bluuebunny/crossref_metadata_2025_split huggingface dataset:
RENAL FUNCTION IN NORMOTENSIVE SHEEP IN THE FIRST FOURTEEN WEEKS AFTER CATHETER‐BASED RENAL DENERVATION
Authors: Booth Lindsea C , McArdle Zoe , Yao Song T , Malone Sally , Lankadeva Yugeesh , Kosaka Junko , Schlaich Markus , May Clive N 
Published: November 2023

BackgroundCatheter‐based renal denervation (RDN) has emerged as a novel treatment for resistant hypertension by targeting the afferent sensory and efferent sympathetic renal nerves to reduce blood pressure. Recent evidence suggests that there is partial functional and anatomical reinnervation at 5 months after catheter‐based RDN and complete reinnervation after 11 months. The function of the reinnervated renal nerves has not been investigated in conscious animals.AimTo examine the effects of reinnervation of the renal nerves on renal function 1, 8 and 14 weeks after renal denervation using the Symplicity Flex catheter.MethodsNormotensive merino ewes underwent a battery of physiological challenges, including salt load, salt depletion, periods of mild hypertension and mild hypotension, during which changes in renal blood flow, heart rate, mean arterial pressure and neurohormonal markers were measured. Ewes then underwent either sham or bilateral RDN using the Symplicity Flex catheter. Physiological challenges were repeated at 1, 8 and 14 weeks’ post‐RDN or sham denervation. Renal sympathetic nerve activity was recorded 8 and 14 weeks after sham or bilateral RDN.ResultsOne week after RDN, cumulative sodium excretion was lower compared with pre‐RDN levels in response to 0.1 mM saline/kg/min i.v. for 100 min (935±49 mmol and 619±52 mmol, respectively). Eight weeks after RDN the cumulative sodium excretion was lower in the RDN group compared to pre‐RDN (58±10 mmol and 31 ± 3 mmol, respectively) at the end of a 135 mM i.v. saline load at 0.09 mL/kg/min for 4 hours. There were no changes with sham denervation. In addition, we made the first recordings in conscious animals of renal sympathetic nerve activity after bilateral catheter‐based RDN.ConclusionsThe preliminary data from the present study suggest that there are significant changes in renal function after catheter‐based RDN.
Macrophage‐Dependent Impairment of α2 Autoreceptor Inhibition of Ca2+ Currents in Sympathetic Neurons Contributes to Hypertension in DOCA‐Salt Rats
Authors: Mui Ryan , Fernandes Roxanne , Galligan James 
Published: November 2023

Norepinephrine (NE) release from perivascular sympathetic nerves is regulated by prejunctional alpha‐2 autoreceptors (α2AR), which inhibit nerve terminal N‐type Ca2+ channels. We showed previously that macrophage infiltration and superoxide production in mesenteric arteries (MA) impairs α2AR‐mediated inhibition of NE release. We tested the hypothesis that macrophages disrupt α2AR coupling to N‐type Ca2+ channels in sympathetic neurons.MethodsThe DOCA‐salt rat model of hypertension was used for this study. Immunohistochemistry was used to localize macrophages in MA. Ca2+ current inhibition was evaluated using whole‐cell patch clamp on cultured sympathetic neurons of the celiac ganglion. Liposome‐encapsulated clodronate (LEC) was used to deplete macrophages.ResultsMacrophage infiltration is increased in MA of DOCA‐salt hypertensive rats. The α2AR agonists NE and UK14304 inhibit Ca2+ currents in neurons from normotensive but not hypertensive rats. In all neurons, yohimbine (α2AR antagonist) attenuates the effects of NE and dialysis of GppNHp (non‐hydrolyzable GTP analog) inhibits Ca2+ current equally. In DOCA‐salt rats, LEC treatment prevents macrophage infiltration in MA, reduces blood pressure elevation, and preserves α2AR‐mediated inhibition of Ca2+ current in sympathetic neurons.ConclusionsIn DOCA‐salt hypertensive rats, α2AR dysfunction leads to impaired modulation of Ca2+ current that is independent of factors downstream of receptor activation. Macrophage depletion preserves α2AR function and protects against blood pressure elevation.Support or Funding InformationP01 HL070687
EETs oppositely regulate pulmonary and systemic pressure in hypoxia
Authors: Kandhi Sharath , Qin Jun , Froogh Ghezal , Alruwaili Norah , Wolin Michael S. , Huang An , Sun Dong 
Published: November 2023

