Changes In Vascular Reactivity Research Articles

Reproducibility of blood oxygen level-dependent signal changes with end-tidal carbon dioxide alterations.

Hypercapnia has been utilized as a stimulus to elicit changes in cerebral blood flow (CBF). However, in many instances it has been delivered in a non-controlled method that is often difficult to reproduce. The purpose of this study was to examine the within- and between-visit reproducibility of blood oxygen level-dependent (BOLD) signal changes to an iso-oxic square wave alteration in end-tidal carbon dioxide partial pressure (Pet CO2 ). Two 3-Tesla (3T) MRI scans were performed on the same visit, with two square wave alterations administered per scan. The protocol was repeated on a separate visit with minimum of 3days between scanning sessions. Pet CO2 was altered to stimulate changes in cerebral vascular reactivity (CVR), while Pet O2 was held constant. Eleven subjects (six females; mean age 26·5±5·7years) completed the full testing protocol. Excellent within-visit square wave reproducibility (ICC>0·75) was observed. Similarly, square waves were reproducible between scanning sessions (ICC>0·7). This study demonstrates BOLD signal changes in response to alterations in Pet CO2 are reproducible both within- and between-visit MRI scans.

Lipid-lowering drugs prevent neurovascular and cognitive consequences of cardiopulmonary bypass

Inflammatory injury and hypoperfusion following cardiopulmonary bypass (CPB) are associated with potential brain injury in relationship between CPB, memory impairment, changes in cerebral vascular reactivity and both systemic and cerebral inflammatory reaction. The objective of this study was to assess the preventive effect of a pretreatment with simvastatin or fenofibrate on neurovascular and cognitive consequences of CPB. Male Sprague–Dawley rats were treated by control diet, simvastatin 10mg/kg/day or fenofibrate 200mg/kg/day for 14days before CPB surgery and were sacrificed immediately after surgery or 24h later. Cognitive function, vascular reactivity, neuronal counts in CA1 and CA3 hippocampal regions, and inflammatory markers were assessed. CPB induced memory impairment and endothelial dysfunction 24h after surgery associated with neuronal loss. Neuronal loss was reduced by simvastatin or fenofibrate treatment in parallel to memory alteration prevention. Pretreatment by simvastatin and fenofibrate prevented CPB-induced endothelial dysfunction. CPB led to early and marked release of TNFα and overexpression of ICAM-1. Both inflammatory marker expression was decreased in the pretreated groups by lipid-lowering drugs. In a rat model of CPB, we demonstrated that simvastatin and fenofibrate protected against CPB-induced endothelial dysfunction, cerebral and systemic inflammation in parallel to memory impairment prevention.

Vascular Dysfunction in Pneumocystis-Associated Pulmonary Hypertension Is Related to Endothelin Response and Adrenomedullin Concentration

Pulmonary hypertension subsequent to an infectious disease can be due to vascular structural remodeling or to functional alterations within various vascular cell types. In our previous mouse model of Pneumocystis-associated pulmonary hypertension, we found that vascular remodeling was not responsible for observed increases in right ventricular pressures. Here, we report that the vascular dysfunction we observed could be explained by an enhanced response to endothelin-1 (20% greater reduction in lumen diameter, P≤0.05), corresponding to an up-regulation of similar magnitude (P≤0.05) of the endothelin A receptor in the lung tissue. This effect was potentially augmented by a decrease in production of the pulmonary vasodilator adrenomedullin of almost 70% (P≤0.05). These changes did not occur in interferon-γ knockout mice similarly treated, which do not develop pulmonary hypertension under these circumstances. Surprisingly, we did not observe any relevant changes in the vascular endothelial nitric oxide synthase vasodilatory response, which is a common potential site of inflammatory alterations to pulmonary vascular function. Our results indicate the diverse mechanisms by which inflammatory responses to prior infections can cause functionally relevant changes in vascular responses in the lung, promoting the development of pulmonary hypertension.

Cerebral reactivity in migraine patients measured with functional near-infrared spectroscopy.

