bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decreased T‐regulatory cells are associated with blood pressure elevation and sympathoexcitaton in hypertensive rats (875.10)
Authors: Katsuki Masato , Hirooka Yoshitaka , Kishi Takuya , Sunagawa Kenji 
Published: June 2021

Background: Previous reports have suggested that T‐regulatory cells (Tregs) prevent angiotensin II (AngII)‐induced hypertension and organ damage. Abnormal sympathoexcitation is a major factor in the pathogenesis of hypertension. The aim of the present study was to determine whether Tregs are involved in the development of hypertension, and whether blockade of brain AngII type 1 receptors (AT1R)‐induced sympathoinhibition affects Tregs or not.Methods and Results: We examined Tregs in stroke‐prone spontaneously hypertensive rats (SHRSP) at 3 week (early pre‐hypertensive stage), 5 week (late pre‐hypertensive stage), or 15 week (established hypertensive stage) old, and in age‐matched normotensive Wistar‐Kyoto rats (WKY). CD4+CD25+Foxp3+ cells in the spleen and blood did not differ between WKY and early pre‐hypertensive SHRSP, whereas significantly decreased both in late pre‐hypertensive and established hypertensive SHRSP (p<0.05). In established hypertensive SHRSP, intracerebroventricular infusion of losartan (AT1R blocker) for 2 weeks was done to cause depressor response with central sympathoinhibition, and Foxp3 mRNA expression in the spleen was significantly higher than in vehicle‐treated SHRSP.Conclusion: Decreases in T‐Regulatory cells precede blood pressure elevation in SHRSP, thereby Tregs play a key role in the development of hypertension associated with sympathoexcitation.
Brain ACE2 overexpression reduces DOCA‐salt hypertension independently of endoplasmic reticulum stress (875.3)
Authors: Xia Huijing , Queiroz Thyago , Lazartigues Eric 
Published: June 2021

Endoplasmic reticulum (ER) stress was recently reported to contribute to hypertension. We previously observed that ACE2 in the paraventricular nucleus (PVN) is pivotal for blunting DOCA‐salt hypertension. To assess the contribution of ER stress, the PVN was collected from non‐transgenic (NT, n=4) and transgenic mice overexpressing brain ACE2 (SA, n=4), submitted to sham or 3 wk DOCA‐salt. ER stress (Bip, ATF4) and autophagy (LC3, LAMP2) markers were measured by Western blot. Baseline expression of Bip (1±0.07 vs. 0.96±0.11), ATF4 (1±0.06 vs. 0.99±0.02), LC3 II/I (1±0.02 vs. 1.16±0.11) and LAMP2 (1±0.08 vs. 0.97±0.05) were similar in NT and SA mice. Surprisingly, DOCA‐salt treatment did not alter these markers in NT (1.13±0.13; 1.14±0.05; 1.14±0.09; 1.13±0.09, respectively) or SA (1.04±0.04; 1.19±0.09; 1.1±0.07; 1.18±0.06, respectively) mice, despite a significant increase in blood pressure (BP, telemetry) in NT and a smaller rise in SA mice. To further assess the role of ER stress in DOCA‐salt hypertension, NT mice (n=8) were infused icv with TUDCA (5 µg/day, 21 days), an ER stress inhibitor, during DOCA‐salt treatment. DOCA‐salt alone significantly increased BP (127±5 vs. 101±2 mmHg, P<0.05), however, this increase was not affected by TUDCA (123±4 mmHg). Our data suggest that ER stress does not contribute to DOCA‐salt hypertension and that ACE2 blunts this neurogenic hypertension independently of ER stress.Grant Funding Source: Supported by AHA (12EIA830004)
Angiotensin II contributes to sympathetically‐mediated hypertension in autonomic failure (875.4)
Authors: Arnold Amy , Okamoto Luis , Gamboa Alfredo , Shibao Cyndya , Raj Satish , Robertson David , Biaggioni Italo 
Published: June 2021

