scholarly journals Spontaneous Intracerebral Hemorrhage during Acute and Chronic Hypertension in Mice

2009 ◽  
Vol 30 (1) ◽  
pp. 56-69 ◽  
Author(s):  
Yoshinobu Wakisaka ◽  
Yi Chu ◽  
Jordan D Miller ◽  
Gary A Rosenberg ◽  
Donald D Heistad

Oxidative stress and matrix metalloproteinases (MMPs) contribute to hemorrhagic transformation after ischemic stroke and brain injury after intracerebral hemorrhage (ICH). The goal of this study was to develop a new model of spontaneous ICH, based on the hypothesis that acute, superimposed on chronic, hypertension produces ICH. We hypothesized that increases in angiotensin II (AngII)-mediated oxidative stress and activation of MMPs are associated with, and may precede, spontaneous ICH during hypertension. In C57BL/6 mice, chronic hypertension was produced with AngII infusion and an inhibitor of nitric oxide synthase. During chronic hypertension, mice with acute hypertension from injections of AngII developed ICH. Oxidative stress and MMP levels increased in the brain even before developing ICH. Active MMPs colocalized with a marker of oxidative stress, especially on cerebral vessels that appeared to lead toward regions with ICH. Incidence of ICH and levels of oxidative stress and MMP-9 were greater in mice with acute hypertension produced by AngII than by norepinephrine. In summary, we have developed an experimental model of ICH during hypertension that may facilitate studies in genetically altered mice. We speculate that acute hypertension, especially when induced by AngII, may be critical in spontaneous ICH during chronic hypertension, possibly through oxidative stress and MMP-9.

2020 ◽  
pp. 126-128
Author(s):  
Yu.Yu. Kobeliatskyi

Background. Stroke is a major cause of severe disability. Working capacity is restored only in 10-20 % of stroke survivors. Stroke mortality in Ukraine is twice as high as in Western Europe. About 87 % of all strokes are ischemic strokes (II). Leading risk factors for stroke include hypertension, hypercholesterolemia, smoking, obesity, and diabetes. Objective. To describe the management of acute IS (AIS) in the practice of an anesthesiologist. Materials and methods. Analysis of literature data on this issue. Results and discussion. The ideal therapeutic approach for AIS should include reperfusion, inhibition of inflammatory processes, cytoprotection, prevention of complications and their treatment. Extreme caution should be exercised during thrombolytic therapy, as thrombolysis increases the risk of intracerebral hemorrhage. However, a meta-analysis by Y. Shoujiang et al. (2018) found that symptomatic intracerebral hemorrhage occurs in 1.9 % of patients who had received intravenous recombinant tissue plasminogen activator. These hemorrhages did not increase mortality. Excellent treatment results were observed in 74.8 % of patients with AIS. According to the analysis of the VISTA database, the end result of thrombolytic therapy can be predicted based on the initial severity of stroke on the NIHHS scale. Interestingly, hemorrhagic transformation after thrombolysis is associated with lower serum calcium. Lower blood calcium levels are associated with an increased incidence of cerebral hemorrhage in patients with AIS due to atrial fibrillation or rheumatic heart disease. In the treatment of patients with AIS it is advisable to use Neurocytin (“Yuria-Pharm”), which contains citicoline and a balanced isotonic electrolyte solution. Neurocytin helps to avoid hypocalcemia and, consequently, brain hemorrhages. Citicoline is a multimodal agent with neuroprotective and neuroregenerative properties. Citicoline has a wide therapeutic window, as this substance is effective at different time and biochemical stages of the ischemic cascade. The maximum effect of citicoline is observed in cases when it is administered as early as possible after AIS in patients who cannot undergo reperfusion therapy. Citicoline is able to reduce the size of the ischemic focus in the brain. Intensive blood pressure (BP) control also reduces the risk of intracranial hemorrhages without increasing mortality, although previous studies have suggested that a rapid decrease in BP may exacerbate cerebral ischemia. Endovascular treatment of AIS in the most acute phase involves selective thrombolysis, or mechanical thrombextraction, or thromboaspiration. The therapeutic window for the last two procedures for vessels of the carotid pool is 6 hours. When deciding to perform thromboaspiration, it is mandatory to perform and evaluate computed tomography-perfusiography of the brain. About 80-85 % of patients with AIS do not meet the selection criteria for revascularization therapy. There is also no effective therapy for such patients in the acute period. In recent years, it has been proposed to replace the term “neuroprotection” with the term “brain cell cytoprotection”, as the former does not reflect the direction of the impact on all components of the neurovascular unit and white matter. A separate aspect of brain cytoprotection is protection against ischemic reperfusion injury. For this purpose, edaravon (Ksavron, “Yuria-Pharm”) is used, which eliminates free radicals, reduces calcium flow into the cells, prevents cell adhesion to the endothelium, enhances the release of nitric oxide and inhibits the inflammatory response, neutralizing all stages and consequences of ischemic stroke. In Japan, edaravon has been included into AIS treatment guidelines since 2009. T. Yamaguchi et al. (2017) found that co-administration of edaravon and recombinant tissue plasminogen activator within 4.5 hours after AIS led to less intracranial hemorrhages and better treatment outcomes. Early use of edaravon also reduces mortality. S. Kono et al. (2013) also state that edaravon may be a good adjunct to alteplase to enhance recanalization and reduce the likelihood of hemorrhagic transformation. With the administration of edaravon within the first 24 hours after stroke, one in three patients has no post-stroke sequelae, and 70 % of patients have a significant improvement in general neurological status. If edaravon is prescribed within the first 72 hours after AIS, the general condition improves significantly in half of the patients. Edaravon (Ksavron) increases the frequency of early recanalization during thrombolysis. Conclusions. 1. Citicoline is a multimodal agent with neuroprotective and neuroregenerative properties. 2. Edaravon (Ksavron) is an ischemic cascade blocker for the empirical treatment of AIS or transient ischemic attacks. 3. The combination of edaravon (Ksavron) and citicoline (Neurocytin) as part of comprehensive therapy allows to each the advanced protection of the neurovascular unit in AIS.