BackgroundThere are two major theories describing the pathophysiology of migraines. Vascular theory explains that migraines resulted from vasodilation of meningeal vessels irritating the trigeminal nerves and causing pain. More recently, a neural theory of migraine has been proposed, which suggests that cortical hyperexcitability leads to cortical spreading depression (CSD) causing migraine-like symptoms. Chronic migraine requires prophylactic therapy. When oral agents fail, there are several intravenous agents that can be used. Understanding underlying causes of migraine pain would help to improve efficacy of migraine medications by changing their mechanism of action. Yet to date no study has been made to investigate the link between vascular changes in response to medications for migraine versus pain improvements. Functional near-infrared spectroscopy (NIRS) has been used as an inexpensive, rapid, non-invasive and safe technique to monitor cerebrovascular dynamics.MethodIn this study, a multi-distance near-infrared spectroscopy device has been used to investigate the cortical vascular reactivity of migraine patients in response to drug infusions and its possible correlation with changes in pain experienced. We used the NIRS on 41 chronic migraine patients receiving three medications: magnesium sulfate, valproate sodium, and dihydroergotamine (DHE). Patients rated their pain on a 1–10 numerical scale before and after the infusion.ResultsNo significant differences were observed between the medication effects on vascular activity from near channels measuring skin vascularity. However, far channels—indicating cortical vascular activity—showed significant differences in both oxyhemoglobin and total hemoglobin between medications. DHE is a vasoconstrictor and decreased cortical blood volume in our experiment. Magnesium sulfate has a short-lived vasodilatory effect and increased cortical blood volume in our experiment. Valproate sodium had no significant effect on blood volume. Nonetheless, all three reduced patients’ pain based on self-report and no significant link was observed between changes in cortical vascular reactivity and improvement in migraine pain as predicted by the vascular theory of migraine.ConclusionNIRS showed the potential to be a useful tool in the clinical setting for monitoring the vascular reactivity of individual patients to various migraine and headache medications.

Changes in cerebral vascular reactivity and structure following prolonged exposure to high altitude in humans.

Although high-altitude exposure can lead to neurocognitive impairment, even upon return to sea level, it remains unclear the extent to which brain volume and regional cerebral vascular reactivity (CVR) are altered following high-altitude exposure. The purpose of this study was to simultaneously determine the effect of 3weeks at 5050m on: (1) structural brain alterations; and (2) regional CVR after returning to sea level for 1week. Healthy human volunteers (n=6) underwent baseline and follow-up structural and functional magnetic resonance imaging (MRI) at rest and during a CVR protocol (end-tidal PCO2 reduced by -10, -5 and increased by +5, +10, and +15mmHg from baseline). CVR maps (%mmHg(-1)) were generated using BOLD MRI and brain volumes were estimated. Following return to sea level, whole-brain volume and gray matter volume was reduced by 0.4±0.3% (P<0.01) and 2.6±1.0% (P<0.001), respectively; white matter was unchanged. Global gray matter CVR and white matter CVR were unchanged following return to sea level, but CVR was selectively increased (P<0.05) in the brainstem (+30±12%), hippocampus (+12±3%), and thalamus (+10±3%). These changes were the result of improvement and/or reversal of negative CVR to positive CVR in these regions. Three weeks of high-altitude exposure is reflected in loss of gray matter volume and improvements in negative CVR.

Chronic black tea extract consumption improves endothelial function in ovariectomized rats.