Angiotensin (Ang) II contributes to hypertension by direct vasoconstriction, and indirectly by promoting sympathetic activation. The importance of the latter to blood pressure regulation remains controversial, particularly in clinical populations. As a novel approach to test the hypothesis that Ang II promotes sympathetically‐mediated hypertension, we compared depressor responses to the Ang II AT1 receptor antagonist losartan in central autonomic failure (AF) patients in whom supine hypertension is driven by residual sympathetic tone to peripheral AF patients with noradrenergic denervation and sympathetic‐independent hypertension. Single dose losartan (50 mg, PO) was administered at bedtime to 10 peripheral and 7 central AF patients, with supine blood pressure measured q2 hours for 12 hours in a randomized, double‐blind, placebo‐controlled study. There were no differences in plasma Ang II levels between groups (42±3 central vs. 43±5 pg/ml peripheral AF; p=0.734); however, peak depressor responses to losartan were significantly greater in central (‐43±10 mmHg) compared to peripheral AF patients (‐19±8 mmHg; p<0.05). These findings suggest that Ang II contributes to residual sympathetic tone in central autonomic failure, and through this mechanism to hypertension. Overall, these patients provide a unique model to assess the importance of Ang II‐sympathetic interactions in human hypertension.Grant Funding Source: Supported by AHA grant 11POST7330010 and NIH grants HL056693, 5U54NS065736 and UL1TR000445.
Astrocyte‐specific angiotensin II type 1 receptor knockout by using cre‐loxp system attenuates left ventricular remodeling after myocardial infarction (875.9)
Authors: Isegawa Kengo , Hirooka Yoshitaka , Kishi Takuya , Sunagawa Kenji 
Published: June 2021

Background: Brain angiotensin II type 1 receptor (AT1R)‐induced pathways (i.e., apoptosis, oxidative stress, and sympathoexcitation) worsen left ventricular (LV) remodeling after myocardial infarction (MI). Although astrocytes were recently suggested to have multiple and important functions in neurovascular unit, normal astrocytes have little AT1R. We hypothesized that MI‐induced abnormal expression of astrocyte AT1R, not neuron, would be a primary cause of worsening LV remodeling.Methods and Results: We generated astrocyte‐specific AT1R knockout mice (astrocyte/AT1R (‐/‐)). In astrocyte/AT1R (+/+) mice at 1 month after MI, we examined brainstem tissues by double immunohistostaining for glial fibrillary acidic protein (GFAP) and AT1R, and determined GFAP positive cells had morphologic changes with increased AT1R expression compared to sham mice without MI. In astrocyte/AT1R (‐/‐) at 1 month after MI, GFAP positive cells with AT1R expression were not observed. LV size at 1 month after MI was smaller in astrocyte/AT1R (‐/‐) than in astrocyte/AT1R (+/+) mice. Heart weight of astrocyte/AT1R (‐/‐) at 1 month after MI was lighter than that of astrocyte/AT1R (+/+) mice.Conclusion: Targeted deletion of AT1R in astrocytes attenuated LV dilatation after MI. These findings suggest that MI‐induced abnormal expression of AT1R in astrocytes is potential primary cause of worsening LV remodeling after MI.
Examination of changes in the immune system in rats exposed to different doses of lithium for a long‐term period (876.4)
Authors: Matur Erdal , Darıyerli Nuran , Akyol Sibel , Toplan Selmin , Özdemir Semra 
Published: June 2021