AimTo study the effects of epoxyeicosatrienoic acids (EETs) on the pulmonary and systemic circulations in response to hypoxia.MethodsMale wild type (WT) and soluble epoxide hydrolase knockout (sEH‐KO) mice, and WT mice fed with a sEH inhibitor (t‐TUCB; 1mg/kg/day) via oral gavage for 4 weeks, were used. Right ventricular systolic pressure (RVSP) and systemic arterial pressures (MABP) were recorded via catheterizations, in response to breathing 100% and 10% oxygen (hypoxia).ResultsBaseline of RVSP was comparable among the three groups of mice, whereas, MABP was significantly lower in sEH‐KO and TUCB‐treated groups compared to WT mice. Exposure of mice to hypoxia elicited significant increases in RVSP with more predominant increases in TUCB‐treated and sEH‐KO than WT mice. 14,15‐EEZE that had no effects on responses of WT mice, prevented hypoxia‐induced elevation of RVSP in other two groups. Hypoxia decreased MABP, which was reversed by EEZE in sEH‐KO and TUCB‐treated mice.ConclusionsHypoxia elicited the elevation of RVSP but reduction of MABP, responses that were potentiated, as a function of the deletion of sEH gene and inhibition of sEH activity.Support or Funding Information(This work was supported by NIH HL070653 and HL115124)
Stellate and Pyramidal Neurons in Goldfish Telencephalon Respond Differently to Anoxia and GABA Receptor Inhibition
Authors: Hossein‐Javaheri Nariman 
Published: November 2023

During anoxia the mammalian brain undergoes hyper‐excitability and cell death while the common goldfish (Carassius auratus) is anoxia tolerant and by suppressing electrical activity of the brain, prevents excitotoxic cell death. This mechanism in goldfish is not fully understood however they may rely on neurotransmitters and neuromodulators to suppress energy consumption during anoxia. In our experiment we investigated the possible roles of γ‐amino butyric acid (GABA), the major inhibitory neurotransmitter, in goldfish telencephalon neurons during anoxia. Utilizing whole‐cell and perforated patch clamp recording techniques, we found that with anoxia, membrane potential in inhibitory stellate neurons and excitatory pyramidal neurons increased; however, stellate cells became more depolarized and generated action potentials while the pyramidal neurons showed suppressed electrical activity. To further investigate the importance of GABA in anoxic survival, we blocked the GABAA receptors during anoxia using an antagonist (gabazine, 25μM). Gabazine significantly suppresses neuronal activity in stellate neurons and increased action potential firing in the pyramidal cells, suppressing the anoxic response in these neurons. Since membrane potential depolarized with anoxia, we applied GABA (5mM) to both cell types during normoxia and measured changes in membrane potential. We calculated the GABA reversal potential (EGABA) and observed that with anoxia, membrane potential shifts towards a depolarizing EGABA. We were able to conclude that GABA release during anoxia significantly suppresses neuronal activity and increases anoxic survival. This is an example of natural adaptive mechanism in goldfish which could also be investigated in mammalian brain as a protective mechanism against anoxic injuries.Support or Funding Informationdiscovery accelerator supplement grant
Amino Acids as Fates of Anoxia‐Induced Lactate Loads in the Painted Turtle
Authors: Hill Craig A. , Yarasheski Kevin E. , Warren Daniel E. 
Published: November 2023

