bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long term effects of gamma‐tocopherol nebulization in cutaneous burn and smoke inhalation with early excision and skin autografting in sheep
Authors: Yamamoto Yusuke , Enkhbaatar Perenlei , Kraft Edward R , Rehberg Sebas‐tian , Sousse Linda E , Traber Lillian D , Traber Daniel L 
Published: June 2021

We have previously reported that airway nebulization of gamma tocopherol (g‐T) had a beneficial effect in ovine model of acute respiratory distress syndrome. We hypothesized that nebulization of g‐T into the airway will effectively improve long‐term pulmonary function and wound healing following acute lung injury.MethodTen ewes were subjected to 20%TBSA, third‐degree flame burn and smoke inhalation (36 breaths of cool cotton smoke) under deep anesthesia. One g of g‐T dissolved in 2.2 mL of ethanol was continuously delivered by customized aerosolization device for 48 hrs, starting 3 h post‐injury (Treated group, n=5). Control animals (n=5) were not nebulized. At 24 h post‐injury, escharectomy and skin autografting was performed in both groups. All animals were placed on ventilator and weaning from the ventilator was initiated if PaO2/FiO2 was above 250 at 48 h post‐injury. The sheep were monitored for 3 weeks.ResultsAt 96 h post‐injury, all animals were weaned from ventilator. PaO2/FiO2 (mean±SD) was 505±42 in the treated and 489±47 in the control groups at 3 weeks. Lung bloodless wet‐to‐dry weight ratio (mean±SD) was 2.87±0.16 in the treated and 4.72±1.95 in the control groups (p<0.05). The percentage of the surviving graft area (mean±SD) was 84.2±7.5% in treated and 78.7±5.3% in the control groups.ConclusionThe nebulization of g‐T improved long‐term pulmonary oxygenation, reduced lung water content, and increased wound healing following acute lung injury in sheep. Delivery of g‐T into the lungs may be an effective approach in management of burn patients with concomitant lung injury.
Potentially useful interactions between theophylline and salbutamol on cytokine release in human monocytes
Authors: Ezeamuzie Charles , Shihab Puthiyaveetil 
Published: June 2021

This study investigated the in vitro interaction between theophylline and salbutamol on cytokine generation from human monocytes and compared it with the interaction between dexamethasone and salbutamol. Purified monocytes pre‐treated with the drugs (alone or in combination) were stimulated with LPS for 24h and the released TNF‐α and IL‐6 determined by ELISA. Salbutamol (≥ 0.1μM) significantly inhibited the release of TNF‐α, but also significantly enhanced that of IL‐6. In contrast, theophylline (50μM), as well as dexamethasone (0.1μM) strongly inhibited the generation of both cytokines. When used in combination, the effects of theophylline and salbutamol were additive in inhibiting TNF‐α release but theophylline blocked the IL‐6‐enhancing effect of salbutamol. A similar effect was seen when dexamethasone was combined with salbutamol. These results show that β2‐agonists have opposing effects on the generation of TNF‐α and IL‐6, but that when combined with theophylline, the latter, like dexamethasone, was capable of augmenting the anti‐inflammatory effects of the β2‐agonists while preventing their pro‐inflammatory effect. Thus, theophylline may have a potentially useful steroid‐sparing effect.Sponsored by Kuwait Foundation for Science (KFAS) grant # 2005‐130‐203
Oscillations in microvessel networks with RBC suspensions: Preliminary in vitro experimental results in a 3 node network
Authors: Carr Russell T , Maher Meaghan , Geddes John B 
Published: June 2021

