An In Vitro Evaluation of Emboli Trajectories Within a Three-Dimensional Physical Model of the Circle of Willis Under Cerebral Blood Flow Conditions

Diabetes is the primary pathological factor attributed to Alzheimer’s disease and vascular cognitive impairment. Previous studies demonstrated that hyperglycemia promoted oxidative stress in the cerebral vasculature. Cerebrovascular pericytes contribute to maintaining blood-brain barrier (BBB) integrity and regulating cerebral blood flow (CBF). However, whether hyperglycemia diminishes the contractile capability of pericytes, impairs CBF autoregulation and increases BBB permeability are unclear. In the present study, we examined the role of pericytes in cerebrovascular function and cognition in diabetes using cell culture in vitro , isolated penetrating arterioles ex vivo and CBF autoregulation in vivo . Reactive oxygen species were elevated in high glucose (HG, 30 mM) treated vs. normal glucose (NG, 5.5 mM) treated pericytes. Further, mitochondrial superoxide production was increased in HG-treated vs. NG-treated group (13.24 ± 1.01 arbitrary unit (a.u.)/30min vs. 6.98 ± 0.36 a.u./30min). Mitochondrial respiration decreased in HG-treated vs. NG-treated pericytes (3718 ± 185.9 pmol/min/mg, n=10 vs. 4742 ± 284.5 pmol/min/mg, n=10) as measured by a Seahorse XFe24 analyzer. HG-treated pericytes displayed fragmented mitochondria in association with increased fission protein (DRP1) and decreased fusion protein (OPA1) expression. HG-treated pericytes displayed lower contractile capability than NG-treated cells (20.23 ± 7.15% vs. 29.46 ± 9.41%). The myogenic response was impaired in penetrating arterioles isolated from diabetic rats in comparison with non-diabetic rats. Autoregulation of CBF measured by a laser Doppler flowmeter was impaired in diabetic rats compared with non-diabetic rats. Diabetic rats exhibited greater BBB leakage than control rats. The cognitive function was examined using an eight-arm water maze. Diabetic rats took longer time to escape than the non-diabetic rats indicating learning and memory deficits. In conclusion, hyperglycemia induces pericyte dysfunction by altering mitochondrial dynamics and diminishing contractile capability, which promotes BBB leakage, decreases CBF autoregulation and contributes to diabetes-related dementia.

Download Full-text

In vitro and in vivo evaluation of hypothermia on pharmacokinetics and pharmacodynamics of nimodipine in rabbits

Journal of International Medical Research ◽

10.1177/0300060517720056 ◽

2017 ◽

Vol 46 (1) ◽

pp. 335-347 ◽

Cited By ~ 1

Author(s):

Yu-xing Fei ◽

Tian-hong Zhang ◽

Jing Zhao ◽

He Ren ◽

Ya-nan Du ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Protein Binding ◽

Plasma Concentrations ◽

Liver Microsomes ◽

Intrinsic Clearance ◽

Pharmacokinetics And Pharmacodynamics ◽

In Vivo Evaluation

Objective To investigate the effect of hypothermia on the pharmacokinetics and pharmacodynamics of nimodipine in rabbits using in vivo and in vitro methods. Methods Five healthy New Zealand rabbits received a single dose of nimodipine (0.5 mg/kg) intravenously under normothermic and hypothermic conditions. Doppler ultrasound was used to monitor cerebral blood flow, vascular resistance, and heart rate. In vitro evaluations of protein binding, hepatocyte uptake and intrinsic clearance of liver microsomes at different temperatures were also conducted. Results Plasma concentrations of nimodipine were significantly higher in hypothermia than in normothermia. Nimodipine improved cerebral blood flow under both conditions, but had a longer effective duration during the hypothermic period. Low temperature decreased the intrinsic clearance of liver microsomes, with no change in protein binding or hepatocyte uptake of nimodipine. Conclusion Nimodipine is eliminated at a slower rate during hypothermia than during normothermia, mainly due to the decreased activity of cytochrome P450 enzymes. This results in elevated system exposure with little enhancement in pharmacological effect.