2008 ◽  
Vol 108 (2) ◽  
pp. 269-275 ◽  
Author(s):  
Katsutoshi Nakahata ◽  
Hiroyuki Kinoshita ◽  
Toshiharu Azma ◽  
Naoyuki Matsuda ◽  
Keiko Hama-Tomioka ◽  
...  

Background Vascular dysfunction induced by hyperglycemia has not been studied in cerebral parenchymal circulation. The current study was designed to examine whether high glucose impairs dilation of cerebral parenchymal arterioles via nitric oxide synthase, and whether propofol recovers this vasodilation by reducing superoxide levels in the brain. Methods Cerebral parenchymal arterioles in the rat brain slices were monitored using computer-assisted videomicroscopy. Vasodilation induced by acetylcholine (10 to 10 m) was obtained after the incubation of brain slices for 60 min with any addition of l-glucose (20 mm), d-glucose (20 mm), or propofol (3 x 10 or 10 m) in combination with d-glucose (20 mm). Superoxide production in the brain slice was determined by dihydroethidium (2 x 10 m) fluorescence. Results Addition of d-glucose, but not l-glucose, reduced arteriolar dilation by acetylcholine, whereas the dilation was abolished by the neuronal nitric oxide synthase inhibitor S-methyl-l-thiocitrulline (10 m). Both propofol and the superoxide dismutase mimetic Tempol (10 m) restored the arteriolar dilation in response to acetylcholine in the brain slice treated with d-glucose. Addition of d-glucose increased superoxide production in the brain slice, whereas propofol, Tempol, and the nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase inhibitor apocynin (1 mm) similarly inhibited it. Conclusions Clinically relevant concentrations of propofol ameliorate neuronal nitric oxide synthase-dependent dilation impaired by high glucose in the cerebral parenchymal arterioles via the effect on superoxide levels. Propofol may be protective against cerebral microvascular malfunction resulting from oxidative stress by acute hyperglycemia.


