scholarly journals Transient Hypoperfusion to Ischemic/Anoxic Spreading Depolarization is Related to Autoregulatory Failure in the Rat Cerebral Cortex

2021 ◽  
Author(s):  
Ákos Menyhárt ◽  
Dániel Péter Varga ◽  
Orsolya M. Tóth ◽  
Péter Makra ◽  
Ferenc Bari ◽  
...  
Keyword(s):  
Neurovascular Coupling ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Laser Speckle ◽  
Doppler Flowmetry ◽  
Neuronal Viability ◽  
Cerebrovascular Autoregulation ◽  
Spreading Depolarization ◽  
Arterial Blood ◽  
Contrast Analysis

Abstract Background In ischemic stroke, cerebral autoregulation and neurovascular coupling may become impaired. The cerebral blood flow (CBF) response to spreading depolarization (SD) is governed by neurovascular coupling. SDs recur in the ischemic penumbra and reduce neuronal viability by the insufficiency of the CBF response. Autoregulatory failure and SD may coexist in acute brain injury. Here, we set out to explore the interplay between the impairment of cerebrovascular autoregulation, SD occurrence, and the evolution of the SD-coupled CBF response. Methods Incomplete global forebrain ischemia was created by bilateral common carotid artery occlusion in isoflurane-anesthetized rats, which induced ischemic SD (iSD). A subsequent SD was initiated 20–40 min later by transient anoxia SD (aSD), achieved by the withdrawal of oxygen from the anesthetic gas mixture for 4–5 min. SD occurrence was confirmed by the recording of direct current potential together with extracellular K+ concentration by intracortical microelectrodes. Changes in local CBF were acquired with laser Doppler flowmetry. Mean arterial blood pressure (MABP) was continuously measured via a catheter inserted into the left femoral artery. CBF and MABP were used to calculate an index of cerebrovascular autoregulation (rCBFx). In a representative imaging experiment, variation in transmembrane potential was visualized with a voltage-sensitive dye in the exposed parietal cortex, and CBF maps were generated with laser speckle contrast analysis. Results Ischemia induction and anoxia onset gave rise to iSD and aSD, respectively, albeit aSD occurred at a longer latency, and was superimposed on a gradual elevation of K+ concentration. iSD and aSD were accompanied by a transient drop of CBF (down to 11.9 ± 2.9 and 7.4 ± 3.6%, iSD and aSD), but distinctive features set the hypoperfusion transients apart. During iSD, rCBFx indicated intact autoregulation (rCBFx < 0.3). In contrast, aSD was superimposed on autoregulatory failure (rCBFx > 0.3) because CBF followed the decreasing MABP. CBF dropped 15–20 s after iSD, but the onset of hypoperfusion preceded aSD by almost 3 min. Taken together, the CBF response to iSD displayed typical features of spreading ischemia, whereas the transient CBF reduction with aSD appeared to be a passive decrease of CBF following the anoxia-related hypotension, leading to aSD. Conclusions We propose that the dysfunction of cerebrovascular autoregulation that occurs simultaneously with hypotension transients poses a substantial risk of SD occurrence and is not a consequence of SD. Under such circumstances, the evolving SD is not accompanied by any recognizable CBF response, which indicates a severely damaged neurovascular coupling.

scholarly journals Rapid Neuronal Ultrastructure Disruption and Recovery during Spreading Depolarization-Induced Cytotoxic Edema

2020 ◽  
Vol 30 (10) ◽  
pp. 5517-5531 ◽  
Author(s):  
Sergei A Kirov ◽  
Ioulia V Fomitcheva ◽  
Jeremy Sword
Keyword(s):  
Tissue Perfusion ◽  
Ultrastructural Level ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Structural Basis ◽  
Cytotoxic Edema ◽  
Spreading Depolarization ◽  
Synaptic Circuits ◽  
Common Carotid Artery Occlusion

Abstract Two major pathogenic events that cause acute brain damage during neurologic emergencies of stroke, head trauma, and cardiac arrest are spreading depolarizing waves and the associated brain edema that course across the cortex injuring brain cells. Virtually nothing is known about how spreading depolarization (SD)-induced cytotoxic edema evolves at the ultrastructural level immediately after insult and during recovery. In vivo 2-photon imaging followed by quantitative serial section electron microscopy was used to assess synaptic circuit integrity in the neocortex of urethane-anesthetized male and female mice during and after SD evoked by transient bilateral common carotid artery occlusion. SD triggered a rapid fragmentation of dendritic mitochondria. A large increase in the density of synapses on swollen dendritic shafts implies that some dendritic spines were overwhelmed by swelling or merely retracted. The overall synaptic density was unchanged. The postsynaptic dendritic membranes remained attached to axonal boutons, providing a structural basis for the recovery of synaptic circuits. Upon immediate reperfusion, cytotoxic edema mainly subsides as affirmed by a recovery of dendritic ultrastructure. Dendritic recuperation from swelling and reversibility of mitochondrial fragmentation suggests that neurointensive care to improve tissue perfusion should be paralleled by treatments targeting mitochondrial recovery and minimizing the occurrence of SDs.

