Angiotensin II attenuates functional hyperemia in the mouse somatosensory cortex

2003 ◽  
Vol 285 (5) ◽  
pp. H1890-H1899 ◽  
Author(s):  
Ken Kazama ◽  
Gang Wang ◽  
Kelly Frys ◽  
Josef Anrather ◽  
Costantino Iadecola
Keyword(s):  
Angiotensin Ii ◽  
Somatosensory Cortex ◽  
Neural Activity ◽  
Brain Regions ◽  
Synaptic Activity ◽  
Nitric Oxide Donor ◽  
Ang Ii ◽  
Functional Hyperemia ◽  
Doppler Flowmetry ◽  
Whisker Stimulation

We investigated whether angiotensin II (ANG II), a peptide that plays a central role in the genesis of hypertension, alters the coupling between synaptic activity and cerebral blood flow (CBF), a critical homeostatic mechanism that assures adequate cerebral perfusion to active brain regions. The somatosensory cortex was activated by stroking the facial whiskers in anesthetized C57BL/6J mice while local CBF was recorded by laser-Doppler flowmetry. Intravenous ANG II infusion (0.25 μg·kg–1·min–1) increased mean arterial pressure (MAP) from 82 ± 2 to 102 ± 3 mmHg ( P < 0.05) without affecting resting CBF ( P > 0.05). ANG II attenuated the CBF increase produced by whisker stimulation by 65% ( P < 0.05) but did not affect the response to hypercapnia or to neocortical application of the nitric oxide donor S-nitroso- N-acetyl penicillamine ( P > 0.05). The effect of ANG II on functional hyperemia persisted if the elevation in MAP was offset by controlled hemorrhage or prevented by topical application of the peptide to the activated cortex. ANG II did not reduce the amplitude of the P1 wave of the field potentials evoked by whisker stimulation ( P > 0.05). Infusion of phenylephrine increased MAP ( P > 0.05 from ANG II) but did not alter the functional hyperemic response ( P > 0.05). The data suggest that ANG II alters the coupling between CBF and neural activity. The mechanisms of the effect are not related to the elevation in MAP and/or to inhibition of the synaptic activity evoked by whisker stimulation. The imbalance between CBF and neural activity induced by ANG II may alter the homeostasis of the neuronal microenvironment and contribute to brain dysfunction during ANG II-induced hypertension.

The neurovascular dysfunction induced by angiotensin II in the mouse neocortex is sexually dimorphic

2008 ◽  
Vol 294 (1) ◽  
pp. H156-H163 ◽  
Author(s):  
H. Girouard ◽  
A. Lessard ◽  
C. Capone ◽  
T. A. Milner ◽  
C. Iadecola
Keyword(s):  
Angiotensin Ii ◽  
Sexually Dimorphic ◽  
Ang Ii ◽  
Doppler Flowmetry ◽  
Female Mice ◽  
Cranial Window ◽  
Cerebrovascular Complications ◽  
Ovariectomized Mice ◽  
Whisker Stimulation ◽  
Estrogen Administration

Women are less susceptible to the cerebrovascular complications of hypertension, such as a stroke and vascular dementia. The mechanism of such protection may be related to a reduced vulnerability of women to the cerebrovascular actions of hypertension. To test this hypothesis, we used a model of hypertension based on infusion of angiotensin II (ANG II), an octapeptide that plays a key role in hypertension and produces cerebrovascular dysregulation. Cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry in anesthetized (urethane-chloralose) C57BL/6J male and female mice equipped with a cranial window. ANG II administration (0.25 μg·kg−1·min−1 iv × 30–45 min) elevated arterial pressure equally in both sexes but attenuated the CBF increase induced by whisker stimulation or by the endothelium-dependent vasodilator acetylcholine (ACh) in male but not in female mice. The administration of ANG II for 7 days (2.74 mg·kg−1·day−1), using osmotic minipumps, also attenuated these cerebrovascular responses in male, but not female, mice. The reduced susceptibility to the effect of ANG II in female mice was abolished by ovariectomy and reinstated by estrogen administration to ovariectomized mice. Administration of estrogen to male mice abolished the ANG II-induced attenuation of CBF responses. We conclude that female mice are less susceptible to the cerebrovascular dysregulation induced by ANG II, an effect related to estrogen. Such protection from the deleterious cerebrovascular effects of hypertension may play a role in the reduced vulnerability to the cerebrovascular complications of hypertension observed in women.