2013 ◽  
Vol 33 (7) ◽  
pp. 1008-1014 ◽  
Author(s):  
Mohammed Sabri ◽  
Jinglu Ai ◽  
Elliot Lass ◽  
Josephine D'abbondanza ◽  
R Loch Macdonald

Delayed complications of subarachnoid hemorrhage (SAH) such as angiographic vasospasm, cortical spreading ischemia, microcirculatory dysfunction, and microthrombosis are reported in both patients and animal models of SAH. We demonstrated previously that SAH is associated with increased oxidative stress in the brain parenchyma, and that this correlates with dysfunction of endothelial nitric oxide synthase (eNOS) (homodimeric uncoupling). Uncoupling of eNOS exacerbated oxidative stress and enhanced nitric oxide (NO) depletion, and was associated with multiple secondary complications such as microthrombosis, neuronal apoptosis, and release of reactive oxygen species. Thus, we hypothesized that genetic abbrogation of eNOS would confer a beneficial effect on the brain after SAH. Using a prechiasmatic injection model of SAH, we show here that eNOS knockout (KO) significantly alleviates vasospasm of the middle cerebral artery and reduces superoxide production. Endothelial nitric oxide synthase KO also affected other nitric oxide synthase isoforms. It significantly increases neuron nitric oxide synthase expression but has no effect on inducible nitric oxide synthase. Endothelial nitric oxide synthase KO decreases Zn2+ release after SAH, reduces microthrombi formation, and prevent neuronal degeneration. This work is consistent with our findings where, after SAH, increased oxidative stress can uncouple eNOS via Zn2+ thiolate oxidation, or theoretically by depletion or oxidation of tetrahydrobiopterin, resulting in a paradoxical release of superoxide anion radical, further exacerbating oxidative stress and microvascular damage.


2009 ◽  
Vol 111 (5) ◽  
pp. 995-1000 ◽  
Author(s):  
Dong Wook Kim ◽  
So-Hyang Im ◽  
Jeong-Yeon Kim ◽  
Dong-Eog Kim ◽  
Goo Taeg Oh ◽  
...  

Object Hematoma size and brain edema after intracerebral hemorrhage (ICH) are important prognostic factors. Inducible nitric oxide synthase (iNOS) is induced after cerebral ischemia and is known to be involved in secondary neuronal injury, but its significance in ICH is unknown. The authors tested whether iNOS would influence hematoma size and brain edema after ICH. Methods The authors used C57BL/6 and iNOS knockout mice for all the experiments. Experimental ICH was induced by the intrastriatal stereotactic administration of bacterial collagenase. Brain tissue was obtained at 72 hours after ICH. The volume of hematoma was quantified by spectrophotometric assay, and the brain water content was measured. The investigators also measured blood-brain barrier permeability using Evans blue dye. Results There was no significant difference in hematoma size between the 2 groups. The brain water content of the lesional hemisphere was higher in C57BL/6 mice than in iNOS knockout mice. More Evans blue leakage in the brain was observed in C57BL/6 control mice than in iNOS knockout mice. Immunohistochemistry showed iNOS immunoreactivity in the perihematoma areas of C57BL/6 mice but not in the iNOS knockout mice. Conclusions When hematoma size was similar, iNOS knockout mice had significantly less brain edema than their littermates. These results suggest that iNOS modulation might become an antiedematous therapy for ICH.


1999 ◽  
Vol 17 (1) ◽  
pp. 45-55 ◽  
Author(s):  
A.E.-D El-Husseini ◽  
J Williams ◽  
P.B Reiner ◽  
S Pelech ◽  
S.R Vincent

2021 ◽  
pp. 096032712199944
Author(s):  
Mohamed IA Hassan ◽  
Fares EM Ali ◽  
Abdel-Gawad S Shalkami

Aim: Hepatic ischemia/reperfusion (I/R) injury is a syndrome involved in allograft dysfunction. This work aimed to elucidate carvedilol (CAR) role in hepatic I/R injury. Methods: Male rats were allocated to Sham group, CAR group, I/R group and CAR plus I/R group. Rats subjected to hepatic ischemia for 30 minutes then reperfused for 60 minutes. Oxidative stress markers, inflammatory cytokines and nitric oxide synthases were measured in hepatic tissues. Results: Hepatocyte injury following I/R was confirmed by a marked increase in liver enzymes. Also, hepatic I/R increased the contents of malondialdehyde however decreased glutathione contents and activities of antioxidant enzymes. Furthermore, hepatic I/R caused elevation of toll-like receptor-4 (TLR-4) expression and inflammatory mediators levels such as tumor necrosis factor-α, interleukin-6 and cyclooxygenase-II. Hepatic I/R caused down-regulation of endothelial nitric oxide synthase and upregulation of inducible nitric oxide synthase expressions. CAR treatment before hepatic I/R resulted in the restoration of liver enzymes. Administration of CAR caused a significant correction of oxidative stress and inflammation markers as well as modulates the expression of endothelial and inducible nitric oxide synthase. Conclusions: CAR protects liver from I/R injury through reduction of the oxidative stress and inflammation, and modulates endothelial and inducible nitric oxide synthase expressions.