scholarly journals Calcineurin Inhibitor, FK506, Prevents Reduction in the Binding Capacity of Cyclic AMP-Dependent Protein Kinase in Ischemic Gerbil Brain

1997 ◽  
Vol 17 (4) ◽  
pp. 412-420 ◽  
Author(s):  
Kortaro Tanaka ◽  
Yasuo Fukuuchi ◽  
Hiroyuki Nozaki ◽  
Eiichiro Nagata ◽  
Taro Kondo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Blood Vessels ◽  
Binding Capacity ◽  
Specific Inhibitor ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Dependent Protein Kinase ◽  
Arterial Blood ◽  
Dependent Protein

We examined the effects of FK506, a specific inhibitor of calcineurin, on the binding capacity of cyclic AMP-dependent protein kinase (cAMP-DPK) in gerbils subjected to 2-h cerebral hemispheric ischemia. FK506 (0.1 mg/kg) was infused intravenously at 15 min prior to the induction of ischemia by common carotid artery occlusion. The binding capacity of cAMP-DPK was evaluated by autoradiographic analysis of the cAMP binding, and cerebral blood flow (CBF) was measured by the [14C] iodoantipyrine method. In the sham-operated gerbils, FK506 significantly increased mean arterial blood pressure and tended to decrease CBF, suggesting that FK506 may constrict systemic blood vessels as well as cerebral blood vessels. On the other hand, cAMP binding was not altered by FK506 in the sham-operated gerbils. In the ischemia group of gerbils, FK506 prevented any significant reduction of cAMP binding in the hippocampus CA1 and cerebral cortices on the ischemic side, whereas it exerted no significant influence on the cAMP binding of the nonischemic side. The values of CBF were comparable between the vehicle-treated gerbils and FK506-treated gerbils in the ischemic regions. Preservation of cAMP binding indicates that intracellular signal transduction via cAMP-DPK can be maintained by FK506 despite ischemia, suggesting that this agent may be beneficial for reducing ischemic tissue damage.

scholarly journals Some Aspects of the Physiology and Anatomy of the Cardiovascular System of the Ferret, Mustela Putorius Furo

1979 ◽  
Vol 13 (3) ◽  
pp. 215-220 ◽  
Author(s):  
P. L. R. Andrews ◽  
A. J. Bower ◽  
O. Illman
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Vagal Stimulation ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Resting Heart Rate ◽  
Mustela Putorius ◽  
Arterial Blood ◽  
Great Vessels ◽  
Vagal Innervation

Summary The resting heart rate was monitored in SO urethane-anaesthetized (387 ± 54 beats/min) and 4 conscious (341 ± 39 beats/min) ferrets. The arterial blood pressure in the anaesthetized animals was 140/110 ± 35/31 mmHg. The circulatory responses to vagal stimulation, carotid artery occlusion and a variety of humoral agents were examined. The vagal innervation of the heart and of the distribution of the great vessels are described.

scholarly journals Vascular protection and regenerative effects of intranasal DL-3-N-butylphthalide treatment after ischaemic stroke in mice

2020 ◽  
pp. svn-2020-000364
Author(s):  
Mengyao Qu ◽  
Jingjie Zhao ◽  
Yingying Zhao ◽  
Jinmei Sun ◽  
Liping Liu ◽  
...  
Keyword(s):  
Ischaemic Stroke ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Vehicle Group ◽  
Sensorimotor Function ◽  
Vascular Protection ◽  
Doppler Flowmetry ◽  
Infarct Region ◽  
Common Carotid Artery Occlusion ◽  
Endothelial Nitric Oxide

ObjectiveTo investigate the effects of DL-3-N-butylphthalide (NBP) via intranasal delivery after ischaemic stroke in mice.MethodsC57BL/6 mice were divided into three groups: sham, stroke with vehicle and stroke with NBP treatment. Ischaemic stroke was induced by permanent ligation of right middle cerebral artery with 7 min common carotid artery occlusion. NBP (100 mg/kg) or vehicle was intranasally administered at 1 hour after stroke and repeated once a day until sacrifice. Bromodeoxyuridine (BrdU) (50 mg/kg/day) was given from the third day until sacrifice. Sensorimotor function was tested during 1–21 days after stroke. Local cerebral blood flow in the ischaemic and peri-infarct regions was measured using laser Doppler flowmetry before, during and 3 days after ischaemia. Expressions of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase as well as regenerative marker BrdU in the peri-infarct region were analysed by western blotting and immunohistochemical methods.ResultsCompared with the vehicle group, NBP treatment significantly increased the VEGF expression in the poststroke brain. Stroke mice that received NBP showed significantly less vascular damage after stroke and more new neurons and blood vessels in the peri-infarct region at 21 days after stroke. In the adhesive removal test, the sensorimotor function of stroke mice treated with NBP performed significantly better at 1, 3 and 7 days after stroke compared with vehicle controls.ConclusionDaily intranasal NBP treatment provides protective and neurogenic/angiogenic effects in the poststroke brain, accompanied with functional improvements after a focal ischaemic stroke in mice.