scholarly journals Presynaptic Angiotensin II AT1 Receptors Enhance Inhibitory and Excitatory Synaptic Neurotransmission to Motoneurons and Other Ventral Horn Neurons in Neonatal Rat Spinal Cord

2005 ◽  
Vol 94 (2) ◽  
pp. 1405-1412 ◽  
Author(s):  
Murat Oz ◽  
Keun-Hang Yang ◽  
Michael J. O'Donovan ◽  
Leo P. Renaud
Keyword(s):  
Spinal Cord ◽  
Angiotensin Ii ◽  
Ventral Horn ◽  
Synaptic Activity ◽  
Neonatal Rat ◽  
Ang Ii ◽  
Synaptic Neurotransmission ◽  
Excitatory Neurotransmission ◽  
Ventral Spinal Cord

In neonatal spinal cord, we previously reported that exogenous angiotensin II (ANG II) acts at postsynaptic AT1 receptors to depolarize neonatal rat spinal ventral horn neurons in vitro. This study evaluated an associated increase in synaptic activity. Patch clamp recordings revealed that 38/81 thoracolumbar (T7–L5) motoneurons responded to bath applied ANG II (0.3–1 μM; 30 s) with a prolonged (5–10 min) and reversible increase in spontaneous postsynaptic activity, selectively blockable with Losartan ( n = 5) but not PD123319 ( n = 5). ANG-II-induced events included both spontaneous inhibitory (IPSCs; n = 6) and excitatory postsynaptic currents (EPSCs; n = 5). While most ANG induced events were tetrodotoxin-sensitive, ANG induced a significant tetrodotoxin-resistant increase in frequency but not amplitude of miniature IPSCs ( n = 7/13 cells) and EPSCs ( n = 2/7 cells). In 35/77 unidentified neurons, ANG II also induced a tetrodotoxin-sensitive and prolonged increase in their spontaneous synaptic activity that featured both IPSCs ( n = 5) and EPSCs ( n = 4) when tested in the presence of selective amino acid receptor antagonists. When tested in the presence of tetrodotoxin, ANG II was noted to induce a significant increase in the frequency but not the amplitude of mIPSCs ( n = 9) and mEPSCs ( n = 8). ANG also increased spontaneous motor activity from isolated mouse lumbar ventral rootlets. Collectively, these observations support the existence of a wide pre- and postsynaptic distribution of ANG II AT1 receptors in neonatal ventral spinal cord that are capable of influencing both inhibitory and excitatory neurotransmission.

scholarly journals Relative Changes in Cerebral Blood Flow and Neuronal Activity in Local Microdomains during Generalized Seizures

2004 ◽  
Vol 24 (9) ◽  
pp. 1057-1068 ◽  
Author(s):  
Hrachya Nersesyan ◽  
Peter Herman ◽  
Ersan Erdogan ◽  
Fahmeed Hyder ◽  
Hal Blumenfeld
Keyword(s):  
Visual Cortex ◽  
Somatosensory Cortex ◽  
Neuronal Activity ◽  
Barrel Cortex ◽  
Similar Distribution ◽  
Somatosensory Stimulation ◽  
Doppler Flowmetry ◽  
Absence Seizures ◽  
Generalized Seizures ◽  
Whisker Stimulation