Purpose Menopause escalates the risk of cardiovascular diseases in women. There is an unmet need for better treatment strategy for estrogen-deficiency-related cardiovascular complications. Here we investigated the impact of chronic black tea extract (BT) consumption on cardiovascular function and lipid metabolism using a rat model of estrogen deficiency.MethodsFemale Sprague–Dawley rats were ovariectomized (OVX) and treated with BT (15 mg/kg/day, 4 weeks; active ingredients: theaflavins) or estrogen (E2) treatment for 4 weeks. Serum was collected for measuring cholesterol, triacylglycerol and estradiol levels. Changes in vascular reactivity were examined. The protein levels of NADPH oxidases were assessed by Western blotting. Reactive oxygen species (ROS) level was measured using dihydroethidium fluorescence imaging. The concentrations of cGMP were measured using ELISA kit.ResultsAortic rings from control, BT-treated and E2-treated OVX rats exhibited a greater increase in Phe-induced contraction after inhibition of NO synthase compared with those from OVX rats. ACh-induced endothelium-dependent relaxations were augmented in aortae and renal arteries in BT/E2-treated OVX rats than in OVX rats. BT/E2 treatment improved flow-mediated dilatation in small mesenteric resistance arteries of OVX rats. BT/E2 treatment restored the eNOS phosphorylation level and reversed the up-regulation of NADPH oxidases and ROS overproduction in OVX rat aortae. ACh-stimulated cGMP production was significantly elevated in the aortae from BT- and E2-treated rats compared with those from OVX rats. BT/E2 treatment reduced circulating levels of total cholesterol.ConclusionsThe present study reveals the novel benefits of chronic BT consumption to reverse endothelial dysfunction and favorably modifying cholesterol profile in a rat model of estrogen deficiency and provides insights into developing BT as beneficial dietary supplements for postmenopausal women.

Changes in Oxidative Stress and Vascular Reactivity of Thoracic and Abdominal Rat Aorta with Different Periods of Exposure to Hyperbaric Oxygenation

Oxidative stress and the antioxidant defense always seek balance in aerobic systems. Therefore, when O2 is added to an aerobic system during hyperbaric oxygenation, oxidative stress is induced and the antioxidant defense is stimulated. Dose-response curves were established for rat aorta exposed to different agonists. The aorta were from control rats and animals with 3, 10 or 20 HBO sessions. Parameters of vascular reactivity, oxidative stress and antioxidant defense were measured. With hyperbaric oxygenation, vascular reactivity was modified by the altered interaction between oxidative stress and antioxidant defense. The result was a low contractile response, possibly caused by endothelium dependent or independent pathways. Since, acetylcholine did not modify the vascular response, HBO seems to act by endothelium independent pathways related to nitric oxide. Hyperbaric oxygen therapy (HBO) led to an over 60% decrease in all parameters of oxidative stress and antioxidant defense (enzymatic and non-enzymatic) of thoracic aorta, an effect that lasted during the 20 sessions of HBO. This result indicates a probable drastic reduction in ROS and NO production, which could be explained by the capacity of an excess of oxygen to eliminate certain products that are normally involved in chain reactions leading to oxidative stress.

EFFECT OF OZONE THERAPY ON ISCHEMIC REPERFUSION INJURY OF THE HEART AND VASCULAR REACTIVITY IN ADULT MALE DIABETIC ALBINO RAT

Background: Ozone therapy is a form of complementary medicine treatment that aims to increase the amount of oxygen to the body through the introduction of ozone into the body. Objective: Studying the effects of diabetes mellitus, insulin and ozone on ischemic reperfusion (IR) injury on the heart and vascular reactivity in diabetic rat. Material and Methods: Two hundred and fifty adult male albino rats of local strain, weighing 120-150 ±10 grams each, were used in this investigation and divided into: Group I (Normal control group): 10 rats. Group II (Diabetic group -240 rats) were subdivided into 4 subgroups: Group II-a (Diabetic non-treated group - 40 rats), Group II-b (Diabetic insulin-treated group - 40 rats, and Group II-c (Diabetic ozone-treated group - 80 rats Group II-d (Diabetic ozone and insulin-treated group - 80 rats): Rats were submitted to ozone therapy with concomitant treatment with insulin. Supernatant serum was collected in a dry clean tube for estimation of fasting serum glucose, serum total cholesterol, triglycerides, HDL, LDL, LDH, catalase enzyme, glutathione peroxidase, and SOD. Rat aortic rings preparation were used for estimation of changes in vascular reactivity in response to norepinephrine (10-5), vasopressin (10-6 M), indomethacin (10-6 M) and relaxation of aortic rings (preconstricted by NE (10-5) in response to ACh (10-6) and Na+ nitroprusside (10-6) as estimated in different groups. The organ bath was washed out three times with fresh Krebs' solution before the next substance was added and the rings were allowed to stabilize for 1 hour. All results were presented as the mean ± SEM. The data were analyzed using SPSS program version 12. For comparison of statistical significance between different groups, a one way ANOVA with the post hoc of Tukey's multiple comparison test was used. A value of P ≤ 0.05 was considered statistically significant. Results: Ozone therapy caused significant decrease in fasting glucose, total cholesterol, triglycerides, LDL, and lactate dehydrogenase “LDH”, and significant increase in HDL and myocardial antioxidants (catalase, superoxide dismutase “SOD” and glutathione peroxidase). There were a significant increase in cardiac contractility and heart rate during pre-ischemic and ischemic periods. There was a significant decrease in heart rate accompanied by significant increase in cardiac contractility during reperfusion period. Also, ozone treatment produced a significant decrease in vascular reactivity of aortic rings to norepinephrine, vasopressin and indomethacin, with significant increase in percentage of relaxation to acetyl choline “ACh”. Conclusion: Diabetic complications are attributed to the oxidative stress in the body. Ozone activates the antioxidant system affecting the level of glycemia. Ozone prevents oxidative stress by normalizing the organic peroxide levels by activating superoxide dismutase.