The effects of lithium which is widely used for the treatment of bipolar disorder, on the specific and non‐specific immune systems of rats have been investigated. Forty male rats were used. The rats were divided into control and four treatment groups, each contained 8 animals. While control group were fed with standard commercial pellet, 1, 1.4, 1.8 and 2.2 g/kg lithium was added to the diets of group‐I, II, III and IV respectively for 30‐days.Liver, spleen and kidney and body weight were weighed. Total white blood cell, granulocyte, lymphocyte and monocyte percentage, CD3, CD4, CD8, CD161 cells, CD4/CD8 ratio and serum lithium level were determined.The body weight decreased depending on the dose of the lithium. Treatments did not affect the relative weight of the organs studied. Granulocyte percentage was increased (P=0.026) significantly related to lithium dose. CD3 and CD4 cell ratios significantly decreased (P= 0.004 and P= 0.005 respectively) in rats fed with 2.2 g/kg lithium added diet. Despite of a numerical decrease in CD4 cells in group which were given 1.8 mg/kg lithium, this decrease was not statistically significant. There was no significant change in rates of CD8, CD161 cells in peripheral blood. On the other hand the rate of CD4/CD8 cells in groups given lithium 1.8g/kg and 2.2g/kg dosages were found to be significantly low when compared with the control and the other groups.It is concluded that lithium therapy may activate the non‐specific immune system by increasing the granulocytes percentage, but it has negative influences on the body weight, cells of CD3, CD4 and CD4/CD8 rate which are the key cells of the specific immune system.Grant Funding Source: This work was supported by the Research Fund of Istanbul University
Identification of corticotropin‐releasing hormone neurons in paraventricular nucleus in rats (876.6)
Authors: Li De‐Pei 
Published: June 2021

Corticotropin‐releasing factor (CRH) neurons in the paraventricular nucleus (PVN) are the essential component of the hypothalamus‐pituitary‐adrenal axis play a critical role in the regulation of autonomic, endocrine and behavioral responses to stress. Assessment of the CRH neurons provides valuable information on cellular mechanisms during physiological and disease process. However, CRH neurons in the rats cannot be reliably identified in live tissues since the identification of CRH neurons requires neuronal labeling and post‐mortem immunohistochemistry. To efficiently identifying CRH neurons in live tissue, we constructed a CRH promoter‐GFP plasmid and integrated this sequence into an adeno‐associated virus (AAV) vector. This AAV‐CRH promoter‐GFP vector was delivered into the rat PVN through microinjection (100 nl). The hypothalamic slices containing GFP‐tagged neurons was immunostained with a specific antibody against CRH. We found that 76.4% CRH immunoreactivity positive PVN neurons colocalized with GFP and 92.8% GFP‐tagged PVN neurons expressed CRH immunoreactivity. Whole‐cell recordings were performed on these GFP‐tagged CRH neurons in hypothalamic slice to assess their electrophysiological properties. Therefore, this AAV‐CRH‐GFP reliably targets CRH neurons in rat brain for in vitro assessment.Grant Funding Source: NIH: MH096086
Pharmacological hypothermia by Trpv1 agonism provides neuroprotection following ischemic stroke (877.13)
Authors: Cao Zhijuan , Balasubramanian Adithya , Marrelli Sean 
Published: June 2021

Stroke is the leading cause of death and major cause of long‐term disability. Current therapeutic hypothermia by physical cooling shows the potential for neuroprotection in animal ischemic stroke, but causes complications and often requires sedation and muscle paralysis. The limitations restrict the translational application in clinic. Our previous studies show agonism of transient receptor potential vanilloid 1 (TRPV1) by dihydrocapsaicin (DHC) induces reliable and reversible pharmacological hypothermia (PH). We hypothesize that DHC induced hypothermia provides neuroprotection in ischemic stroke mice.Acute response of HR, BP and cerebral perfusion to the therapeutic dose of DHC were measured. C57BL/6 WT and TRPV1 KO mice were treated with therapeutic doses (1.25, 1.25 mg/kg) and high doses (30, 15 mg/kg) at two consecutive days. After one month recovery, the temperature change response of DHC (1.25 mg/kg) was applied to evaluate the potential TRPV1 desensitization. Focal cerebral I/R (one hour ischemia + 24 hours reperfusion) was induced by distal middle cerebral artery plus common carotid artery transient occlusion in conscious WT and TRPV1 KO mice. PH (8 hours) was initiated 90 minutes after start of reperfusion by DHC infusion (osmotic pump). Neurofunction (by behavioral tests) and infarct volume (by TTC staining) were measured at 24 hours.DHC (1.25 mg/kg) had no measurable effect on HR and cerebral perfusion, did not desensitize TRPV1 channels, but produced a slight transient drop in BP (<6mmHg). In I/R mice, DHC infusion produced mild hypothermia, decreased infarct volume by 87%, and improved neurofunctional score. The hypothermic and neuroprotective effects were absent in TRPV1 KO mice or mice maintained normothermic with heat support.TRPV1 agonism provides an effective and well‐tolerated PH for acute cerebral I/R neuroprotection. Hypothermic and neuroprotective effects are specifically through TRPV1 agonism.Grant Funding Source: Supported by NIH R21 NS077413, R01 HL088435 (SPM) and AHA Pre Doctoral fellowship 16900006 (ZJC).
Therapeutic hypothermia achieves neuroprotection via a decrease in acetylcholine with a concurrent increase in carnitine in the neonatal hypoxia‐ischemia (877.2)
Authors: Kajimura Mayumi , Takenouchi Toshiki , Nakanishi Tsuyoshi , Sugiura Yuki , Hishiki Takako , Suematsu Makoto 
Published: June 2021