We have been exploring spontaneous oscillations caused by rheological properties of blood in the microcirculation. The range of parameters over which the oscillations occur in a simple 2 node network is too small to verify our predictions experimentally. The parameter range for oscillations is much greater for a three node topology. Three steady states often exist in 3 node networks. Of these three steady states, one is unstable, suggesting that flow through such a network may exhibit nonlinear bistability. One of the stable steady states has clockwise flow in one branch and the other stable steady state has counter clockwise flow in that branch. The computation predicts that the flow ratio at which the change in direction exhibits a hysteresis.We have constructed a 3 node network of microchannels having 50 μm diameters. We conducted flow experiments using RBC suspensions and isotonic saline to test our bistability hysteresis prediction. Our model experiments did not reveal such a hysteresis but exhibited spontaneous oscillations. These fluctuations occur over a range of experimental conditions. We present video evidence of oscillations from these flow experiments. These are the first data we have obtained to test our predictions of microvascular fluctuations because of nonlinear dynamics.Financial Support by UNH Research Experience Apprenticeship Program (REAP)
Distinct phenotypes after cell‐specific deletion of Cx40: Loss in endothelial cells impairs conduction in arterioles and loss in renin‐producing cells elevates blood pressure
Authors: Jobs Alexander , Kurtz Armin , de Wit Cor 
Published: June 2021

The gap junction protein connexin40 (Cx40) is important in cardiovascular and renal physiology as concluded from mice globally deficient for Cx40. They exhibit hypertension, renin excess, and impaired conduction of dilations along the endothelium. However, the exact contribution of endothelial Cx40 vs. Cx40 expressed in renin‐producing cells is unknown. In mice carrying a cell‐specific deletion of Cx40 in endothelial (EC) or renin‐producing cells (RPC) arteriolar responses and blood pressure were measured in vivo.Local stimulation of arterioles using ACh or bradykinin (Bk) elicited dilations that conducted rapidly without attenuation of the amplitude to upstream, remote sites (1200 μm) in mice carrying a floxed Cx40 gene (control). In contrast, remote dilations were significantly attenuated in EC‐Cx40ko (ACh by 28%, Bk by 32%) but not in RPC‐Cx40ko. However, local and remote dilations initiated by adenosine were comparable in all 3 groups of mice. Interestingly, awake EC‐Cx40ko were normotensive (EC‐Cx40ko: 115, control: 113 mmHg) whereas RPC‐Cx40ko exhibited a significantly elevated mean arterial pressure (138 mmHg) and heart weight.These data demonstrate that EC‐specific deletion of Cx40 impairs conduction of endothelium‐dependent dilations, however, per se does not increase blood pressure. Conversely, elevated pressure in RPC‐Cx40ko does not affect such signal conduction along arterioles.
Prolyl hydroxylase inhibition attenuates hypoxia‐induced hyperpermeability via iNOS upregulation
Authors: Wood John Gibson , Moncure Michael , Thomas James H. , Holloway Naomi B. , Gonzalez Norberto C. 
Published: June 2021

Acute systemic hypoxia (Hx) increases leukocyte adherence and vascular permeability in post‐capillary venules of rats. When animals are chronically hypoxic, the initial microvascular inflammation resolves in part due to upregulation of inducible nitric oxide synthase (iNOS). Inhibition of prolyl hydroxylase (PHD) has been shown to increase hypoxia‐inducible factor‐1 (HIF‐1) levels, which can increase iNOS expression.ObjectiveThis study evaluated whether inhibition of PHD attenuated Hx‐induced increased vascular permeability, and if upregulation of iNOS was involved.MethodsHx was produced by a reduction in inspired O2 from 21% to 10%. Intravital microscopy was used to measure vascular permeability in mesenteric venules of anesthetized rats. The PHD inhibitor EDHB was administered to rats 24 hrs prior to experiments.ResultsHx increased vascular permeability markedly in vehicle‐treated rats but significantly less in EDHB‐treated rats. Superfusion of the mesentery with the iNOS inhibitor L‐NIL caused a significant increase in vascular permeability during Hx in EDHB‐ but not vehicle‐treated rats.ConclusionThese results show that inhibition of PHD reduces Hx‐induced hyperpermeability in part through iNOS upregulation, and are consistent with a HIF‐1‐dependent mechanism.
Measurements of isolated glomerular albumin permeability do not change in a variety of proteinuric conditions
Authors: Sage Leslie M , Ferguson Joanne , Neal Christopher R , Harper Steven J , Bates David O , Salmon Andrew HJ 
Published: June 2021