Arsenic causes aortic dysfunction and systemic hypertension in rats: Augmentation of angiotensin II signaling

The groundwater pollutant arsenic can cause various cardiovascular disorders. Angiotensin II, a potent vasoconstrictor, plays an important role in vascular dysfunction by promoting changes in endothelial function, vascular reactivity, tissue remodeling and oxidative stress. We investigated whether modulation of angiotensin II signaling and redox homeostasis could be a mechanism contributing to arsenic-induced vascular disorder. Rats were exposed to arsenic at 25, 50 and 100ppm of sodium arsenite through drinking water consecutively for 90days. Blood pressure was recorded weekly. On the 91st day, the rats were sacrificed for blood collection and isolation of thoracic aorta. Angiotensin converting enzyme and angiotensin II levels were assessed in plasma. Aortic reactivity to angiotensin II was assessed in organ-bath system. Western blot of AT1 receptors and G protein (Gαq/11), ELISA of signal transducers of MAP kinase pathway and reactive oxygen species (ROS) generation were assessed in aorta. Arsenic caused concentration-dependent increase in systolic, diastolic and mean arterial blood pressure from the 10th, 8th and 7th week onwards, respectively. Arsenic caused concentration-dependent enhancement of the angiotensin II-induced aortic contractile response. Arsenic also caused concentration-dependent increase in the plasma levels of angiotensin II and angiotensin converting enzyme and the expression of aortic AT1 receptor and Gαq/11 proteins. Arsenic increased aortic protein kinase C activity and the concentrations of protein tyrosine kinase, extracellular signal-regulated kinase-1/2 and vascular endothelial growth factor. Further, arsenic increased aortic mRNA expression of Nox2, Nox4 and p22phox, NADPH oxidase activity and ROS generation. The results suggest that arsenic-mediated enhancement of angiotensin II signaling could be an important mechanism in the arsenic-induced vascular disorder, where ROS could augment the angiotensin II signaling through activation of MAP kinase pathway.

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Objective: Alterations in vascular reactivity play important roles in diabetic vascular complications which, in turn, can develop into further serious complications. Geraniol and 10-gingerol are two ginger ingredients with reported anti-inflammatory and antioxidant activities. The present work investigates the effect of geraniol and 10-gingerol on the changes in vascular reactivity associated with diabetes. Design and method: Diabetes was induced in rats by single intraperitoneal injection of streptozotocin (50 mg.kg-1). Animals were left for 8 weeks after streptozotocin injection to develop vascular complications. Then, rings of rat isolated thoracic aorta were used to measure the vasoconstrictor responses to cumulative concentrations of phenylephrine (PE) and the relaxation responses to the endothelial dependent relaxant acetylcholine (ACh). Results: Streptozotocin injection induced moderate hyperglycemia that lasts for 8 weeks. Aortic rings isolated from diabetic animals (C) showed exaggerated contractility responses to PE while showing impaired dilatation responses to ACh compared with control animals (C). While not affecting basal aortic contractility, incubating diabetic aorta for 1 hour with geraniol (R) or 10-gingerol (G) in a concentration range (0.01–1 μM) reduced the exaggerated response to PE. In addition, geraniol or 10-gingerol incubation improved the impaired relaxation response to ACh in a dose dependent manner.Conclusions: In conclusion, both geraniol and 10-gingerol restore normal vascular reactivity in aorta isolated from diabetic rats. Addition of geraniol and 10-gingerol to diabetic therapy may provide superior to alleviate the associated vascular complications.

