Acute reaction of arterial blood vessels after experimental subarachnoid hemorrhage – An in vivo microscopic study

Contractility of all types of invertebrate and vertebrate muscle is dependent upon the actions and interactions of two divalent cations, viz., calcium (Ca2+) and magnesium (Mg2+) ions. The data presented and reviewed herein contrast the actions of several organic Ca2+ channel blockers with the natural, physiologic (inorganic) Ca2+ antagonist, Mg2+, on microvascular and macrovascular smooth muscles. Both direct in vivo studies on microscopic arteriolar and venular smooth muscles and in vitro studies on different types of blood vessels are presented. It is clear from the studies done so far that of all Ca2+ antagonists examined, only Mg2+ has the capability to inhibit myogenic, basal, and hormonal-induced vascular tone in all types of vascular smooth muscle. Data obtained with verapamil, nimopidine, nitrendipine, and nisoldipine on the microvasculature are suggestive of the probability that a heterogeneity of Ca2+ channels, and of Ca2+ binding sites, exists in different microvascular smooth muscles; although some appear to be voltage operated and others, receptor operated, they are probably heterogeneous in composition from one vascular region to another. Mg2+ appears to act on voltage-, receptor-, and leak-operated membrane channels in vascular smooth muscle. The organic Ca2+ channel blockers do not have this uniform capability; they demonstrate a selectivity when compared with Mg2+. Mg2+ appears to be a special kind of Ca2+ channel antagonist in vascular smooth muscle. At vascular membranes it can (i) block Ca2+ entry and exit, (ii) lower peripheral and cerebral vascular resistance, (iii) relieve cerebral, coronary, and peripheral vasospasm, and (iv) lower arterial blood pressure. At micromolar concentrations (i.e., 10–100 μM), Mg2+ can cause significant vasodilatation of intact arterioles and venules in all regional vasculatures so far examined. Although Mg2+ is three to five orders of magnitude less potent than the organic Ca2+ channel blockers, it possesses unique and potentially useful Ca2+ antagonistic properties.

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Experimental Subarachnoid Hemorrhage Causes Early and Long-Lasting Microarterial Constriction and Microthrombosis: An in-vivo Microscopy Study

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2011.154 ◽

2011 ◽

Vol 32 (3) ◽

pp. 447-455 ◽

Cited By ~ 113

Author(s):

Benjamin Friedrich ◽

Frank Müller ◽

Sergej Feiler ◽

Karsten Schöller ◽

Nikolaus Plesnila

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Subarachnoid Hemorrhage ◽

Perfusion Pressure ◽

Early Brain Injury ◽

Microscopy Study ◽

Cerebral Microvessels ◽

Experimental Subarachnoid Hemorrhage ◽

Pial Arterioles

Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is characterized by a severe, cerebral perfusion pressure (CPP)-independent reduction in cerebral blood flow suggesting alterations on the level of cerebral microvessels. Therefore, we aimed to use in-vivo imaging to investigate the cerebral microcirculation after experimental SAH. Subarachnoid hemorrhage was induced in C57/BL6 mice by endovascular perforation. Pial arterioles and venules (10 to 80 μm diameter) were examined using in-vivo fluorescence microscopy, 3, 6, and 72 hours after SAH. Venular diameter or flow was not affected by SAH, while >70% of arterioles constricted by 22% to 33% up to 3 days after hemorrhage ( P<0.05 versus sham). The smaller the investigated arterioles, the more pronounced the constriction ( r2=0.92, P<0.04). Approximately 30% of constricted arterioles were occluded by microthrombi and the frequency of arteriolar microthrombosis correlated with the degree of constriction ( r2=0.93, P<0.03). The current study demonstrates that SAH induces microarterial constrictions and microthrombosis in vivo. These findings may explain the early CPP-independent decrease in cerebral blood flow after SAH and may therefore serve as novel targets for the treatment of early perfusion deficits after SAH.

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Early release of high-mobility group box 1 (HMGB1) from neurons in experimental subarachnoid hemorrhage in vivo and in vitro

Journal of Neuroinflammation ◽

10.1186/1742-2094-11-106 ◽

2014 ◽

Vol 11 (1) ◽

pp. 106 ◽

Cited By ~ 81

Author(s):

Qing Sun ◽

Wei Wu ◽

Yang-Chun Hu ◽

Hua Li ◽

Dingding Zhang ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

High Mobility ◽

High Mobility Group ◽

Early Release ◽

Experimental Subarachnoid Hemorrhage

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Alterations in Serotonin and Neuropeptide Y Content of Cerebrovascular Sympathetic Nerves following Experimental Subarachnoid Hemorrhage

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1989.45 ◽

1989 ◽

Vol 9 (3) ◽

pp. 271-279 ◽

Cited By ~ 36

Author(s):

A. Jackowski ◽

A. Crockard ◽

G. Burnstock ◽

J. Lincoln

Keyword(s):