Download Full-text

Serial measurement of regional cerebral blood flow in patients with SAH using 133Xe inhalation and emission computerized tomography

Journal of Neurosurgery ◽

10.3171/jns.1984.60.5.0916 ◽

1984 ◽

Vol 60 (5) ◽

pp. 916-922 ◽

Cited By ~ 86

Author(s):

Bruce Mickey ◽

Sissel Vorstrup ◽

Bo Voldby ◽

Helle Lindewald ◽

Aage Harmsen ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Computerized Tomography ◽

Cerebral Arteries ◽

Three Dimensional ◽

Neurological Deficits ◽

Content Type ◽

Serial Measurement ◽

Regional Flow ◽

Delayed Neurological Deterioration

✓ A noninvasive three-dimensional method for measuring cerebral blood flow (CBF), xenon-133 inhalation and emission computerized tomography, was used to investigate the CBF changes accompanying delayed neurological deterioration following subarachnoid hemorrhage (SAH). A total of 67 measurements were performed on 20 patients in Hunt and Hess' clinical Grades I to III in the first 21 days post SAH. Five patients with normal CBF tomograms on admission developed delayed neurological deficits in the 2nd week after hemorrhage, at which time repeat CBF tomograms in four patients revealed large areas of well defined regional flow decrease in the vascular territories of the anterior or middle cerebral arteries. Severe vasospasm was noted in three of these patients in whom arteriography was performed in the 2nd week post SAH. Diffuse bihemispheric CBF decreases were noted later in the course of delayed neurological deficits; however, measurements obtained soon after the onset of focal symptoms suggest that the only CBF decreases directly produced by vasospasm in Grade III patients are regional changes.

Download Full-text

Amylin: Localization, Effects on Cerebral Arteries and on Local Cerebral Blood Flow in the Cat

The Scientific World JOURNAL ◽

10.1100/tsw.2001.23 ◽

2001 ◽

Vol 1 ◽

pp. 168-180 ◽

Cited By ~ 33

Author(s):

Lars Edvinsson ◽

Peter J. Goadsby ◽

Rolf Uddman

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Blood Vessels ◽

Cerebral Arteries ◽

In Vivo Studies ◽

Cerebral Blood Vessels ◽

Local Cerebral Blood Flow ◽

Doppler Flowmetry

Amylin and adrenomedullin are two peptides structurally related to calcitonin gene-related peptide (CGRP). We studied the occurrence of amylin in trigeminal ganglia and cerebral blood vessels of the cat with immunocytochemistry and evaluated the role of amylin and adrenomedullin in the cerebral circulation by in vitro and in vivo pharmacology. Immunocytochemistry revealed that numerous nerve cell bodies in the trigeminal ganglion contained CGRP immunoreactivity (-ir); some of these also expressed amylin-ir but none adrenomedullin-ir. There were numerous nerve fibres surrounding cerebral blood vessels that contained CGRP-ir. Occasional fibres contained amylin-ir while we observed no adrenomedullin-ir in the vessel walls. With RT-PCR and Real-Time�PCR we revealed the presence of mRNA for calcitonin receptor-like receptor (CLRL) and receptor-activity-modifying proteins (RAMPs) in cat cerebral arteries. In vitro studies revealed that amylin, adrenomedullin, and CGRP relaxed ring segments of the cat middle cerebral artery. CGRP and amylin caused concentration-dependent relaxations at low concentrations of PGF2a-precontracted segment (with or without endothelium) whereas only at high concentration did adrenomedullin cause relaxation. CGRP8-37 blocked the CGRP and amylin induced relaxations in a parallel fashion. In vivo studies of amylin, adrenomedullin, and CGRP showed a brisk reproducible increase in local cerebral blood flow as examined using laser Doppler flowmetry applied to the cerebral cortex of the a-chloralose�anesthetized cat. The responses to amylin and CGRP were blocked by CGRP8-37. The studies suggest that there is a functional sub-set of amylin-containing trigeminal neurons which probably act via CGRP receptors.