The painted turtle is the most anoxia tolerant tetrapod known. During its over‐winter hibernation which often occurs in anoxic ponds, it is capable of accumulating lactate to greater than 200mM in the plasma alone. We sought to determine whether or not amino acid synthesis serves as a metabolic fate of the lactate carbon accumulated during anoxia and recovery following anoxia at 10°C and 20°C. We hypothesized that most amino acid synthesis would occur during the recovery following anoxia. To investigate this, a bolus of [U‐13C]‐lactate tracer was delivered via an arterial catheter during the anoxia and allowed to equilibrate prior to recovery. Plasma was sampled throughout the dive and subsequent recovery, and liver, pectoralis, and ventricle were sampled at the end of anoxia and at the end of recovery. The enrichments of alanine, glycine, valine, methionine, aspartate, and glutamate in plasma samples and tissue extracts were measured using gas chromatography and mass spectrometry. Results show a clear difference between the end of anoxia versus the end of recovery following anoxia in both the plasma and in the cytosolic free amino acids. Furthermore, enrichment was significantly different in the liver versus pectoralis and ventricle. Direct enrichment of alanine as M+3 alanine from pyruvate was observed, but the remaining amino acids were primarily enriched as M+2, with less M+3 and M+4, showing that the lactate carbon persists for at least one turn of the citric acid cycle (CAC). The anaplerotic amino acids, glutamate and aspartate, were also highly enriched, indicating elevated pyruvate carboxylase activity and potentially representing an auxiliary pool for rapid replenishment of CAC intermediates when needed. Future studies include amino acid tracer experiments to investigate the specific utilization of amino acids during anoxia and particularly during recovery, as well as further investigation of the amphibolic metabolism inherent to the citric acid cycle. This work is the first of its kind, and makes a significant contribution towards the development of the turtle model for metabolic studies.Support or Funding InformationThis work was supported by the NIH; Dr. Daniel Warren (R15 DK097700), and the Washington University Biomedical Mass Spectrometry Research Facility (P41 GM103422, P30 DK020579, P30 DK056341).
Structure and Function of Dragonfly Looming‐Sensitive Neurons
Authors: Slugaski Cara 
Published: November 2023

In this project, I aim to identify specific neurons in the dragonfly brain that respond selectively to looming stimuli. In the dragonfly nerve cord, there are large visual neurons, called Target Selective Descending Neurons (TSDNs). These neurons respond selectively to small moving stimuli, which mimic the movements of dragonfly prey. The response of these neurons is the steering movement of the dragonfly's wings, allowing them to predict the location of their prey for accurate interception. A subset of the TSDNs show large and precisely timed responses to the expanding image of an approaching object. I will be studying these “looming‐sensitive” neurons, researching what visual information they are sending to the flight system. This material will allow for the analysis of the anatomical structure in the dragonfly brain. The visual responses of these dragonflies suggests that the looming‐sensitive neurons are the specific TSDNs called MDT3 and DIT3, but in order to confirm this prediction, we must visualize the anatomy of the brain. With the use of a dye called Lucifer yellow, we can trace the response of the looming stimuli to a specific area of the brain. By injecting the dye with a recording microelectrode, we can positively identify these specific neurons.Support or Funding InformationUnion College Undergraduate Research Committee
Does pulse contour analysis provide a valid estimate of cardiac output during spaceflight?
Authors: Yee Nicholas J , Zuj Kathryn A , Greaves Danielle K , Hughson Richard L 
Published: November 2023