Subarachnoid Hemorrhage ◽

Neuropeptide Y ◽

Sympathetic Nerve ◽

Blood Clot ◽

Cerebral Arteries ◽

Immunohistochemical Analysis ◽

Sympathetic Nerves ◽

Nerve Fibers ◽

Arterial Blood ◽

Experimental Subarachnoid Hemorrhage

The effect of an experimental subarachnoid hemorrhage (SAH) upon neurotransmitter content in sympathetic nerves supplying the major cerebral arteries of the rat has been examined by immunohistochemical analysis and high performance liquid chromatography with electrochemical detection (HPLC–ECD). In particular, changes that occur in sympathetic nerve content of the vasoconstrictor agents serotonin (5-HT) and neuropeptide Y (NPY), which are colocalized with noradrenaline, were assessed. Subarachnoid hemorrhage was induced by a single injection of autologous arterial blood into the cerebrospinal fluid (CSF) space of the cisterna magna. The density of 5-HT-containing and NPY-containing perivascular nerve fibers per unit area of vessels was measured at defined intervals from 15 min to 5 days post-SAH. In addition, an HPLC study was performed to quantify the actual amounts of 5-HT and noradrenaline present in circle of Willis vessels at 3 h post-SAH. Comparison was made with sham-operated animals and animals that received a cisternal injection of buffered saline in place of blood. Our results reveal a major increase in cerebrovascular sympathetic nerve content of serotonin, arising by uptake, presumably from subarachnoid blood clot, within the first 3 h post-SAH. Neuropeptide Y content, however, decreased from 3 up to 48 h posthemorrhage. By 3 days post-SAH, when the majority of subarachnoid clot had resorbed, the sympathetic nerve content of both NPY and 5-HT was restored to normal. This pattern of change was not observed in either sham-operated or saline-injected controls.

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Angiotensin IV Reverses the Acute Cerebral Blood Flow Reduction after Experimental Subarachnoid Hemorrhage in the Rat

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1994.143 ◽

1994 ◽

Vol 14 (6) ◽

pp. 1096-1099 ◽

Cited By ~ 45

Author(s):

Liisa Näveri ◽

Christer Strömberg ◽

Juan M. Saavedra

Keyword(s):

Subarachnoid Hemorrhage ◽

Saline Group ◽

Ang Ii ◽

Doppler Flowmetry ◽

Blood Flow Reduction ◽

Experimental Subarachnoid Hemorrhage ◽

Ang Iv ◽

Oxide Synthase

The effect of angiotensin (ANG) IV on CBF after experimental subarachnoid hemorrhage (SAH) was studied in rats using laser–Doppler flowmetry. ANG IV (1 μg/kg/min i.v.) or saline treatments were started 20 min after SAH. ANG IV increased CBF (from 45 to 84% of baseline) by 60 min. In the saline group, CBF remained low (51%). Pretreatment with the specific ANG II antagonist Sar1, Ile8-ANG II did not antagonize ANG IV. Determination of nitric oxide synthase (NOS) activity in vitro or inhibition of NOS in vivo did not support a role for NO in the action of ANG IV.

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Magnetic Resonance Angiography Shows Increased Arterial Blood Supply Associated with Murine Mammary Cancer

International Journal of Biomedical Imaging ◽

10.1155/2019/5987425 ◽

2019 ◽

Vol 2019 ◽

pp. 1-6

Author(s):

Devkumar Mustafi ◽

Abby Leinroth ◽

Xiaobing Fan ◽

Erica Markiewicz ◽

Marta Zamora ◽

...

Keyword(s):

Mammary Gland ◽

Magnetic Resonance ◽

Contrast Agents ◽

Blood Vessels ◽

Cancer Progression ◽

Virgin Female ◽

Mammary Glands ◽

Dce Mri ◽

Arterial Blood

Breast cancer is a major cause of morbidity and mortality in Western women. Tumor neoangiogenesis, the formation of new blood vessels from pre-existing ones, may be used as a prognostic marker for cancer progression. Clinical practice uses dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to detect cancers based on increased blood flow and capillary permeability. However, DCE-MRI requires repeated injections of contrast media. Therefore we explored the use of noninvasive time-of-flight (TOF) MR angiography for serial studies of mouse mammary glands to measure the number and size of arteries feeding mammary glands with and without cancer. Virgin female C3(1) SV40 TAg mice (n=9), aged 18-20 weeks, were imaged on a 9.4 Tesla small animal scanner. Multislice T2-weighted (T2W) images and TOF-MRI angiograms were acquired over inguinal mouse mammary glands. The data were analyzed to determine tumor burden in each mammary gland and the volume of arteries feeding each mammary gland. After in vivo MRI, inguinal mammary glands were excised and fixed in formalin for histology. TOF angiography detected arteries with a diameter as small as 0.1 mm feeding the mammary glands. A significant correlation (r=0.79; p< 0.0001) was found between tumor volume and the arterial blood volume measured in mammary glands. Mammary arterial blood volumes ranging from 0.08 mm3 to 3.81 mm3 were measured. Tumors and blood vessels found on in vivo T2W and TOF images, respectively, were confirmed with ex vivo histological images. These results demonstrate increased recruitment of arteries to mammary glands with cancer, likely associated with neoangiogenesis. Neoangiogenesis may be detected by TOF angiography without injection of contrast agents. This would be very useful in mouse models where repeat placement of I.V. lines is challenging. In addition, analogous methods could be tested in humans to evaluate the vasculature of suspicious lesions without using contrast agents.