1998 ◽  
Vol 274 (1) ◽  
pp. C245-C252 ◽  
Author(s):  
Junsuke Igarashi ◽  
Masashi Nishida ◽  
Shiro Hoshida ◽  
Nobushige Yamashita ◽  
Hiroaki Kosaka ◽  
...  

The effects of nitric oxide (NO) produced by cardiac inducible NO synthase (iNOS) on myocardial injury after oxidative stress were examined. Interleukin-1β induced cultured rat neonatal cardiac myocytes to express iNOS. After induction of iNOS,l-arginine enhanced NO production in a concentration-dependent manner. Glutathione peroxidase (GPX) activity in myocytes was attenuated by elevated iNOS activity and by an NO donor, S-nitroso- N-acetyl-penicillamine (SNAP). Although NO production by iNOS did not induce myocardial injury, NO augmented release of lactate dehydrogenase from myocyte cultures after addition of H2O2(0.1 mM, 1 h). Inhibition of iNOS with Nω-nitro-l-arginine methyl ester ameliorated the effects of NO-enhancing treatments on myocardial injury and GPX activity. SNAP augmented the myocardial injury induced by H2O2. Inhibition of GPX activity with antisense oligodeoxyribonucleotide for GPX mRNA increased myocardial injury by H2O2. Results suggest that the induction of cardiac iNOS promotes myocardial injury due to oxidative stress via inactivation of the intrinsic antioxidant enzyme, GPX.


Author(s):  
Theresa Chikopela ◽  
Douglas C. Heimburger ◽  
Longa Kaluba ◽  
Pharaoh Hamambulu ◽  
Newton Simfukwe ◽  
...  

Abstract Background Endothelial function is dependent on the balance between vasoconstrictive and vasodilatory substances. The endothelium ability to produce nitric oxide is one of the most crucial mechanisms in regulating vascular tone. An increase in inducible nitric oxide synthase contributes to endothelial dysfunction in overweight persons, while oxidative stress contributes to the conversion of nitric oxide to peroxynitrite (measured as nitrotyrosine in vivo) in underweight persons. The objective of this study was to elucidate the interaction of body composition and oxidative stress on vascular function and peroxynitrite. This was done through an experimental design with three weight groups (underweight, normal weight and overweight), with four treatment arms in each. Plasma nitrotyrosine levels were measured 15–20 h post lipopolysaccharide (LPS) treatment, as were aortic ring tension changes. Acetylcholine (ACh) and sodium nitroprusside (SNP) challenges were used to observe endothelial-dependent and endothelial-independent vascular relaxation after pre-constriction of aortic rings with phenylephrine. Results Nitrotyrosine levels in saline-treated rats were similar among the weight groups. There was a significant increase in nitrotyrosine levels between saline-treated rats and those treated with the highest lipopolysaccharide doses in each of the weight groups. In response to ACh challenge, Rmax (percentage reduction in aortic tension) was lowest in overweight rats (112%). In response to SNP, there was an insignificantly lower Rmax in the underweight rats (106%) compared to the normal weight rats (112%). Overweight rats had a significant decrease in Rmax (83%) in response to SNP, signifying involvement of a more chronic process in tension reduction changes. A lower Rmax accompanied an increase in peroxynitrite after acetylcholine challenge in all weight groups. Conclusions Endothelial dysfunction, observed as an impairment in the ability to reduce tension, is associated with increased plasma peroxynitrite levels across the spectrum of body mass. In higher-BMI rats, an additional role is played by vascular smooth muscle in the causation of endothelial dysfunction.


2011 ◽  
Vol 301 (5) ◽  
pp. H2093-H2101 ◽  
Author(s):  
Baptiste Kurtz ◽  
Helene B. Thibault ◽  
Michael J. Raher ◽  
John R. Popovich ◽  
Sharon Cawley ◽  
...  