There is broad agreement that generalized tonic–clonic seizures (GTCS) and normal somatosensory stimulation are associated with increases in regional CBF. However, the data regarding CBF changes during absence seizures are controversial. Electrophysiologic studies in WAG/Rij rats, an established animal model of absence seizures, have shown spike-wave discharges (SWD) that are largest in the perioral somatosensory cortex while sparing the visual cortex. Recent functional magnetic resonance imaging (fMRI) studies in the same model have also shown localized increases in fMRI signals in the perioral somatosensory cortex during SWD. Because fMRI signals are only indirectly related to neuronal activity, the authors directly measured CBF and neuronal activity from specific microdomains of the WAG/Rij cortex using a specially designed probe combining laser-Doppler flowmetry and extracellular microelectrode recordings under fentanyl/haloperidol anesthesia. Using this approach, parallel increases in neuronal activity and CBF were observed during SWD in the whisker somatosensory (barrel) cortex, whereas the visual cortex showed no significant changes. For comparison, these measurements were repeated during somatosensory (whisker) stimulation, and bicuculline-induced GTCS in the same animals. Interestingly, whisker stimulation increased neuronal activity and CBF in the barrel cortex more than during SWD. During GTCS, much larger increases that included both the somatosensory and visual cortex were observed. Thus, SWD in this model produce parallel localized increases in neuronal activity and CBF with similar distribution to somatosensory stimulation, whereas GTCS produce larger and more widespread changes. The normal response to somatosensory stimulation appears to be poised between two abnormal responses produced by two physiologically different types of seizures.

Modulation of angiotensin II binding sites in neuronal cultures by mineralocorticoids

1989 ◽  
Vol 256 (1) ◽  
pp. C121-C129 ◽  
Author(s):  
C. Sumners ◽  
M. J. Fregly
Keyword(s):  
Angiotensin Ii ◽  
Binding Sites ◽  
Specific Binding ◽  
Brain Regions ◽  
Neuronal Cultures ◽  
Type I ◽  
Moderate Increase ◽  
Ang Ii ◽  
Specific Binding Sites ◽  
Drinking Response

Previous studies have determined that mineralocorticoid hormones are able to increase the number of angiotensin II (ANG II)-specific binding sites in rat diencephalon and in neuronal cultures and also increase the drinking response elicited by centrally injected ANG II. In the present study, we have examined the specificity and mechanisms of this mineralocorticoid action. In neuronal cultures from the hypothalamus and brain stem (H/BS), both D-aldosterone and deoxycorticosterone acetate (DOCA) caused significant time- and dose-dependent increases in 125I-labeled ANG II-specific binding. This effect was not mimicked by the synthetic glucocorticoid dexamethasone, or by testosterone, beta-estradiol or progesterone. However, the steroid corticosterone induced a moderate increase in [125I] ANG II binding. This may have occurred as a result of its high affinity for the mineralocorticoid type I receptor. DOCA was ineffective in increasing [125I]ANG II specific binding both in neuronal cultures prepared from the cerebellum and in pure astrocytic glial cultures, indicating that this mineralocorticoid effect is specific both for neurons and for certain brain regions. The increase in [125I]ANG II-specific binding elicited by DOCA was abolished by cotreatment with the mineralocorticoid receptor blockers mespirenone or ZK97894 and by cotreatment with cycloheximide. Taken together, these observations suggest that the mineralocorticoid-induced increase in [125I]ANG II-specific binding in H/BS neuronal cultures is a specific event, which is mediated via mineralocorticoid type I receptors and which requires protein synthesis.

scholarly journals Aβ-Induced Vascular Oxidative Stress and Attenuation of Functional Hyperemia in Mouse Somatosensory Cortex

2004 ◽  
Vol 24 (3) ◽  
pp. 334-342 ◽  
Author(s):  
Laibaik Park ◽  
Josef Anrather ◽  
Colleen Forster ◽  
Ken Kazama ◽  
George A Carlson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Free Radical ◽  
Somatosensory Cortex ◽  
Nitrosative Stress ◽  
Functional Hyperemia ◽  
Cerebral Microvessels ◽  
Free Radical Production ◽  
Radical Production ◽  
Whisker Stimulation ◽  
Vascular Oxidative Stress