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Mg2+-induced endothelium-dependent relaxation of blood vessels and blood pressure lowering: role of NO

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.278.3.r628 ◽

2000 ◽

Vol 278 (3) ◽

pp. R628-R639 ◽

Cited By ~ 43

Author(s):

Zhi-Wei Yang ◽

Asefa Gebrewold ◽

Maja Nowakowski ◽

Bella T. Altura ◽

Burton M. Altura

Keyword(s):

Blood Pressure ◽

Blood Vessels ◽

Pressure Effects ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Arterial Blood ◽

No Release ◽

Endothelium Dependent Relaxation

In vitro extracellular Mg2+ concentration ([Mg2+]0) produces endothelium-dependent and endothelium-independent relaxations in rat aorta in a concentration-dependent manner. These relaxant effects of Mg2+ on intact rat aortic rings, but not denuded rat aortic rings, were suppressed by either N G-monomethyl-l-arginine (l-NMMA), N ω-nitro-l-arginine methyl ester (l-NAME), or methylene blue. The inhibitory effects of l-NMMA and l-NAME could be reversed partly by l-arginine. [Mg2+]0-induced dilatation in vivo in rat mesenteric arterioles and venules was almost completely inhibited by N G-nitro-l-arginine andl-NMMA. Removal of extracellular Ca2+concentration ([Ca2+]0) or buffering intracellular Ca2+ concentration in endothelial cells, with 10 μM 1,2-bis(2-aminophenoxy)ethane- N, N, N′, N′-tetraacetic acid-AM, markedly attenuated the relaxant effects of Mg2+. Mg2+ produced nitric oxide (NO) release from the intact aortic rings in a concentration-dependent manner. Removal of [Ca2+]0 diminished the increased NO release induced by elevated levels of [Mg2+]0. In vivo infusion of increasing doses (1–30 μM/min) of MgSO4, directly into the femoral veins of anesthetized rats, elicited significant concentration-dependent sustained increases in serum total Mg and concomitant decreases in arterial blood pressure. Before and after employment of various doses of MgSO4, intravenous administration of either l-NMMA (10 mg/kg) orl-NAME (10 mg/kg) increased (i.e., reversed) the MgSO4-lowered blood pressure markedly, and intravenous injection of l-arginine restored partially the increased blood pressure effects of both l-NMMA andl-NAME. Our results suggest that 1) small blood vessels are very dependent on NO release for Mg2+dilatations and 2) the endothelium-dependent relaxation induced by extracellular Mg2+ is mediated by release of endothelium-derived relaxing factor-NO from the endothelium, and requires Ca2+ and formation of guanosine 3′,5′-cyclic monophosphate.

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Reintroduction of the Rat for Experimental Subarachnoid Hemorrhage with Accelerated Clot Formation: A Low Mortality Model with Persistent Clots as a Precondition for Studies in Vasospasm

Journal of Neurological Surgery Part A Central European Neurosurgery ◽

10.1055/s-0038-1641561 ◽

2018 ◽

Vol 79 (05) ◽

pp. 424-433 ◽

Cited By ~ 1

Author(s):

Ulrich Budde ◽

Ralf Middendorff ◽

Gerd Manthei ◽

Andre Kemmling ◽

Bastian Tiemann ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Tissue Factor ◽

Rat Model ◽

Animal Studies ◽

Clot Formation ◽

Delayed Effects ◽

In Vivo Testing ◽

Experimental Subarachnoid Hemorrhage

Background Cerebral vasospasm as a delayed, possibly treatable sequel of subarachnoid hemorrhage (SAH) is a focus of experimental animal research. For this purpose, the rat is not a good model because of the difficulty creating a stable subarachnoid clot that persists > 1 to 2 days and could induce vasospasm. Only in rat models with a high mortality of ∼ 50% or more can SAH and its effects be investigated. Therefore, other animals than rodents are used for investigating the delayed effects of SAH. Only animal studies addressing the acute effects of SAH use rats. Objective We designed a model that allows intensive clot formation combined with low mortality to facilitate studies on the delayed effects of experimental SAH, for example, delayed vasospasm or other alterations of vessels. Methods After in vitro acceleration of the clotting process in the rats' blood by tissue factor and preliminary in vivo testing, we induced a SAH by injecting blood together with tissue factor in 22 rats. We analyzed clot expansion, length of clot persistence, chronic alterations, and histologic changes. Results The injection of blood supplemented by tissue factor led to persistent voluminous blood clots in the subarachnoid space close to the large arteries. Despite the pronounced SAH, all animals survived, allowing investigation of delayed SAH effects. All animals killed within the first 7 days after surgery had extensive clots; in some animals, the clots remained until postoperative day 12. During further clot degradation connective tissue appeared, possibly as a precursor of SAH-related late hydrocephalus. Conclusion The injection of blood together with tissue factor significantly improves SAH induction in the rat model. This rat model allows studying delayed SAH effects as found in humans.

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