Albuminuria is the hallmark of glomerular disease. The oncometric assay of glomerular albumin permeabilityA has been used to measure glomerular reflection coefficient to albumin (σalb) in clinically‐relevant circumstancesA. We have previously reported theoretical limitations of this assayB, and here report practical assay limitations.Single glomeruli, isolated by graded sieving, were held on an aspiration pipette. Glomerular volume (V) was recorded during incubation in BSA solution (Valb) of known oncotic pressure. The incubating solution was exchanged for an iso‐oncotic solution of dextran molecules (>100kDa MW after dialysis), and glomerular volume was remeasured (Vdex). Vdex/Valb describes σalb.σalb was measured in healthy mouse glomeruli before and after exposure to pronase and protamine. No changes were observed (pronase: pre 0.99±0.02; post 0.99±0.01 (7); p>0.9) (protamine: pre 0.95±0.01; post 0.95±0.01 (7); p>0.8).In addition, σalb was not different between glomeruli from mice with (0.95±0.03 (30)) or without (0.95±0.02 (24)) streptozotocin‐induced diabetic albuminuria (p>0.7), nor between glomeruli from rats with (1.00±0.01 (9)) or without (0.99±0.01 (8)) spontaneous proteinuria (p>0.6).We conclude that this assay is inadequate for glomerular albumin permeability measurements.
Na‐K‐ATPase activity involved in noise induced blood‐labyrinth‐barrier leakage
Authors: Shi Xiaorui , Nuttall Alfred L. 
Published: June 2021

Na+/K+‐ATPase plays an important role in mediating barrier integrity in the polarized epithelial cells. In the cochlea, we found that Na+/K+‐ATPase subunit alpha 1 was the most abundant protein of the vascular tissue in the blood‐labyrinth‐barrier (BLB) and was expressed predominantly at the luminal side of the endothelium. Na‐K‐ATPase is known to be required for controlling the tight junctions in epithelial cells. In this study, we investigated the involvement of Na+/K+‐ATPase in noise induced BLB leakage. In mice, the expression and activity of Na+/K+‐ATPase were found to be correlated with the changes of expression of tight junction proteins as well as the change in BLB permeability. Increased expression of Na+/K+‐ATPase, at both transcriptional and protein levels, occurred after noise exposure at 120 dB SPL for 3h per day for two days. However, Na+/K+‐ATPase enzymatic activity was significantly decreased. There was a significant decrease in endothelial tight junction membrane contact points. In vitro inhibition of Na+, K+‐ATPase by ouabain corroborated the in vivo studies and showed swelling of capillary endothelial cells and increased ratio between occludin phosphorylation and dephosphorylation. The results support a functional link between Na+, K+‐ATPase and occludin in the BLB as one of the mechanisms for noise induced in the BLB.Support: NIDCD DC 00888, NIDCD DC 00105, NIDCD DC 005983 (p30)
Microprojections amplify EC response to SMC stimulation: A theoretical study
Authors: Nagaraja Sridevi , Kapela Adam , Tsoukias Nikolaos 
Published: June 2021

Microvascular tone and blood flow are controlled by a wide network of signaling pathways. To increase fundamental understanding of these signaling events we have developed detailed mathematical models of calcium dynamics and membrane electrophysiology in isolated endothelial and smooth muscle cells and validated them against subcellular‐ and cellular‐level data. Single cell models were then integrated into multicellular/whole vessel models to incorporate microprojections in EC with localized IKCa channels and microdomains in SMC with localized NaKα2 isoform sodium potassium pumps and study their effects on agonist induced vasorelaxation and vasoconstriction. Myondothelial IP3 diffusion reduces SMC depolarization during stimulation with Norepinephrine. The effect was increased threefold by the presence of microprojections. Thus, simulations suggest a role for microprojections in amplifying an IP3 mediated negative feedback loop during SM stimulation. Accumulation of K+ ions between the microprojections and SMC seems to play a minor role in inducing hyperpolarization in SMC via activation of NaKα2 pumps. On the contrary, it antagonizes transfer of hyperpolarization via MEGJ by reducing EC hyperpolarization. The proposed integrative computational model allows the analysis of complex microcirculatory function in health and disease and provides a tool for hypotheses testing and for guiding new experimentation in the microcirculation.(Supported by NIH SC1HL95101).
Carotid Baroreflex Function in African Americans at Rest
Authors: Fulton Diana , Hodge T. Glenn , Vespoli Kalen , Keller David M. 
Published: June 2021