We investigated the role of vascular oxidative stress in the mechanisms of the impairment in cerebrovascular regulation produced by the amyloid-β peptide (Aβ). In particular, we sought to provide evidence of vascular oxidative stress in mice overexpressing the amyloid precursor protein (APP) and to determine whether the Aβ-induced attenuation in functional hyperemia is mediated by free radical overproduction. Oxidative/nitrosative stress was assessed by 3-nitrotyrosine immunoreactivity, while free radical production was determined in cerebral microvessels by hydroethidine microfluorography. To study functional hyperemia the somatosensory cortex was activated by whisker stimulation while local blood flow was monitored by laser-Doppler flowmetry. It was found that APP mice show signs of oxidative/nitrosative stress in pial and intracerebral blood vessels well before they develop oxidative stress in neurons and glia or amyloid plaques. Treatment of cerebral microvessels isolated from wild-type mice with Aβ (1 μM) increased free radical production as assessed by the hydroethidine technique. The Aβ-induced attenuation of the increase in somatosensory cortex blood flow produced by whisker stimulation was prevented by treatment with the free radical scavengers MnTBAP or tiron. These data provide evidence that in APP mice vascular oxidative stress precedes the development of parenchymal oxidative stress, and that Aβ-produced vascular reactive oxygen species are involved in the attendant attenuation in functional hyperemia. Thus, vascular oxidative stress is an early event in the course of the brain dysfunction produced by APP overexpression and Aβ, and, as such, could be the target of early therapeutic interventions based on antioxidants.

Central injection of angiotensin II alters catecholamine activity in rat brain

1983 ◽  
Vol 244 (2) ◽  
pp. R257-R263 ◽  
Author(s):  
C. Sumners ◽  
M. I. Phillips
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Rat Brain ◽  
Pressor Response ◽  
Pressure Control ◽  
Brain Regions ◽  
Ang Ii ◽  
Raphe Magnus ◽  
Data Points ◽  
Substantial Change

Centrally injected angiotensin II (ANG II) produces a pressor response. The effect of ANG II injected intracerebroventricularly on catecholamine utilization in specific rat brain regions was examined. A pressor dose of ANG II stimulated an increase in norepinephrine (NE) utilization in the locus coeruleus, raphe magnus and AI regions of the brain stem, and in the hypothalamus. These increases in NE utilization were selective, and dopamine utilization was not altered in the same regions. Also, the changes in NE utilization were direct and not due to the rise in blood pressure caused by ANG II, since a similar pressor effect caused by intravenously injected hypertonic saline did not alter NE utilization in any of the above regions. Areas such as the subfornical organ and organum vasculosum of the lamina terminalis that contain both catecholamines and ANG II receptors did not show a substantial change in catecholamine utilization after intracerebroventricularly injected ANG II. This study demonstrates that specific brain NE rich regions are activated by intracerebroventricular injection of ANG II. Some of these regions correlate with known blood pressure control centers and the data points to brain catecholaminergic regions which are involved in the central ANG II pressor response.

scholarly journals Angiotensin II stimulates internalization and degradation of arterial myocyte plasma membrane BK channels to induce vasoconstriction

2015 ◽  
Vol 309 (6) ◽  
pp. C392-C402 ◽  
Author(s):  
M. Dennis Leo ◽  
Simon Bulley ◽  
John P. Bannister ◽  
Korah P. Kuruvilla ◽  
Damodaran Narayanan ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Angiotensin Ii ◽  
Cerebral Arteries ◽  
Bk Channels ◽  
Bk Channel ◽  
Nitric Oxide Donor ◽  
Ang Ii ◽  
Functional Responses ◽  
Early Endosomes ◽  
Arterial Contractility