Postischemic Responsiveness of Pial Vessels to Hypercapnia.

Reactions of pial vessels to hypercapnia were studied in Wistar rats one week after global cerebral ischemia. In ischemic rats, the responsiveness of pial vessels to hypercapnia was diminished, which promoted a decrease in cerebral perfusion reserve. Changes in vascular responsiveness in the arterial and venous subdivisions of the vascular bed were observed and probably resulted from ischemia-provoked down-regulation of the vascular tone.

Chronic ouabain treatment induces Rho kinase activation.

Ouabain is an endogenous Na(+)/K(+)-ATPase inhibitor whose chronic administration induces hypertension. Endogenous ouabain levels increase in human essential hypertension. On the other hand, Rho/Rho kinase (ROCK) pathway has been implicated in various animal models of hypertension. In the current work, we evaluated the possible involvement of Rho kinase in ouabain-induced hypertension. Ouabain was administered daily (20 µg/kg, i.p.) to Wistar rats for 6 weeks. After the ouabain treatment, we evaluated the possible changes in vascular responses to KCl and phenylephrine alone and in the presence of Rho kinase inhibitor Y27632. We also determined the expressions of ROCKs, Rho A and phosphorylation of myosin binding subunit of myosin light chain phosphatase (pMYPT) and activation of Rho A. Agonist-induced contractions in the presence of Y27632 are significantly decreased and Y27632-induced relaxations in aortas precontracted with phenylephrine are significantly enhanced with the chronic treatment of ouabain. Although the expressions of ROCK I and ROCK II remained unchanged, pMYPT expression was significantly increased in ouabain-treated group. Moreover, Rho A expression and activation were decreased after treatment with ouabain. Although Rho kinase expression did not change in aortas, increased basal Rho kinase activation may contribute to the development of ouabain-induced hypertension. Our current data present the first evidence that Rho kinase is involved in the development of ouabain-induced hypertension in rats.

Dimethylarginine dimethylaminohydrolase 2 regulates nitric oxide synthesis and hemodynamics and determines outcome in polymicrobial sepsis.

Nitric oxide is a key to numerous physiological and pathophysiological processes. Nitric oxide production is regulated endogenously by 2 methylarginines, asymmetric dimethylarginine (ADMA) and monomethyl-L-arginine. The enzyme that specifically metabolizes asymmetric dimethylarginine and monomethyl-L-arginine is dimethylarginine dimethylaminohydrolase (DDAH). The first isoform dimethylarginine dimethylaminohydrolase 1 has previously been shown to be an important regulator of methylarginines in both health and disease. This study explores for the first time the role of endogenous dimethylarginine dimethylaminohydrolase 2 in regulating cardiovascular physiology and also determines the functional impact of dimethylarginine dimethylaminohydrolase 2 deletion on outcome and immune function in sepsis. Mice, globally deficient in Ddah2, were compared with their wild-type littermates to determine the physiological role of Ddah2 using in vivo and ex vivo assessments of vascular function. We show that global knockout of Ddah2 results in elevated blood pressure during periods of activity (mean [SEM], 118.5 [1.3] versus 112.7 [1.1] mm Hg; P=0.025) and changes in vascular responsiveness mediated by changes in methylarginine concentration, mean myocardial tissue asymmetric dimethylarginine (SEM) was 0.89 (0.06) versus 0.67 (0.05) μmol/L (P=0.02) and systemic nitric oxide concentrations. In a model of severe polymicrobial sepsis, Ddah2 knockout affects outcome (120-hour survival was 12% in Ddah2 knockouts versus 53% in wild-type animals; P<0.001). Monocyte-specific deletion of Ddah2 results in a similar pattern of increased severity to that seen in globally deficient animals. Ddah2 has a regulatory role both in normal physiology and in determining outcome of severe polymicrobial sepsis. Elucidation of this role identifies a mechanism for the observed relationship between Ddah2 polymorphisms, cardiovascular disease, and outcome in sepsis.