Although therapeutic hypothermia has been shown to improve neurologic outcomes after the perinatal cerebral hypoxia‐ischemia, etiology remains unknown. To decipher mechanisms whereby hypothermia regulates metabolism in different regions of the brain, we took a two‐step approach; metabolomics to target metabolic pathways responding to lowering temperature, and quantitative imaging mass spectrometry (Q‐IMS) to reveal spatial alterations in targeted metabolites at specific regions of the brain. 7‐day postnatal rats underwent permanent ligation of left common carotid artery followed by exposure to 8% O2 for 2.5 hrs. Pups were returned to normoxia at either 38 °C or 30 °C for 3 hrs. Brain metabolism was rapidly fixed by in‐situ freezing. Profiling of 107metabolites showed that hypothermia diminishes the carbon biomass related to acetyl‐moieties such as pyruvate and acetyl CoA; conversely, it increases deacetylated metabolites such as carnitine and choline. Q‐IMS indicated that hypothermia diminishes ACh contents specifically in hippocampus and amygdala. The decrease is associated with an inverse increase in carnitine in the same anatomical regions. These findings imply that therapeutic hypothermia achieves neuroprotective effects by mediating acetylation status with coordinated suppression of acetyl CoA which resides in metabolic crossroads of glycolysis, amino acid catabolism and ketolysis.Grant Funding Source: Grant‐in‐Aid for Scientific Research 24791121 and 24500448 from the Japan Society for the Promotion
Pinocembrin protects against beta‐amyloid‐induced toxicity in neurons through inhibiting RAGE‐independent signaling pathways and regulating mitochondrion‐mediated apoptosis (877.4)
Authors: Liu Rui , Zhou Dan , Zhang Li , Zhang Li , Zhang Tian‐tai , Du Guan‐hua 
Published: June 2021

Amyloid‐β (Aβ) peptides accumulate in the brain and initiate a cascade of pathological events in Alzheimer’s disease (AD). The receptor for advanced glycation end products (RAGE) has been implicated to mediate Aβ‐induced perturbations in AD. Pinocembrin was approved by the SFDA of China for clinical use for stroke patients and evidenced with neuroprotection against Aβ‐induced toxicity, but the therapeutic role and mechanism are not ascertained. Here, we report that pinocembrin improves cognition and protects neuron against Aβ‐mediated toxicity. Oral treatment of pinocembrin for 8 days improved cognitive function, preserved ultrastructural neuropils and decreased neurodegeneration in Aβ‐treated mice. Pinocembrin did not provide sufficient effect on inhibiting Aβ production. However, it inhibited the upregulation of RAGE transcripts and protein expression both in vivo and in vitro, and then, markedly depressed the activation of MAPK pathways and the downstream NF‐κB inflammatory response subsequent to Aβ‐RAGE interaction. In addition, pinocembrin alleviated mitochondrial dysfunction, and regulated mitochondrion‐mediated apoptosis. In conclusion, pinocembrin showed cognitive improvement and neuronal protection in AD models. The mechanisms were illustrated on RAGE‐dependent transduction inhibition and mitochondrion protection. It appears to be a promising candidate for the prevention and therapy of AD.Grant Funding Source: National Natural Science Foundation of China (No. 81102830)
Post‐TBI administration of DHA selectively suppresses pro‐inflammatory and promotes resolving microglial activation (877.5)
Authors: Harvey Lloyd , Begum Gulnaz , Dixon C. , Sun Dandan 
Published: June 2021