African Americans (AA) are at relatively high risk for the development of hypertension. However, little is known regarding dynamic blood pressure control (e.g., arterial baroreflex function) in this racial population prior to the development of hypertension. The purpose of this study was to test the hypothesis that normotensive AA would exhibit reduced carotid baroreflex control of heart rate (HR) and mean arterial pressure (MAP) at rest compared to age, gender and fitness‐matched Caucasian Americans (CA). Eight subjects (4 in each racial group) underwent multiple 5‐sec trials of Neck Pressure (NP, +40 Torr: simulated carotid hypotension) and Neck Suction (NS, −60 Torr: simulated carotid hypertension). The peak HR and MAP responses to NP and NS were determined relative to pre‐stimulus values and used to calculate the Response Range (i.e., the difference between averaged peak responses to NP and NS) for the respective variable for each subject. Although somewhat lower in AA (14.5±3.2 mmHg), the MAP Response Range was not statistically different compared to CA (20.1±1.7 mmHg, P = 0.19). However, the HR Response Range approached statistical significance in AA (17.2±4.3 bpm) compared to CA (30.8±3.5 bpm, P = 0.051). These findings indicate possible inherent differences in carotid baroreflex function between racial populations at different risk for the development of hypertension.Supported by NIH Grant R15HL096103
Involuntary breathing movements improve cerebral oxygenation during apnea struggle phase in elite divers
Authors: Dujic Zeljko , Uglesic Lovro , Breskovic Toni , Valic Zoran , Heusser Karsten , Marinovic Jasna , Ljubkovic Marko , Palada Ivan 
Published: June 2021

We investigated whether the involuntary breathing movements (IBM) during struggle phase of apnea, together with peripheral vasoconstriction and progressive hypercapnia, have a positive effect in maintaining cerebral blood volume. The central hemodynamics, arterial oxygen saturation, brain regional oxyhemoglobin, deoxyhemoglobin and total hemoglobin changes (bO2Hb, bdHb and bTHb, respectively) and IBM were monitored during maximal dry apneas in 8 elite divers. The frequency of IBM increased and their duration decreased towards the end of the struggle phase, whereas the amplitude was unchanged. In all subjects a consistent increase in bdHb and bTHb was also found during struggle phase, whereas bO2Hb changed biphasically. Mean arterial pressure (MAP) was elevated during the struggle phase although there was no further rise in the peripheral resistance, suggesting unchanged peripheral vasoconstriction and implying the beneficial influence of the IBM on the cardiac output recovery. The IBM‐induced short lasting sudden increases in MAP were followed by similar oscillations in bO2Hb. These results suggest that an increase in the cerebral blood volume observed during the struggle phase of dry apnea is most likely caused by the IBM at the time of the hypercapnia‐induced cerebral vasodilatation and peripheral vasoconstriction.This study was supported by the Croatian Ministry of Science, Education and Sports.
Retinal Reactivity in Type 2 Diabetics
Authors: Lott Mary EJ , Bettermann Kerstin , Slocumb Julia , Smith Bruce , Gardner Thomas , Gabbay Robert 
Published: June 2021