Download Full-text

Quantifying blood flow dynamics during cardiac development: demystifying computational methods

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2017.0330 ◽

2018 ◽

Vol 373 (1759) ◽

pp. 20170330 ◽

Cited By ~ 1

Author(s):

Katherine Courchaine ◽

Sandra Rugonyi

Keyword(s):

Blood Flow ◽

Congenital Heart ◽

Cardiac Development ◽

Three Dimensional ◽

Flow Dynamics ◽

Cardiovascular Development ◽

Flow Conditions ◽

Congenital Heart Malformations ◽

Blood Flow Dynamics ◽

Altered Blood

Blood flow conditions (haemodynamics) are crucial for proper cardiovascular development. Indeed, blood flow induces biomechanical adaptations and mechanotransduction signalling that influence cardiovascular growth and development during embryonic stages and beyond. Altered blood flow conditions are a hallmark of congenital heart disease, and disrupted blood flow at early embryonic stages is known to lead to congenital heart malformations. In spite of this, many of the mechanisms by which blood flow mechanics affect cardiovascular development remain unknown. This is due in part to the challenges involved in quantifying blood flow dynamics and the forces exerted by blood flow on developing cardiovascular tissues. Recent technologies, however, have allowed precise measurement of blood flow parameters and cardiovascular geometry even at early embryonic stages. Combined with computational fluid dynamics techniques, it is possible to quantify haemodynamic parameters and their changes over development, which is a crucial step in the quest for understanding the role of mechanical cues on heart and vascular formation. This study summarizes some fundamental aspects of modelling blood flow dynamics, with a focus on three-dimensional modelling techniques, and discusses relevant studies that are revealing the details of blood flow and their influence on cardiovascular development. This article is part of the Theo Murphy meeting issue ‘Mechanics of development’.

Download Full-text

Cerebral Blood Flow Heterogeneity in Preterm Sheep: Lack of Physiologic Support for Vascular Boundary Zones in Fetal Cerebral White Matter

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600597 ◽

2007 ◽

Vol 28 (5) ◽

pp. 995-1008 ◽

Cited By ~ 44

Author(s):

Melissa M McClure ◽

Art Riddle ◽

Mario Manese ◽

Ning Ling Luo ◽

Dawn A Rorvik ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

White Matter ◽

Ischemia Reperfusion ◽

Three Dimensional ◽

Cerebral White Matter ◽

Periventricular White Matter ◽

Fetal Sheep ◽

Border Zones ◽

Neurologic Disability

Periventricular white matter (PVWM) injury is the leading cause of neurologic disability in survivors of prematurity. To address the role of ischemia in PVWM and cerebral cortical injury, we hypothesized that immaturity of spatially distal vascular ‘end zones’ or ‘border zones’ predisposes PVWM to greater decreases in cerebral blood flow (CBF) than more proximal structures. We quantified regional CBF with fluorescently labeled microspheres in 0.65 gestation fetal sheep in histopathologically defined three-dimensional regions by post hoc digital dissection and coregistration algorithms. Basal flow in PVWM was significantly lower than in gyral white matter and cortex, but was equivalent in superficial, middle, and deep PVWM. Absolute and relative CBF (expressed as percentage of basal) did not differ significantly during ischemia or reperfusion between PVWM, gyral white matter, or cortex. Moreover, CBF during ischemia-reperfusion was equivalent in three adjacent PVWM levels and was not consistent with the magnitude of severity of PVWM injury, defined by TUNEL (terminal deoxynucleotidyltransferase-mediated dUPT nick end labeling) staining. However, the magnitude of ischemia was predicted by the severity of discrete cortical lesions. Hence, unlike cerebral cortex, unique CBF disturbances did not account for the distribution of PVWM injury. Previously defined cellular maturational factors, thus, appear to have a greater influence on PVWM vulnerability to ischemic injury than the presence of immature vascular boundary zones.