We investigated the manifestation of neuroinflammation after traumatic brain injury (TBI) and the efficacy of docosahexaenoic acid (DHA) in reducing neuroinflammation. TBI was induced by cortical contusion injury in Sprague Dawley rats. Either DHA (16 mg/kg in DMSO) or vehicle DMSO (1 ml/kg) was administered interperitonially at 5 min after TBI, followed by a daily dose for 3‐21 days. TBI triggered activation of microglia, detected by increase of Iba1 positively stained microglial cells in cortical tissues at 3‐21 days post‐TBI. The neuroinflammatory response was further characterized by an increased expression of the pro‐inflammatory marker CD16/32 in Iba1+ microglia at 3‐7 days post‐TBI. The Iba1+ microglia surrounded cortical neurons exhibiting ER stress. In contrast, DHA reduced acute neuronal damage and ER stress at 3 days post‐TBI. DHA‐treated TBI brains also showed significantly less CD16/32+ and Iba1+ microglial population, but increased CD206+/Iba1+ microglial (phagocytic) population. In summary, this study demonstrated that TBI induces a profound neuroinflammatory response that is characterized by pro‐inflammatory microglial activation. ER stress‐associated inflammation may play a role in the activation of microglia. Post‐TBI administration of DHA reduces neuronal damage, ER stress, and promotes the resolving microglial activation.Grant Funding Source: Supported by Univ. of Pitt. startup funds, endowed Chair Professorship (DS) & VA RR&D grant (CED).
Crude oil impairs cardiac excitation‐contraction coupling in fish (878.3)
Authors: Block Barbara , Brette Fabien , Cros Caroline , Incardona John , Scholz Nathaniel 
Published: June 2021

New research from oil spills (Deepwater Horizon, Gulf of Mexico) indicates that crude oil is a toxicant that produces cardiac defects. The developing fish heart is a sensitive target organ for the toxic effects of crude oil‐derived polycyclic aromatic hydrocarbons (PAHs). Specific cardiotoxicity phenotypes have been identified in which cardiac excitability, contractility and morphology are impacted. Little is known about the toxic effects of crude oil upon cardiac function in vertebrates. We isolated myocytes from the hearts of fish and show that 4 types of crude oils collected during the Deepwater Horizon oil spill prolonged myocyte action potential duration. This prolongation is due to a block of K+ channel current, homologous to the hERG channel in human. In addition, crude oil exposure decreases Ca2+ current and Ca2+ cycling in isolated myocytes. These results indicate that excitation‐contraction coupling in fish is disrupted by low concentrations of crude oil. Our findings confirm a cardiotoxic mechanism for crude oil and reveal a potential for life threatening cardiac arrhythmias in vertebrates.Grant Funding Source: NOAA
Using PU4ii corrosion casts to characterize the tracheal system of the grasshopper leg (879.21)
Authors: Ferrara Nicholas , Lew James , Kirkton Scott 
Published: June 2021

The lightweight, air‐filled tracheal system has enabled insects to be the most evolutionary successful animals on the planet. While adult Schistocerca americana grasshoppers use abdominal pumping and convection to drive oxygen through their head, thorax, and abdomen, it is less clear how oxygen delivery occurs down the metathoracic jumping leg. We cannulated the tracheal system of an adult grasshopper and injected PU4ii [vasQtec, Switzerland] low viscosity polymer resin, to create a corrosion cast of the tracheal system of the metathoracic leg. After the resin had solidified, tissues were chemically digested, leaving only the tracheal cast. The cast revealed a highly organized system. In the femur, six primary tracheae [0.2‐0.3 mm diameter] run along the proximodistal axis, connected via more than 20 secondary tracheae [0.09‐0.2 mm] running along the dorsoventral axis in a chevron pattern. Secondary tracheae form a network around the femur between the dorsal and ventral primary tracheae on each face. Many tertiary tracheae [9‐25 µm] descend from the chevrons into the muscle cavity. The lateral face of the femur has an additional central primary tracheae and 40° angled chevrons, while the medial face has only dorsal and ventral primary tracheae and 130° angled chevrons. Air sacs have been observed in multiple locations down the leg: at the junction between the primary and secondary tracheae, in the hip and knee joints, and in the tibial spikes. Results indicate PU4ii resin yields higher resolution casts than alternative methods using Mercox resin.Grant Funding Source: Supported by Union College Undergraduate Research Grants
Blood flow distribution following adrenergic blockade and nitric oxide production inhibition in embryonic American alligators, Alligator mississippiensis (879.4)
Authors: Kohl Zachary , Tate Kevin , Elsey Ruth , Crossley Dane 
Published: June 2021

