from the SFO and the cardiovascular system. These cells in turn may activate neurons involved in the control of a variety of autonomic functions.

Differential regulation of central vasopressin in transgenic rats harboring the mouse Ren-2 gene

1994 ◽  
Vol 267 (3) ◽  
pp. R786-R791 ◽  
Author(s):  
A. Moriguchi ◽  
C. M. Ferrario ◽  
K. B. Brosnihan ◽  
D. Ganten ◽  
M. Morris
Keyword(s):  
Blood Pressure ◽  
Ang Ii ◽  
Intracerebroventricular Infusion ◽  
Renin Gene ◽  
The Central Nervous System ◽  
Angiotensin Peptide ◽  
Lower Brain Stem ◽  
The Brain ◽  
Rat Genome ◽  
Supraoptic Nuclei

The transgenic (TG) rat carrying the mouse renin gene (mRen-2d) has provided a unique opportunity to explore central interactions between the brain renin-angiotensin (RAS) and vasopressin (AVP) systems. To evaluate the hypothalamic vasopressin axis in the TG rat, we measured the central nervous system concentrations of AVP and determined the effect of angiotensin II (ANG II) and its NH2-terminal heptapeptide [angiotensin-(1-7)] on blood pressure, heart rate, and AVP release using brain microdialysis. Intracerebroventricular infusion of ANG II or ANG-(1-7) in control rats increased local AVP release from the paraventricular and supraoptic nuclei. The ANG II infusion was associated with a significant increase in blood pressure not observed with ANG-(1-7). In contrast, the angiotensin peptide-induced central AVP responses and the ANG II-induced blood pressure increase were absent in the TG animal. The plasma AVP responses to ANG II and ANG-(1-7) were comparable in the control and TG rats. The TG rats exhibited a 22-fold higher level of AVP in the dorsal lower brain stem but had lower AVP levels in the posterior pituitary and the median eminence compared with control rats. These results suggest that insertion of the mouse renin gene into the rat genome leads to alterations in the AVP axis in terms of AVP peptide content and angiotensin-induced cardiovascular and AVP responses.

scholarly journals How NaCl raises blood pressure: a new paradigm for the pathogenesis of salt-dependent hypertension

2012 ◽  
Vol 302 (5) ◽  
pp. H1031-H1049 ◽  
Author(s):  
Mordecai P. Blaustein ◽  
Frans H. H. Leenen ◽  
Ling Chen ◽  
Vera A. Golovina ◽  
John M. Hamlyn ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cerebrospinal Fluid ◽  
Signaling Pathway ◽  
Vascular Resistance ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Circumventricular Organs ◽  
Ang Ii ◽  
Dietary Salt ◽  
New Paradigm

Excess dietary salt is a major cause of hypertension. Nevertheless, the specific mechanisms by which salt increases arterial constriction and peripheral vascular resistance, and thereby raises blood pressure (BP), are poorly understood. Here we summarize recent evidence that defines specific molecular links between Na+ and the elevated vascular resistance that directly produces high BP. In this new paradigm, high dietary salt raises cerebrospinal fluid [Na+]. This leads, via the Na+-sensing circumventricular organs of the brain, to increased sympathetic nerve activity (SNA), a major trigger of vasoconstriction. Plasma levels of endogenous ouabain (EO), the Na+ pump ligand, also become elevated. Remarkably, high cerebrospinal fluid [Na+]-evoked, locally secreted (hypothalamic) EO participates in a pathway that mediates the sustained increase in SNA. This hypothalamic signaling chain includes aldosterone, epithelial Na+ channels, EO, ouabain-sensitive α2 Na+ pumps, and angiotensin II (ANG II). The EO increases (e.g.) hypothalamic ANG-II type-1 receptor and NADPH oxidase and decreases neuronal nitric oxide synthase protein expression. The aldosterone-epithelial Na+ channel-EO-α2 Na+ pump-ANG-II pathway modulates the activity of brain cardiovascular control centers that regulate the BP set point and induce sustained changes in SNA. In the periphery, the EO secreted by the adrenal cortex directly enhances vasoconstriction via an EO-α2 Na+ pump-Na+/Ca2+ exchanger-Ca2+ signaling pathway. Circulating EO also activates an EO-α2 Na+ pump-Src kinase signaling cascade. This increases the expression of the Na+/Ca2+ exchanger-transient receptor potential cation channel Ca2+ signaling pathway in arterial smooth muscle but decreases the expression of endothelial vasodilator mechanisms. Additionally, EO is a growth factor and may directly participate in the arterial structural remodeling and lumen narrowing that is frequently observed in established hypertension. These several central and peripheral mechanisms are coordinated, in part by EO, to effect and maintain the salt-induced elevation of BP.

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