scholarly journals Acute Functional Recovery of Cerebral Blood Flow after Forebrain Ischemia in Rat

2008 ◽  
Vol 28 (7) ◽  
pp. 1275-1284 ◽  
Author(s):  
Chao Zhou ◽  
Tomokazu Shimazu ◽  
Turgut Durduran ◽  
Janos Luckl ◽  
Daniel Y Kimberg ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Cerebral Ischemia ◽  
Statistical Parametric Mapping ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Laser Speckle ◽  
Activation Area ◽  
Blood Flow Response ◽  
Flow Response

After complete cerebral ischemia, the postischemic blood flow response to functional activation is severely attenuated for several hours. However, little is known about the spatial and temporal extent of the blood flow response in the acute postischemic period after incomplete cerebral ischemia. To investigate the relative cerebral blood flow (rCBF) response in the somatosensory cortex of rat to controlled vibrissae stimulation after transient incomplete ischemia (15-min bilateral common carotid artery occlusion + hypotension), we employed laser speckle imaging combined with statistical parametric mapping. We found that the ischemic insult had a significant impact on the baseline blood flow ( P <0.005) and the activation area in response to functional stimulation was significantly reduced after ischemia ( P < 0.005). The maximum rCBF response in the activation area determined from the statistical analysis did not change significantly up to 3 h after ischemia ( P > 0.1). However, the time when rCBF response reached its maximum was significantly delayed ( P < 0.0001) from 2.4 ± 0.2 secs before ischemia to 3.6 ± 0.1 secs at 20 mins into reperfusion ( P < 0.001); the delay was reduced gradually to 2.9 ± 0.2 secs after 3 h, which was still significantly greater than that observed before the insult ( P = 0.04).

scholarly journals Rho-Kinase Inhibition Improves Ischemic Perfusion Deficit in Hyperlipidemic Mice

2013 ◽  
Vol 34 (2) ◽  
pp. 284-287 ◽  
Author(s):  
Hwa Kyoung Shin ◽  
Paul L Huang ◽  
Cenk Ayata
Keyword(s):  
Single Dose ◽  
Vascular Dysfunction ◽  
Rho Kinase ◽  
Tissue Perfusion ◽  
Artery Occlusion ◽  
Laser Speckle ◽  
Rock Inhibitor ◽  
Arterial Blood ◽  
Apolipoprotein E Knockout Mice ◽  
Rock Inhibition

Hyperlipidemia is a major cardiovascular risk factor associated with progressive cerebrovascular dysfunction and diminished collateral perfusion in stroke. Rho-associated kinase (ROCK) may be an important mediator of hyperlipidemic vascular dysfunction. We tested the efficacy of acute or chronic ROCK inhibition on the size of dynamic perfusion defect using laser speckle flowmetry in hyperlipidemic apolipoprotein E knockout mice fed on a high-fat diet for 8 weeks. Mice were studied at an age before the development of flow-limiting atherosclerotic stenoses in aorta and major cervical arteries. Focal ischemia was induced by distal middle cerebral artery occlusion (dMCAO) during optical imaging. The ROCK inhibitor fasudil (10 mg/kg) was administered either as a single dose 1 hour before ischemia onset, or daily for 4 weeks. Fasudil decreased both baseline arterial blood pressure and cerebrovascular resistance (CVR) by ∼15%, and significantly improved tissue perfusion during dMCAO. Interestingly, peri-infarct depolarizations were also reduced. Chronic treatment did not further enhance these benefits compared with acute treatment with a single dose. These data show that ROCK inhibition improves CVR and ischemic tissue perfusion in hyperlipidemic mice.