Arterial smooth muscle cells (myocytes) express large-conductance Ca2+-activated K+ (BK) channel α and auxiliary β1 subunits that modulate arterial contractility. In arterial myocytes, β1 subunits are stored within highly mobile rab11A-positive recycling endosomes. In contrast, BKα subunits are primarily plasma membrane-localized. Trafficking pathways for BKα and whether physiological stimuli that regulate arterial contractility alter BKα localization in arterial myocytes are unclear. Here, using biotinylation, immunofluorescence resonance energy transfer (immunoFRET) microscopy, and RNAi-mediated knockdown, we demonstrate that rab4A-positive early endosomes traffic BKα to the plasma membrane in myocytes of resistance-size cerebral arteries. Angiotensin II (ANG II), a vasoconstrictor, reduced both surface and total BKα, an effect blocked by bisindolylmaleimide-II, concanavalin A, and dynasore, protein kinase C (PKC), internalization, and endocytosis inhibitors, respectively. In contrast, ANG II did not reduce BKα mRNA, and sodium nitroprusside, a nitric oxide donor, did not alter surface BKα protein over the same time course. MG132 and bafilomycin A, proteasomal and lysosomal inhibitors, respectively, also inhibited the ANG II-induced reduction in surface and total BKα, resulting in intracellular BKα accumulation. ANG II-mediated BK channel degradation reduced BK currents in isolated myocytes and functional responses to iberiotoxin, a BK channel blocker, and NS1619, a BK activator, in pressurized (60 mmHg) cerebral arteries. These data indicate that rab4A-positive early endosomes traffic BKα to the plasma membrane in arterial myocytes. We also show that ANG II stimulates PKC-dependent BKα internalization and degradation. These data describe a unique mechanism by which ANG II inhibits arterial myocyte BK currents, by reducing surface channel number, to induce vasoconstriction.

scholarly journals Purinergic glio-endothelial coupling during neuronal activity: role of P2Y1 receptors and eNOS in functional hyperemia in the mouse somatosensory cortex

2015 ◽  
Vol 309 (11) ◽  
pp. H1837-H1845 ◽  
Author(s):  
Peter Toth ◽  
Stefano Tarantini ◽  
Antonio Davila ◽  
M. Noa Valcarcel-Ares ◽  
Zsuzsanna Tucsek ◽  
...  
Keyword(s):  
Somatosensory Cortex ◽  
Neuronal Activity ◽  
Critical Role ◽  
Neurovascular Coupling ◽  
No Synthase ◽  
Functional Hyperemia ◽  
Inhibitory Effects ◽  
Pathological Conditions ◽  
Whisker Stimulation

Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of cognitive impairment associated with aging and pathological conditions associated with accelerated cerebromicrovascular aging (e.g., hypertension, obesity). Although previous studies demonstrate that endothelial dysfunction plays a critical role in neurovascular uncoupling in these conditions, the role of endothelial NO mediation in neurovascular coupling responses is not well understood. To establish the link between endothelial function and functional hyperemia, neurovascular coupling responses were studied in mutant mice overexpressing or deficient in endothelial NO synthase (eNOS), and the role of P2Y1 receptors in purinergic glioendothelial coupling was assessed. We found that genetic depletion of eNOS (eNOS−/−) and pharmacological inhibition of NO synthesis significantly decreased the CBF responses in the somatosensory cortex evoked by whisker stimulation and by administration of ATP. Overexpression of eNOS enhanced NO mediation of functional hyperemia. In control mice, the selective and potent P2Y1 receptor antagonist MRS2179 attenuated both whisker stimulation-induced and ATP-mediated CBF responses, whereas, in eNOS−/− mice, the inhibitory effects of MRS2179 were blunted. Collectively, our findings provide additional evidence for purinergic glio-endothelial coupling during neuronal activity, highlighting the role of ATP-mediated activation of eNOS via P2Y1 receptors in functional hyperemia.