Model flow is a pulse contour analysis method that provides non‐invasive ambulatory cardiac output, which can characterize potential degradation of cardiovascular function due to long‐duration spaceflight. However, the model flow algorithm has not been tested in altered gravitational environments. The purpose of this study was to use a standard rebreathing measure of cardiac output (COre) to validate the model flow cardiac output (COmf) and to detect potential changes in cardiovascular physiology during spaceflight using the stiffness index, model flow Aortic Age (AGEmf). Data were collected from nine male astronauts (45 ± 7 years old) who were aboard the International Space Station for 6 months. Testing occurred pre‐flight and inflight approximately 3 weeks before returning to Earth. Rebreathing cardiac output was collected using the Pulmonary Function System. The arterial pressure waveform was collected using finger photoplethysmography for the determination of COmf and AGEmf. Changes in COmf with spaceflight did not match changes in COre (p < 0.001). COre increased from pre‐flight to inflight (4.8 ± 0.7 L/min and 7.0 ± 1.4 L/min, respectively; p < 0.01) while COmf remained constant with spaceflight (pre‐flight: 6.2 ± 1.4 L/min and inflight: 5.8 ± 1.1 L/min, respectively; p > 0.05). The model flow algorithm assumes central arterial properties based on age but as changes in COmf were not similar to COre with spaceflight, this assumption appears to have been violated. As well, the stiffness index AGEmf decreased with spaceflight (pre‐flight: 68 ± 16 years old and inflight: 41 ± 9 years old; p < 0.01). These results suggest changes in cardiac function and in arterial properties that invalidate pulse contour analysis during spaceflight.Support or Funding InformationThe research was supported by the Canadian Space Agency, Natural Sciences and Engineering Research Council of Canada, and the American Physiological Society.
Endothelin‐1 Modulates Methacholine‐Induced Cutaneous Vasodilation but not Sweating in Young Human Skin
Authors: Halili Lyra , Singh Maya Sarah , Fujii Naoto , Alexander Lacy M. , Kenny Glen P. 
Published: November 2023

The present study investigated the effect of endothelin‐1 (ET‐1) on cholinergic mechanisms of end‐organs (i.e. skin blood vessels and sweat glands) for heat dissipation. We evaluated the hypothesis that ET‐1 attenuates cholinergic cutaneous vasodilation and sweating through a nitric oxide synthase (NOS)‐dependent mechanism. Cutaneous vascular conductance (CVC) and sweat rate were assessed in three protocols. CVC was normalized to maximal CVC (%CVCmax). In Protocol 1 (n = 8), microdialysis forearm skin sites were perfused with lactated Ringer (Control), 40 pM, 4 nM or 400 nM ET‐1. In Protocol 2 (n = 11) sites were perfused with lactated Ringer (Control), 400 nM ET‐1, 10 mM L‐NNA (a NOS inhibitor) or a combination of 400 nM ET‐1 and 10 mM L‐NNA. In Protocol 3 (n = 8), only two sites (Control and 400 nM ET‐1) were utilized to assess the influence of ET‐1 on the dilation capacity of vascular smooth muscle cells using a dual administration of sodium nitroprusside (SNP). Methacholine (MCh) was co‐administered in a dose‐dependent manner (0.0125, 0.25, 5, 100, 2000 mM, each for 25 min) at all skin sites. 400 nM ET‐1 significantly attenuated increases in CVC compared to Control in response to 0.25 (40 ± 13 vs. 75 ± 10 %CVCmax) and 5 mM (55 ± 11 vs. 91 ± 11 %CVCmax) MCh (both P < 0.05). A high dose of ET‐1 (400 nM) co‐infused with L‐NNA further attenuated CVC relative to the ET‐1 site during 0.25 (23 ± 9 vs. 43 ± 14 %CVCmax), 5 (35 ± 10 vs. 61 ± 12 %CVCmax) and 100 mM (43 ± 12 vs. 70 ± 10 %CVCmax) MCh administration (all P < 0.05). Cutaneous vasodilation in response to SNP was significantly blunted (perfusion units mmHg−1: 1.66 ± 0.30 vs. 0.80 ± 0.17) after administration of 400 nM ET‐1 (P < 0.05). Therefore, we show that ET‐1 attenuates cutaneous vasodilation through a NOS‐independent, possibly through a vascular smooth muscle cell‐dependent mechanism, and that methacholine‐induced sweating is not modulated by ET‐1.Support or Funding InformationThis study was supported by grants from the Natural Sciences and Engineering Research Council of Canada (Discover grant, RGPIN‐06313‐2014; Discovery Grants Program ‐ Accelerator Supplement, RGPAS‐462252‐2014; funds held by Dr. Glen P. Kenny).
Aging Slows Vasoconstriction Dynamics in Skeletal Muscle Resistance Vessels
Authors: Gittemeier Elizabeth Marie , Ericson Tyler J , Verma Rahul , Ghosh Payal , Garcia Emmanuel , Opoku‐Acheampong Alexander , Behnke Bradley Jon 
Published: November 2023