Download Full-text

In-Vitro Evaluation of Hot-Film Anemometry Using a Sensor-Tipped Coronary Guide-wire

ASME 2007 Summer Bioengineering Conference ◽

10.1115/sbc2007-176124 ◽

2007 ◽

Author(s):

Maartje C. F. Geven ◽

Arjen Van Der Horst ◽

Marcel C. M. Rutten ◽

Wilbert Aarnoudse ◽

Nico H. J. Pijls ◽

...

Keyword(s):

Blood Flow ◽

Coronary Arteries ◽

Functional Significance ◽

Guide Wire ◽

Coronary Angiogram ◽

Arterial Tree ◽

In Vitro Evaluation ◽

Coronary Catheterization ◽

Hot Film

During coronary catheterization, the epicardial coronary arteries are visually assessed for stenoses on the coronary angiogram. However, the functional significance of disease in the coronary arterial tree, the increased resistance to blood flow, may easily be over- or underestimated by using a 2D projection.

Download Full-text

In vitro evaluation of three-dimensional ultrasonography based on magnetic scanhead tracking

Ultrasound in Medicine & Biology ◽

10.1016/s0301-5629(98)00098-2 ◽

1998 ◽

Vol 24 (8) ◽

pp. 1161-1167 ◽

Cited By ~ 36

Author(s):

Odd Helge Gilja ◽

Trygve Hausken ◽

Snorri Olafsson ◽

Knut Matre ◽

Svein Ødegaard

Keyword(s):

Three Dimensional ◽

In Vitro Evaluation

Download Full-text

Hemoglobin, NO, and 20-HETE interactions in mediating cerebral vasoconstriction following SAH

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00445.2005 ◽

2006 ◽

Vol 290 (1) ◽

pp. R84-R89 ◽

Cited By ~ 14

Author(s):

Kazuhiko Takeuchi ◽

Noriyuki Miyata ◽

Marija Renic ◽

David R. Harder ◽

Richard J. Roman

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Subarachnoid Hemorrhage ◽

Methyl Ester ◽

Cerebral Vasoconstriction ◽

Vasoactive Factors ◽

Vasoconstrictor Response

Recent studies have indicated that 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to the fall in cerebral blood flow (CBF) after subarachnoid hemorrhage (SAH), but the factors that stimulate the production of 20-HETE are unknown. This study examines the role of vasoactive factors released by clotting blood vs. the scavenging of nitric oxide (NO) by hemoglobin (Hb) in the fall in CBF after SAH. Intracisternal (icv) injection of blood produced a greater and more prolonged (120 vs. 30 min) decrease in CBF than that produced by a 4% solution of Hb. Pretreating rats with Nω-nitro-l-arginine methyl ester (l-NAME; 10 mg/kg iv) to block the synthesis of NO had no effect on the fall in CBF produced by an icv injection of blood. l-NAME enhanced rather than attenuated the fall in CBF produced by an icv injection of Hb. Blockade of the synthesis of 20-HETE with TS-011 (0.1 mg/kg iv) prevented the sustained fall in CBF produced by an icv injection of blood and the transient vasoconstrictor response to Hb. Hb (0.1%) reduced the diameter of the basilar artery (BA) of rats in vitro by 10 ± 2%. This response was reversed by TS-011 (100 nM). Pretreatment of vessels with l-NAME (300 μM) reduced the diameter of BA and blocked the subsequent vasoconstrictor response to the addition of Hb to the bath. TS-011 returned the diameter of vessels exposed to l-NAME and Hb to that of control. These results suggest that the fall in CBF after SAH is largely due to the release of vasoactive factors by clotting blood rather than the scavenging of NO by Hb and that 20-HETE contributes the vasoconstrictor response of cerebral vessels to both Hb and blood.

Download Full-text