Diabetics have impaired vascular reactivity in the microcirculation; however, the time course of this impairment is unclear. Imaging of the retinal blood vessels provides unique insight into the microvasculature.PURPOSETo measure retinal diameter responses to vasoconstrictor and vasodilator stimuli in persons with type 2 diabetes compared to healthy controls.METHODSRetinal blood vessels were continuously imaged with the Dynamic Vessel Analyzer (Imedos, Jena, Germany) as six type 2 diabetics without retinopathy (57±7 yrs) and four healthy controls (53±10 yrs) inhaled 100% oxygen (5 min) and during flicker light‐induced stimulation (5 min).RESULTSThe diabetic compared to the control group had attenuated retinal vein vasoconstriction that was apparent within 2 minutes of hyperoxia (diabetics: −0.7±1.5%, −0.6±1.8%, −2.2±2.7%, −1.1±3.5% vs. controls: −2.9±1.2%, −5.4±0.9%, −7.5±1.6%, −8.4±0.8% at 2, 3, 4, and 5 min; P<0.05). Similar responses were observed in the retinal artery. Diabetics compared to controls also exhibited attenuated vasodilator responses (Artery: 1.1±1.0% vs. 8.6±5.3%; Vein: 2.4±3.2% vs. 7.2±2.6%; P<0.05).CONCLUSIONType 2 diabetics have both attenuated retinal vasodilator responses and early attenuated vasoconstrictor responses in which the mechanisms are unclear. Funded by Pennsylvania Department of Health using Tobacco CURE Funds.
Increased decorin mRNA expression leads to larger collagen fibril diameter in SHR kidney cortex
Authors: Skogstrand Trude , Leh Sabine , Moen Ingrid , Stuhr Linda Elin Birkhaug , Reed Rolf , Iversen Bjarne Magnus , Hultström Michael 
Published: June 2021

It has been shown that the renal hypertensive damage in SHR is accompanied by changes in the synthesis, deposition and breakdown of collagen, in particular in the juxtamedullary cortex (JMC). In the present study, we investigated gene expression using Illumina beadarray microarrays comparing renal cortex from 60 week old SHR with WKY rats.The results showed increased expression of decorin (2.3 fold increase P<0.01). Decorin is a small leucin rich protein (SLRP) which binds collagen and is important in collagen fibril formation. In addition, fibronectin, another SLRP was also increased (1.8 fold increase P<0.01). Finally several forms of fibrillar collagen were upregulated, collagen Ia1 (1.4 fold increase P<0.01), collagen IIIa1 (2.7 fold increase P<0.01) and collagen Ia2 (2.9 fold increase P<0.01). This indicates a changed collagen fibril composition and assembly process.Further, collagen fibril diameter measurements were performed using TEM. The fibril diameters were increased in the JMC of SHR compared to the outer cortex (P<0.05), while diameters in superficial and juxtamedullary cortex were not different in WKY.In conclusion, renal interstitial fibrosis in JMC of SHR is composed of thicker collagen fibrils. This increased fibril diameter may be a result of increased SLRP expression in damaged cortex as well as a changed composition of the collagen fibrils.
Dipeptidyl Peptidase IV Inhibition Attenuates Blood Pressure Rising in Young Spontaneously Hypertensive Rats (SHR)
Authors: Pacheco Bruna Piccolo Muniz , Crajoinas Renato Oliveira , Couto Gisele Kruger , Davel Ana Paula Couto , Rossoni Luciana Venturini , Girardi Adriana Castello Costa 
Published: June 2021

The present study aimed to assess the effect of the dipeptidyl peptidase IV inhibitor sitagliptin on renal function and blood pressure in young (5‐wk‐old) pre‐hypertensive and adult (14‐wk‐old) hypertensive SHR. Sitagliptin was given by oral gavage twice daily at a dose of 20 mg/kg for eight days. As a control, same age SHR received vehicle. After eight days of sitaglipitin administration, systolic (121 ± 3 vs 149 ± 9 mmHg, P = 0.01), diastolic (84 ± 4 vs 105 ± 9 mmHg, P = 0.02), and mean arterial pressures (104 ± 3 vs 125 ± 8 mmHg, P = 0.01) were significantly lower in young treated SHR compared to control. The cumulative urinary volume, sodium and lithium excretion were significantly higher in young treated animals than in controls. Sitagliptin also decreased Na+/H+ exchanger NHE3 expression in proximal tubule (PT) microvilli membrane vesicles (32 ± 4%; P < 0.01) and increased NHE3 phosphorylation at serine 552 (38 ± 6; P < 0.001). In the adult hypertensive SHR DPPIV inhibition did not cause any effect on renal fuction. Likewise, no differences in blood pressure were observed between adult SHR treated with sitagliptin and its correspondent control. Our data suggest that DPPIV inhibition can prevent or delay increases in blood pressure in young pre‐hypertensive SHR partially by inhibiting PT NHE3.Supported by FAPESP and CNPq
Novel Mechanisms of Activation of Endothelial Nitric Oxide Synthase Mediated by Endothelial Transient Receptor Potential Vanilloid Type 1
Authors: Ching Li‐Chieh , Kou Yu Ru , Pan Ching‐Chian , Lee Tzong‐Shyuan 
Published: June 2021