Assessment of cardiovascular function in developing egg‐laying amniotes has been primarily limited to measurements made via catheters in the chorioallantoic membrane (CAM) and potentially invasive femoral and major outflow tract flow probes. Here we assess the capacity of embryonic alligators, Alligator mississippiensis, to regulate blood flow distribution using a minimally invasive microsphere distribution technique at 70 and 90% of development, in eggs incubated in normoxia or 10% hypoxia. Measurements were made in normoxia, acute 10% hypoxia, and acute 10% hypoxia following nitric oxide inhibition or alpha‐receptor blockade. We hypothesized that the embryonic response is concomitant with a redistribution of blood flow to the brain, heart, and CAM vasculature. Embryonic alligators respond to hypoxia with an initial bradycardia followed by a hypertensive tachycardia, however chronic hypoxic incubation blunts this response. Our data suggest that cardiac output is reduced during acute hypoxia in normoxic‐incubated embryos while it is maintained the hypoxic group. In addition, tonic nitric oxide dilation is present at 70% of incubation however inhibition of this tone does not modify total cardiac output at 90% of incubation. Our data suggest that hypoxic development may modify the patterns of blood flow redistribution in embryonic alligators and the mechanisms used to achieve this.Grant Funding Source: NSF CAREER IBN IOS‐0845741 to DAC
Low intensity resistance training promotes peripheral and central adjusts on cardiovascular control (881.6)
Authors: Oliveira Larissa , Macedo Fabricio , de Melo Vitor , Mota Marcelo , da Silva Tharciano Luiz , Fontes Milene , Santana Michael Nadson , dos Santos Robervan , Barreto Andre , dos Santos Márcio Roberto , Santana‐Filho Valter 
Published: June 2021

The aim was to evaluate the effects of low intensity resistance training (RT) on blood pressure, cardiovascular autonomic balance and vascular reactivity. One group of animals were submitted to RT. Control animals (CO) were fictitious trained (no exercise). After 8 weeks of RT or fictitious exercise, blood pressure and pulse interval were recorded and mesenteric artery was removed and sliced in rings for vascular reactivity analysis (Acetilcholine (ACh): 10‐9 ‐ 10‐4 M; Nω‐nitro‐L‐arginine methyl ester hydrochloride (L‐NAME): 100µM). The variabilities of pulse interval, blood pressure and spontaneous baroreflex sensitivity (BRS) were analyzed. RT animals showed a reduction in mean arterial pressure (CO 117.04 ± 2.68 vs RT 105.5 ± 4.28), diastolic arterial pressure (CO 107.71 ± 2.95 vs RT 97 ± 3.42) and heart rate (CO 395 ± 7.1 vs RT 344 ± 13.25). In addition, it was seen in trained animals an increase in cardiac vagal modulation (LF/HF: CO 0.35 ± 0.08 vs RT 0.14 ± 0.03), BRS (CO 0.77 ± 0.01 vs RT 1.05 ± 0.1) and percentage of ACh‐induced relaxation of mesenteric arterial rings (pD2: CO 6.2 ± 0.1 vs RT 7.1 ± 0.1) and addition of L‐NAME reduced the ACh‐induced relaxation (CO 52.0 ± 3.2% vs RT 35.8 ± 3.7%). In conclusion, we observed that low intensity RT was able to promote beneficial cardiovascular adaptations mediated by central and peripheral adjustments.Grant Funding Source: Supported by CNPq Foundation (Brazil)