With advancing age there is a reduced ability to tolerate orthostatic stress and perform exercise. An increase in peripheral vascular resistance (PVR) during both of these challenges, facilitated in part by sympathetically mediated vasoconstriction of resistance arteries, is requisite to maintain central venous return and arterial blood pressure. In aged subjects, the ability to rapidly enhance PVR during orthostatic challenges is diminished, which contributes to orthostatic intolerance in many aged individuals. The purpose of this preliminary investigation was to determine the rate of vasoconstriction to an alpha‐adrenergic agonist (i.e., sympathetic mimetic) in skeletal muscle arteries of young (6 mo old; n=4) and aged (24 mo old; n= 4) Fisher‐344 rats. Resistance arteries from the highly‐oxidative red portion of the gastrocnemius muscle were isolated and cannulated. Thereafter, the temporal characteristics of vasoconstriction [i.e., time‐delay (TD), rate of constriction, time to steady‐state (SS)] were quantified after exposure to 10−4M norepinephrine. With old age, the delay before the onset of constriction was ~ 5x longer than younger counterparts (young, 0.7 ± 0.1 vs. aged, 3.7 ± 0.4 s) and the time to SS was substantially prolonged with old age (young, 6.6 ± 0.4 vs. aged, 19.5 ± 1.2 s). Despite no difference in the overall magnitude of vasoconstriction between groups, the rate of vasoconstriction was blunted with old age (young, 35.9 ± 9.1 vs. aged, 14.1 ± 0.9 μm/s). With old age, there appears to be a severely diminished ability to rapidly vasoconstrict skeletal muscle resistance arteries. During orthostatic stresses, a reduced ability to vasoconstrict peripheral arteries would lead to blood pooling in the periphery and, subsequently, diminished venous return and an inability to maintain mean arterial pressure. The precise mechanisms responsible for the reduced rate of vasoconstriction (e.g., Ca2+ handling, altered vascular mechanical properties) are unknown and are currently being investigated. Whether the same deficits in vasoconstriction are present in arteries of other vascular beds (e.g., splanchnic region) remains to be determined.Support or Funding InformationNational Institutes of Health (AG25622), American Cancer Society (RSG‐14‐150‐01‐CCE)
Repeated moderate heat exposure improves limb endothelial function in humans
Authors: Cui Jian , Lott Mary , Blaha Cheryl , Sinoway Lawrence I. 
Published: November 2023

Limited reports suggest that sauna baths or dry sauna may improve vascular function in patients with peripheral artery disease or heart failure. However, it is unclear if repeated moderate heat exposure (RMHE) with regular warm water baths can improve endothelial function in normal aged individuals. We assessed limb endothelial‐dependent function via measuring brachial flow‐mediated dilation (FMD) in 6 elder volunteers (5 M and 1 F, 59 ± 3 yrs, 177 ± 4 cm, 88 ± 10 kg) after 4 weeks (5 days/week) of warm baths (39–42 °C for 30 min). During each bath, subjects were in the recumbent position in the bathtub with water up to their mid chest, while their forearms were not kept in water. On the days of prior, 1 day post 4 weeks of RMHE and 1 week after end of RMHE, FMD was measured with Doppler ultrasound following 5 minutes of forearm ischemia in a laboratory at ~23 °C. Endothelium‐independent vasodilation was quantified by measuring the brachial artery dilator response to sublingual nitroglycerin (0.4 mg). RMHE led to significant increases in FMD (one‐way repeated measures ANOVA, P=0.019). Compared with prior RMHE (Δ4.98 ± 0.98% from prior ischemia baseline), the FMD increased in all subjects after 4 weeks of RMHE (Δ8.48 ± 1.33%, P=0.033), and returned to baseline diameters one week after completion of RMHE (Δ5.71 ± 0.68%, P=0.915). In contrast, RMHE did not induce significant changes in the dilator response to sublingual nitroglycerin (prior, post, post 1‐wk: Δ11.91 ± 0.70%, Δ11.84 ± 1.05%, Δ11.21 ± 0.33%, P=0.684). These data suggest that repeated moderate heat exposure improves limb endothelial‐dependent function, and does not alter endothelium‐independent vasodilation in normal aged individuals. We speculate the increased blood flow seen with heat exposure may increase vessel shear stress and eNOS activity, which may in turn contribute to the improved chronic endothelial function by the repeated heat exposures. The mechanism(s) should be examined in future studies.Support or Funding InformationAHA 15GRNT24480051 (JC) and P01 HL096570‐05 (LIS)
Nur77 Inhibits Isoproterenol‐Induced Cardiac Fibrosis through Upregulation of Relaxin‐3
Authors: Guo Zhi‐Fu , Zhang Guanxin , You Xiaohua , Yi Bing , Cheng Fang , Sun Jianxin 
Published: November 2023