OBJECTIVEWe investigated the molecular mechanism underlying the role of transient receptor potential vanilloid type 1 (TRPV1) in the activation of endothelial NO synthase (eNOS) in endothelial cells (ECs) and mice.METHODES AND RESULTSIn bovine aortic ECs, TRPV1 ligands (evodiamine or capsaicin) promoted NO production, eNOS phosphorylation and TRPV1‐eNOS interaction, all of which were abrogated by the TRPV1 antagonist capsazepine and extracellular Ca2+ remove. TRPV1 ligands also enhanced the phosphorylation of Akt, calmodulin‐dependent protein kinase II (CaMKII) and TRPV1, and increased interactions of TRPV1 with Akt and CaMKII. Inhibition of PI3K and CaMKII suppressed ligand‐induced increases in TRPV1 phosphorylation, TRPV1‐eNOS interaction and eNOS activation. In vivo experiemnts revealed that TRPV1 activation increased the phosphorylation of Akt, CaMKII and eNOS in the aortas of wild type mice, whereas it failed to activate eNOS in the aortas of TRPV1 deficient mice.CONCLUSIONTRPV1 activation in ECs may trigger a Ca2+‐dependant PI3K/Akt/CaMKII signaling leading to enhanced phosphorylation of TRPV1, increased TRPV1‐eNOS interaction and ultimmately eNOS activation. Thus, in addition to its channel function, the TRPV1 may possess a potential role serving as a scaffold for recruitment and interaction with eNOS, Akt and CaMKII, which may be vital for regulating eNOS activation.
Nitric Oxide Enhances NFATc3 Nuclear Import and Decreases Export
Authors: Bettini Layne , Albertoni‐Borghese Florencia , Majowicz Mónica , Vidal Norberto , Bosc Laura Gonzalez 
Published: June 2021

We have previously shown that nitric oxide (NO) enhances NFATc‐mediated aquaporin‐2 (AQP2) promoter activation in MDCK cells. Also, we have shown that elevation of Ca2+ and NO are required for NFATc3 nuclear accumulation in cerebral artery smooth muscle. Ca2+‐activated calcineurin dephosphorylates NFATc allowing its nuclear import. GSK3, protein kinase A and JNK2 phosphorylate NFATc. The goal of this study was to determine the mechanism by which NO enhances NFAT activity. MDCK cells were transfected with a GFP‐NFATc3 plasmid and nuclear fluorescence intensity was measured over time. To study nuclear import, cells were treated with a Crm‐1 exportin inhibitor, 40 nM leptomicin B, and the Ca2+ ionophore (NFATc activator), 1 μM ionomycin (Io) ± 0.1 mM NONOate (NO donor). To study export, cells were treated for 1 h with Io and then imaged in the presence of 1 μM cyclosporin A (calcineurin inhibitor) ± 0.1 mM NONOate.NO significantly enhanced Io‐induced NFATc3 nuclear import increasing the Ymax without affecting the K (Ymax= 3.6±0.5 vs. 2.4±0.3, n=5, p<0.05). Also, NO decreased NFATc3 nuclear export by increasing the plateau without affecting the K (Plateau= 0.35±0.03 vs. 0.14±0.03, n=5, p<0.05). Our results suggest that NO enhances NFATc nuclear import and decreases export. Future studies will address if NO via protein kinase G is inhibiting any of the kinases that phosphorylate and inactivate NFATc. Supported by AHA SDG.