The effect of ageing on fMRI: Correction for the confounding effects of vascular reactivity evaluated by joint fMRI and MEG in 335 adults.

In functional magnetic resonance imaging (fMRI) research one is typically interested in neural activity. However, the blood‐oxygenation level‐dependent (BOLD) signal is a composite of both neural and vascular activity. As factors such as age or medication may alter vascular function, it is essential to account for changes in neurovascular coupling when investigating neurocognitive functioning with fMRI. The resting‐state fluctuation amplitude (RSFA) in the fMRI signal (rsfMRI) has been proposed as an index of vascular reactivity. The RSFA compares favourably with other techniques such as breath‐hold and hypercapnia, but the latter are more difficult to perform in some populations, such as older adults. The RSFA is therefore a candidate for use in adjusting for age‐related changes in vascular reactivity in fMRI studies. The use of RSFA is predicated on its sensitivity to vascular rather than neural factors; however, the extent to which each of these factors contributes to RSFA remains to be characterized. The present work addressed these issues by comparing RSFA (i.e., rsfMRI variability) to proxy measures of (i) cardiovascular function in terms of heart rate (HR) and heart rate variability (HRV) and (ii) neural activity in terms of resting state magnetoencephalography (rsMEG). We derived summary scores of RSFA, a sensorimotor task BOLD activation, cardiovascular function and rsMEG variability for 335 healthy older adults in the population‐based Cambridge Centre for Ageing and Neuroscience cohort (Cam‐CAN; http://www.cam-can.com). Mediation analysis revealed that the effects of ageing on RSFA were significantly mediated by vascular factors, but importantly not by the variability in neuronal activity. Furthermore, the converse effects of ageing on the rsMEG variability were not mediated by vascular factors. We then examined the effect of RSFA scaling of task‐based BOLD in the sensorimotor task. The scaling analysis revealed that much of the effects of age on task‐based activation studies with fMRI do not survive correction for changes in vascular reactivity, and are likely to have been overestimated in previous fMRI studies of ageing. The results from the mediation analysis demonstrate that RSFA is modulated by measures of vascular function and is not driven solely by changes in the variance of neural activity. Based on these findings we propose that the RSFA scaling method is articularly useful in large scale and longitudinal neuroimaging studies of ageing, or with frail participants, where alternative measures of vascular reactivity are impractical. Hum Brain Mapp 36:2248–2269, 2015. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Maintenance of GLUT4 expression in smooth muscle prevents hypertension-induced changes in vascular reactivity.

Previous studies have shown that expression of GLUT4 is decreased in arterial smooth muscle of hypertensive rats and mice and that total body overexpression of GLUT4 in mice prevents enhanced arterial reactivity in hypertension. To demonstrate that the effect of GLUT4 overexpression on vascular responses is dependent on vascular smooth muscle GLUT4 rather than on some systemic effect we developed and tested smooth-muscle-specific GLUT4 transgenic mice (SMG4). When made hypertensive with angiotensin II, both wild-type and SMG4 mice exhibited similarly increased systolic blood pressure. Responsiveness to phenylephrine, serotonin, and prostaglandin F2α was significantly increased in endothelium-intact aortic rings from hypertensive wild-type mice but not in aortae of SMG4 mice. Inhibition of Rho-kinase equally reduced serotonin-stimulated contractility in aortae of hypertensive wild-type and SMG4-mice. In addition, acetylcholine-stimulated relaxation was significantly decreased in aortic rings of hypertensive wild-type mice, but not in rings of SMG4 mice. Inhibition of either prostacylin receptors or cyclooxygenase-2 reduced relaxation in rings of hypertensive SMG4 mice. Inhibition of cyclooxygenase-2 had no effect on relaxation in rings of hypertensive wild-type mice. Cyclooxygenase-2 protein expression was decreased in hypertensive wild-type aortae but not in hypertensive SMG4 aortae compared to nonhypertensive controls. Our results demonstrate that smooth muscle expression of GLUT4 exerts a major effect on smooth muscle contractile responses and endothelium-dependent vasorelaxation and that normal expression of GLUT4 in vascular smooth muscle is required for appropriate smooth muscle and endothelial responses.