Insulin resistance (IR) and systemic hypertension are independently associated with heart failure. We reported previously that nitric oxide synthase 3 (NOS3) has a beneficial effect on left ventricular (LV) remodeling and function after pressure-overload in mice. The aim of our study was to investigate the interaction of IR and NOS3 in pressure-overload-induced LV remodeling and dysfunction. Wild-type (WT) and NOS3-deficient (NOS3−/−) mice were fed either a standard diet (SD) or a high-fat diet (HFD) to induce IR. After 9 days of diet, mice underwent transverse aortic constriction (TAC). LV structure and function were assessed serially using echocardiography. Cardiomyocytes were isolated, and levels of oxidative stress were evaluated using 2′,7′-dichlorodihydrofluorescein diacetate. Cardiac mitochondria were isolated, and mitochondrial respiration and ATP production were measured. TAC induced LV remodeling and dysfunction in all mice. The TAC-induced decrease in LV function was greater in SD-fed NOS3−/− mice than in SD-fed WT mice. In contrast, HFD-fed NOS3−/− developed less LV remodeling and dysfunction and had better survival than did HFD-fed WT mice. Seven days after TAC, oxidative stress levels were lower in cardiomyocytes from HFD-fed NOS3−/− than in those from HFD-fed WT. Nω-nitro-l-arginine methyl ester and mitochondrial inhibitors (rotenone and 2-thenoyltrifluoroacetone) decreased oxidative stress levels in cardiomyocytes from HFD-fed WT mice. Mitochondrial respiration was altered in NOS3−/− mice but did not worsen after HFD and TAC. In contrast with its protective role in SD, NOS3 increases LV adverse remodeling after pressure overload in HFD-fed, insulin resistant mice. Interactions between NOS3 and mitochondria may be responsible for increased oxidative stress levels in HFD-fed WT mice hearts.


2016 ◽  
Vol 310 (1) ◽  
pp. H39-H48 ◽  
Author(s):  
Masashi Mukohda ◽  
Madeliene Stump ◽  
Pimonrat Ketsawatsomkron ◽  
Chunyan Hu ◽  
Frederick W. Quelle ◽  
...  

Loss of peroxisome proliferator-activated receptor (PPAR)-γ function in the vascular endothelium enhances atherosclerosis and NF-κB target gene expression in high-fat diet-fed apolipoprotein E-deficient mice. The mechanisms by which endothelial PPAR-γ regulates inflammatory responses and protects against atherosclerosis remain unclear. To assess functional interactions between PPAR-γ and inflammation, we used a model of IL-1β-induced aortic dysfunction in transgenic mice with endothelium-specific overexpression of either wild-type (E-WT) or dominant negative PPAR-γ (E-V290M). IL-1β dose dependently decreased IκB-α, increased phospho-p65, and increased luciferase activity in the aorta of NF-κB-LUC transgenic mice. IL-1β also dose dependently reduced endothelial-dependent relaxation by ACh. The loss of ACh responsiveness was partially improved by pretreatment of the vessels with the PPAR-γ agonist rosiglitazone or in E-WT. Conversely, IL-1β-induced endothelial dysfunction was worsened in the aorta from E-V290M mice. Although IL-1β increased the expression of NF-κB target genes, NF-κB p65 inhibitor did not alleviate endothelial dysfunction induced by IL-1β. Tempol, a SOD mimetic, partially restored ACh responsiveness in the IL-1β-treated aorta. Notably, tempol only modestly improved protection in the E-WT aorta but had an increased protective effect in the E-V290M aorta compared with the aorta from nontransgenic mice, suggesting that PPAR-γ-mediated protection involves antioxidant effects. IL-1β increased ROS and decreased the phospho-endothelial nitric oxide synthase (Ser1177)-to-endothelial nitric oxide synthase ratio in the nontransgenic aorta. These effects were completely abolished in the aorta with endothelial overexpression of WT PPAR-γ but were worsened in the aorta with E-V290M even in the absence of IL-1β. We conclude that PPAR-γ protects against IL-1β-mediated endothelial dysfunction through a reduction of oxidative stress responses but not by blunting IL-1β-mediated NF-κB activity.


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