ObjectiveThe orphan nuclear receptor Nur77 plays critical roles in cardiovascular diseases and its expression is markedly induced in the heart after excessive β‐adrenergic receptor (β‐AR) activation and ischemia/reperfusion injury. However, the functional significance of Nur77 in cardiac fibrosis remains unclear. The objective of this study is to determine whether Nur77 is involved in the development of cardiac fibrosis, and if so, to determine the molecular mechanism (s) involved.Methods and ResultsBy using a mouse model of isoproterenol (ISO)‐induced cardiac fibrosis, we show that the ISO‐induced cardiac fibrosis was markedly exacerbated in Nur77 knockout mice, hence highlighting a critical importance of Nur77 in cardiac remodeling. To determine the molecular mechanism involved, we investigated whether Nur77 affects the cardiac expression of relaxin, which has been shown to be a key anti‐fibrotic molecule in the heart under various pathophysiological circumstances. By using qPCR, we found that both relaxin‐1 and relaxin‐3 mRNA are predominantly expressed in mouse cardiomyocytes, as compared with that in cardiac fibroblasts. Importantly, we demonstrate that overexpressing Nur77 robustly increases the expression of relaxin‐3, but not relaxin‐1 in cardiomyocytes, suggesting the specificity of Nur77 regulation on relaxin‐3 in the heart. Indeed, sequential analysis identified two NGFI‐B response elements (NBRE) (5′‐AAAGGTCA‐3′) in the promoter region of relaxin‐3. Site‐directed mutagenesis and promoter functional analysis suggest that these two NBRE motifs are mainly responsible for the Nur77‐induced relaxin‐3 expression in cardiomyocytes. Furthermore, we show that Nur77 specifically binds to the promoter region of relaxin‐3, as demonstrated by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays, under both basal and ISO‐stimulated conditions. Moreover, ISO stimulation markedly increases the expression of relaxin‐3 in wild‐type (WT) mice, but not in Nur77 knockout (KO) mice, further indicating the important role of Nur77 in regulating relaxin‐3 expression in the heart. Continuous infusion of relaxin‐3 through the mini‐osmotic pump implanted subcutaneously for 14 days significantly attenuated cardiac fibrosis of both WT and Nur77 KO mice, as determined by Masson's trichrome (MTC) staining and hydroxyproline assay. Furthermore, pharmacological activation of Nur77 by cytosporone B (CsnB) potently inhibited ISO‐induced cardiac fibrosis in wild‐type mice, but not in Nur77 KO mice.ConclusionTogether, these results demonstrate for the first time that Nur77 is a novel regulator for cardiac fibrosis through upregulating of relaxin‐3, and that targeted activation of Nur77 in the heart may represent a potentially novel therapeutic strategy for preventing cardiac fibrosis.Support or Funding InformationThis research was supported by the US National Institutes of Health (HL103869)