Erythropoietin for the Treatment of Subarachnoid Hemorrhage: A Feasible Ingredient for a Successful Medical Recipe.

Subarachnoid hemorrhage (SAH) following aneurysm bleeding accounts for 6% to 8% of all cerebrovascular accidents. Although an aneurysm can be effectively managed by surgery or endovascular therapy, delayed cerebral ischemia is diagnosed in a high percentage of patients resulting in significant morbidity and mortality. Cerebral vasospasm occurs in more than half of all patients after aneurysm rupture and is recognized as the leading cause of delayed cerebral ischemia after SAH. Hemodynamic strategies and endovascular procedures may be considered for the treatment of cerebral vasospasm. In recent years, the mechanisms contributing to the development of vasospasm, abnormal reactivity of cerebral arteries and cerebral ischemia following SAH, have been investigated intensively. A number of pathological processes have been identified in the pathogenesis of vasospasm, including endothelial injury, smooth muscle cell contraction from spasmogenic substances produced by the subarachnoid blood clots, changes in vascular responsiveness and inflammatory response of the vascular endothelium. To date, the current therapeutic interventions remain ineffective as they are limited to the manipulation of systemic blood pressure, variation of blood volume and viscosity and control of arterial carbon dioxide tension. In this scenario, the hormone erythropoietin (EPO) has been found to exert neuroprotective action during experimental SAH when its recombinant form (rHuEPO) is administered systemically. However, recent translation of experimental data into clinical trials has suggested an unclear role of recombinant human EPO in the setting of SAH. In this context, the aim of the current review is to present current evidence on the potential role of EPO in cerebrovascular dysfunction following aneurysmal subarachnoid hemorrhage.

Alteration of Glial Fibrillary Acidic Protein Immunoreactivity in Astrocytes of the Cerebellum of Diabetic Rats and Potential Effect of Insulin and Ginger

Background: Diabetes causes increased oxidative stress and changes in vascular reactivity in the brain. Ginger has a wide range of pharmacological properties including anti-inflammatory, anti-microbial, antioxidant, and antitumour effects. Aim of the work: The purpose of this study was to clarify the effect of induced type I diabetes on the cerebellum of albino rat and whether these changes could be prevented by insulin and ginger. Material and methods: Forty albino rats were divided randomly into 4 groups; control non-diabetic rats; untreated diabetic rats; insulin-treated diabetic rats and combined insulin-ginger treated diabetic rats. After 8 weeks of treatment, animals were sacrificed; cerebellum was dissected, processed and stained with H&E and immunohistochemistry for Glial Fibrillary Acidic Protein (GFAP). Results: Diabetes caused decrease in the body and cerebellum weights, degeneration of Purkinje cells and decreased expression of GFAP in the astrocytes. Treatment with insulin and ginger decreased the blood glucose level, prevented the loss of body and cerebellar weights and protected the cerebellum against diabetic induced changes. Insulin-ginger treatment prevented the changes of Purkinje cells and increased the expression of GFAP. The combined effect of both insulin and ginger increased the GFAP expression more than each of them separately. Conclusion: The current results suggested that consumption of ginger together with insulin protected purkinji and glial cells against diabetic induced changes and improved GFAP expression. Thus, ginger could attenuate the neurodegeneration observed in the cerebellum of diabetic rats.