Infrared thermal imaging of rat somatosensory cortex with whisker stimulation

2012 ◽  
Vol 112 (7) ◽  
pp. 1215-1222 ◽  
Author(s):  
Takashi Suzuki ◽  
Yasuhiro Ooi ◽  
Junji Seki
Keyword(s):  
Somatosensory Cortex ◽  
Neural Activity ◽  
Thermal Imaging ◽  
Temperature Increase ◽  
Barrel Cortex ◽  
Brain Temperature ◽  
Local Thermal Equilibrium ◽  
Neural Activation ◽  
Whisker Stimulation ◽  
The Brain

The present study aims to validate the applicability of infrared (IR) thermal imaging for the study of brain function through experiments on the rat barrel cortex. Regional changes in neural activity within the brain produce alterations in local thermal equilibrium via increases in metabolic activity and blood flow. We studied the relationship between temperature change and neural activity in anesthetized rats using IR imaging to visualize stimulus-induced changes in the somatosensory cortex of the brain. Sensory stimulation of the vibrissae (whiskers) was given for 10 s using an oscillating whisker vibrator (5-mm deflection at 10, 5, and 1 Hz). The brain temperature in the observational region continued to increase significantly with whisker stimulation. The mean peak recorded temperature changes were 0.048 ± 0.028, 0.054 ± 0.036, and 0.097 ± 0.015°C at 10, 5, and 1 Hz, respectively. We also observed that the temperature increase occurred in a focal spot, radiating to encompass a larger region within the contralateral barrel cortex region during single-whisker stimulation. Whisker stimulation also produced ipsilateral cortex temperature increases, which were localized in the same region as the pial arterioles. Temperature increase in the barrel cortex was also observed in rats treated with a calcium channel blocker (nimodipine), which acts to suppress the hemodynamic response to neural activity. Thus the location and area of temperature increase were found to change in accordance with the region of neural activation. These results indicate that IR thermal imaging is viable as a functional quantitative neuroimaging technique.

scholarly journals The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension

2011 ◽  
Vol 300 (1) ◽  
pp. H397-H407 ◽  
Author(s):  
Carmen Capone ◽  
Giuseppe Faraco ◽  
Laibaik Park ◽  
Xian Cao ◽  
Robin L. Davisson ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Angiotensin Ii ◽  
Time Course ◽  
Ang Ii ◽  
Doppler Flowmetry ◽  
Cranial Window ◽  
Cerebrovascular Function ◽  
Cerebrovascular Dysfunction ◽  
Blood Flow Increase

Hypertension alters cerebrovascular regulation and increases the brain's susceptibility to stroke and dementia. We investigated the temporal relationships between the arterial pressure (AP) elevation induced by “slow pressor” angiotensin II (ANG II) infusion, which recapitulates key features of human hypertension, and the resulting cerebrovascular dysfunction. Minipumps delivering saline or ANG II for 14 days were implanted subcutaneously in C57BL/6 mice ( n = 5/group). Cerebral blood flow was assessed by laser-Doppler flowmetry in anesthetized mice equipped with a cranial window. With ANG II (600 ng·kg−1·min−1), AP started to rise after 9 days ( P < 0.05 vs. saline), remained elevated at 11–17 days, and returned to baseline at 21 days ( P > 0.05). ANG II attenuated the cerebral blood flow increase induced by neural activity (whisker stimulation) or endothelium-dependent vasodilators, an effect observed before the AP elevation (7 days), as well as after the hypertension subsided (21 days). Nonpressor doses of ANG II (200 ng·kg−1·min−1) induced cerebrovascular dysfunction and oxidative stress without elevating AP ( P > 0.05 vs. saline), whereas phenylephrine elevated AP without inducing cerebrovascular effects. ANG II (600 ng·kg−1·min−1) augmented neocortical reactive oxygen species (ROS) with a time course similar to that of the cerebrovascular dysfunction. Neocortical application of the ROS scavenger manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin or the NADPH oxidase peptide inhibitor gp91ds-tat attenuated ROS and cerebrovascular dysfunction. We conclude that the alterations in neurovascular regulation induced by slow pressor ANG II develop before hypertension and persist beyond AP normalization but are not permanent. The findings unveil a striking susceptibility of cerebrovascular function to the deleterious effects of ANG II and raise the possibility that cerebrovascular dysregulation precedes the elevation in AP also in patients with ANG II-dependent hypertension.

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