Plasma and lymph dopamine-beta-hydroxylase and norepinephrine during carotid occlusion

1979 ◽  
Vol 236 (1) ◽  
pp. H96-H100
Author(s):  
M. T. Velasquez ◽  
N. Alexander
Keyword(s):  
General Circulation ◽  
Hepatic Clearance ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Sympathetic Activation ◽  
Peak Response ◽  
Intestinal Lymph ◽  
Arterial Blood ◽  
Dopamine Beta Hydroxylase ◽  
Venous Plasma

Dopamine-beta-hydroxylase (DBH) and norepinephrine (NE) levels in superior mesenteric venous (SMV) and arterial blood and in intestinal lymph were determined sequentially before and during carotid artery occlusion (CAO) in anesthetized rabbits. During the first 15 min of CAO, SMV plasma NE increased 77% but SMV plasma DBH increased only 11%. During the second 15 min of CAO, SMV NE declined to 36% above control but SMV DBH rose further and peaked to 29% above control after CAO was released; arterial DBH and NE showed small insignificant changes. Lymph DBH and NE increased simultaneously throughout the period of CAO. Increases in mean arterial pressure during CAO correlated with superior mesenteric venous NE (r = 0.58, P less than 0.01). In additional experiments, hepatic vein plasma NE was 74% lower than portal vein NE. Thus, during acute sympathetic activation, DBH and NE increase in mesenteric venous plasma and intestinal lymph but the peak response of plasma DBH lags behind that of NE. The degree of NE change in the general circulation is minimized due to hepatic clearance of NE.

scholarly journals Requisite ischemia for spreading depolarization occurrence after subarachnoid hemorrhage in rodents

2016 ◽  
Vol 37 (5) ◽  
pp. 1829-1840 ◽  
Author(s):  
Fumiaki Oka ◽  
Ulrike Hoffmann ◽  
Jeong Hyun Lee ◽  
Hwa Kyoung Shin ◽  
David Y Chung ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Delayed Cerebral Ischemia ◽  
Laser Speckle ◽  
Neurological Outcomes ◽  
Spreading Depolarization ◽  
Arterial Blood ◽  
Electrophysiological Recordings ◽  
Ischemic Tissue

Spontaneous spreading depolarizations are frequent after various forms of human brain injury such as ischemic or hemorrhagic stroke and trauma, and worsen the outcome. We have recently shown that supply-demand mismatch transients trigger spreading depolarizations in ischemic stroke. Here, we examined the mechanisms triggering recurrent spreading depolarization events for many days after subarachnoid hemorrhage. Despite large volumes of subarachnoid hemorrhage induced by cisternal injection of fresh arterial blood in rodents, electrophysiological recordings did not detect a single spreading depolarization for up to 72 h after subarachnoid hemorrhage. Cortical susceptibility to spreading depolarization, measured by direct electrical stimulation or topical KCl application, was suppressed after subarachnoid hemorrhage. Focal cerebral ischemia experimentally induced after subarachnoid hemorrhage revealed a biphasic change in the propensity to develop peri-infarct spreading depolarizations. Frequency of peri-infarct spreading depolarizations decreased at 12 h, increased at 72 h and normalized at 7 days after subarachnoid hemorrhage compared with sham controls. However, ischemic tissue and neurological outcomes were significantly worse after subarachnoid hemorrhage even when peri-infarct spreading depolarization frequency was reduced. Laser speckle flowmetry implicated cerebrovascular hemodynamic mechanisms worsening the outcome. Altogether, our data suggest that cerebral ischemia is required for spreading depolarizations to be triggered after subarachnoid hemorrhage, which then creates a vicious cycle leading to the delayed cerebral ischemia syndrome.

scholarly journals Neurovascular Coupling Varies with Level of Global Cerebral Ischemia in a Rat Model

2012 ◽  
Vol 33 (1) ◽  
pp. 97-105 ◽  
Author(s):  
Wesley B Baker ◽  
Zhenghui Sun ◽  
Teruyuki Hiraki ◽  
Mary E Putt ◽  
Turgut Durduran ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Ischemia ◽  
Carotid Artery ◽  
Electrical Response ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Laser Speckle ◽  
Global Cerebral Ischemia ◽  
Functional Responses ◽  
Bilateral Carotid

In this study, cerebral blood flow, oxygenation, metabolic, and electrical functional responses to forepaw stimulation were monitored in rats at different levels of global cerebral ischemia from mild to severe. Laser speckle contrast imaging and optical imaging of intrinsic signals were used to measure changes in blood flow and oxygenation, respectively, along with a compartmental model to calculate changes in oxygen metabolism from these measured changes. To characterize the electrical response to functional stimulation, we measured somatosensory evoked potentials (SEPs). Global graded ischemia was induced through unilateral carotid artery occlusion, bilateral carotid artery occlusion, bilateral carotid and right subclavian artery (SCA) occlusion, or carotid and SCA occlusion with negative lower body pressure. We found that the amplitude of the functional metabolic response remained tightly coupled to the amplitude of the SEP at all levels of ischemia observed. However, as the level of ischemia became more severe, the flow response was more strongly attenuated than the electrical response, suggesting that global ischemia was associated with an uncoupling between the functional flow and electrical responses.

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