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Objectives Preeclampsia is a hypertensive disorder of pregnancy known to increase the risk of cardiovascular disease in both mothers and offspring later in life. Offspring exposed to a suboptimal intrauterine environment during critical periods of growth may experience altered fetal programming and subsequent long term cardiovascular changes. The aim of this study was to investigate changes in vascular response in offspring from experimental preeclamptic (EPE) compared to normotensive baboon pregnancies (controls), following a high salt diet challenge. Methods After one week of baseline measurements on a standard diet, animals were fed a high salt diet for two weeks. Systolic and diastolic blood pressure (SBP, DBP) were measured and urinary sodium assessed in offspring from EPE (n = 6) and controls (n = 6). A generalized linear model was performed to compare BP between the two groups at both baseline and day 14, adjusted for current age. Data is reported as the mean ± standard error. Significance was set at P Results At baseline there were no differences between the groups for SBP (P = 0.89) and DBP (P = 0.38). After salt loading the EPE group had significantly higher SBP (92 ± 5 mmHg) compared to the control group (83 ± 4 mmHg, P = 0.03). There was no significant difference in DBP between the two groups (P = 0.10). There was no difference in urinary sodium excretion between groups (average for both groups 30 mmol/day). Conclusions Offspring from EPE pregnancies had significantly higher blood pressure after a two week salt challenge, compared with controls. Salt sensitivity may differ in offspring from hypertensive pregnancies due to fetal programming. This could have long term consequences for cardiovascular health of EPE offspring. Further research is required to determine exact mechanisms. Disclosures K.R. Yeung: None. S.M. Lim: None. S. Heffernan: None. S. Pears: None. J.M. Lind: None. A. Hennessy: None. A. Makris: None.

High Salt Intake Increases Blood Pressure in Normal Rats: Putative Role of 20-HETE and No Evidence on Changes in Renal Vascular Reactivity

Background/Aims. High salt (HS) intake may elevate blood pressure (BP), also in animals without genetic salt sensitivity. The development of salt-dependent hypertension could be mediated by endogenous vasoactive agents; here we examined the role of vasodilator epoxyeicosatrienoic acids (EETs) and vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). Methods. In conscious Wistar rats on HS diet systolic BP (SBP) was examined after chronic elevation of EETs using 4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB), a blocker of soluble epoxide hydrolase, or after inhibition of 20-HETE with 1-aminobenzotriazole (ABT). Thereafter, in acute experiments the responses of renal artery blood flow (Transonic probe) and renal regional perfusion (laser-Doppler) to intrarenal acetylcholine (ACh) or norepinephrine were determined. Results. HS diet increased urinary 20-HETE excretion. The SBP increase was not reduced by c-AUCB but prevented by ABT until day 5 of HS exposure. Renal vasomotor responses to ACh or norepinephrine were similar on standard and HS diet. ABT but not c-AUCB abolished the responses to ACh. Conclusions. 20-HETE seems to mediate the early-phase HS diet-induced BP increase while EETs are not engaged in the process. Since HS exposure did not alter renal vasodilator responses to Ach, endothelial dysfunction is not a critical factor in the mechanism of salt-induced blood pressure elevation.

Lipopolysaccharide enhanced renal vascular response to endothelin-1 through ETA overexpression in portal hypertensive rats.

Hypo-perfusion resulting from intense renal vasoconstriction is traditionally contributed to renal dysfunction in advanced liver disease, although cumulative studies demonstrated renal vasodilatation with impaired vascular contractility to endogenous vasoconstrictors in portal hypertension and compensated liver cirrhosis. The pathophysiology of altered renal hemodynamics remains unclear. This study, using a rat model of portal hypertension with superimposed endotoxemia, was designed to delineate the evolution of renal vascular reactivity and vaso-regulatory gene expression during liver disease progression. Rats were randomized into sham surgery (SHAM) or partial portal vein ligation (PVL). Endotoxemia was induced by intraperitoneal injection of lipopolysaccharide (LPS) on the seventh day following surgery. Isolated kidney perfusion was performed at 0.5 h or 5 h after LPS to evaluate renal vascular response to endothelin-1. In contrast to impaired vascular contractility of SHAM rats, PVL rats displayed enhanced renal vascular reactivity to endothelin-1 at 5 h following endotoxemia. There were extensive upregulations of inducible nitric oxide synthase in kidney tissues of endotoxemic rats. The changes of renal endothelin receptor type A (ETA ) level paralleled with the changes of renal vascular reactivity in LPS-treated rats. Compared with SHAM rats, PVL rats showed increased renal ETA and phosphorylated extracellular-signal-regulated kinases 1/2 (p-ERK1/2) at 5 h after LPS. LPS-induced systemic hypotension induces a paradoxical change of renal vascular response to endothelin-1 between SHAM and PVL rats. LPS-induced renal vascular hyperreactivity in PVL rats was associated with upregulation of renal ETA and subsequent activation of ERK1/2 signaling.