bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypoxia‐induced depolarization of pulmonary arterial smooth muscle cells relies on simultaneous inhibition of K+‐currents and redox state alterations
Authors: Knoepp Fenja , Wahl Joel , Ramser Kerstin , Weissmann Norbert 
Published: June 2021

Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to localized alveolar hypoxia that is intrinsic to the pulmonary circulation. By hypoxia‐induced contraction of pulmonary arterial smooth muscle cells (PASMCs), pulmonary capillary blood flow is redirected to alveolar areas of high oxygen partial pressure (pO2), thus maintaining the ventilation‐perfusion ratio. Although the principle of HPV was recognized decades ago the underlying pathway still remains elusive.Voltage gated K+‐channels (Kv‐channels) are known to be redox‐sensitive and crucial for mediating membrane potential in PASMCs ‐ thereby controlling Ca2+‐entry and subsequently vascular tone. Here, we investigated whether acute hypoxia alters the redox state of isolated PASMCs from mice and if this impacts Kv‐channel activity, membrane potential and intracellular Ca2+‐ level.Kv‐currents and membrane potential in response to hypoxia or the oxidizing agent H2O2 were investigated by whole cell patch clamp experiments (voltage and current clamp, resp.) on freshly isolated murine PASMCs. Simultaneously, pO2 was recorded using an optical oxygen sensor and intracellular Ca2+ was measured by ratiometric FURA‐2 imaging. The redox state was monitored by Raman spectroscopy using an excitation wavelength that was in resonance with the hemeproteins (532 nm).Raman‐spectra values for reduced myoglobin (1607 cm−1) and cytochrome c (1622 cm−1) both increased upon exposure of PASMCs to hypoxia (4 % O2) and returned to the initial value upon reverting to normoxia (21 % O2), thus indicating a shift in the cells' redox state. In accordance, Kv‐currents were dose‐dependently inhibited by hypoxia and H2O2, resulting in a depolarization from −37,5 ± 2 mV (before) to −28.09 ± 2 mV after exposure to hypoxia (Mean ± SEM; n = 23; p = < 0,001; paired t‐test). The oxidizing agent H2O2 (124 nM) mimicked this effect under normoxic conditions by elevating the membrane potential of the PASMCs from −37.4 ± 3 mV (before) to −25,2 ± 4 mV upon application of 124 nM H2O2 (Mean ± SEM; n = 5, p = 0,005, paired t‐test) ‐ thereby triggering a rise in intracellular Ca2+.In conclusion, hypoxia induced a shift in redox state in PASMCs, thereby mediating the inhibition of KV‐channels. The resulting depolarization and Ca2+‐entry may account for the contraction of PASMCs – thus initiating HPV.Support or Funding InformationThis study was funded by the German Research Foundation (DFG, CRC 1213) and the Swedish Research Council (Grant 2016‐04220).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Corticospinal and Spinal Excitability to the Biceps and Triceps Brachii is Modulated Differently between Forward and Backward Arm Cycling
Authors: Nippard Anna , Lockyer Evan , Button Duane , Power Kevin 
Published: June 2021

The purpose of this study was to evaluate supraspinal and spinal excitability to the biceps and triceps brachii when comparing forward (FWD) and backward (BWD) arm cycling. Supraspinal and spinal excitability were assessed non‐invasively using transcranial magnetic stimulation (TMS) to elicit motor evoked potentials (MEPs) and transmastoid electrical stimulation (TMES) to elicit cervicomedullary evoked potentials (CMEPs), respectively. MEPs and CMEPs were recorded from the biceps and triceps brachii during FWD and BWD arm cycling at two positions, the 6 and 12 o'clock position. The 6 o'clock position corresponded to mid elbow flexion and extension during FWD and BWD cycling, respectively, while the 12 o'clock position corresponded to mid elbow extension and flexion during FWD and BWD cycling, respectively. Participants completed four arm cycling trials, two FWD and two BWD, at 60 rpm and 25 W. During the flexion phase MEP (p = .001) and CMEP (p = .001) amplitudes of the biceps brachii were higher during FWD cycling. However, during the extension phase MEP (p = .006) and CMEP (p = .003) amplitudes were higher during BWD cycling. For the triceps brachii MEP amplitudes were higher during FWD cycling compared to BWD (p = .027) regardless of the functional phase (flexion vs. extension) of the movement cycle. However, spinal excitability to the triceps brachii was dependent on the functional phase of the movement cycle. During the flexion phase CMEPs of the triceps brachii were higher during FWD cycling compared to BWD (p = .032), but during the extension phase CMEPs were higher during BWD cycling compared to FWD (p = .001). This data suggests that the modulation of CSE and spinal excitability to the biceps brachii is dependent on the functional phase of the movement cycle and on the cycling direction. Also, spinal excitability but not CSE to the triceps brachii is dependent on the functional phase of the movement cycle when comparing FWD and BWD cycling.Support or Funding InformationNSERC Discovery Grant awarded to K.E. PowerThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Balancing Neuroprotection with Functional Recovery: The Potential Role of the PNN in Preventing Excitotoxicity after SCI
Authors: Stoltz Daimen , Silverstein Aaron , Huffman Emily , Alilain Warren 
Published: June 2021

In spinal cord injury (SCI), initial mechanical trauma causes debilitating primary damage to neural cells and blood vessels. Following this, secondary cascades of downstream events occur, including inflammation, ischemia, and excitotoxicity — an increase in intracellular Ca2+ concentration from overactive glutamate (Glu) receptors leading to cell death. Additionally, there is an upregulation of the perineuronal net (PNN), a lattice‐like structure of the extracellular matrix (ECM) which modulates neural communication and homeostasis. The PNN is partially composed of negatively charged chondroitin sulfate proteoglycans (CSPGs). While CSPGs can stabilize plasticity and neuronal growth during development, these molecules become inhibitory to regeneration, sprouting and plasticity after injury, as well as contribute greatly to the glial scar. However, administration of the bacterial enzyme chondroitinase ABC (ChABC) can digest the PNN and CSPGs, ultimately promoting functional recovery. What remains unknown are the other impacts of removing the PNN at very acute stages of injury. We hypothesize that the PNN and its negatively charged CSPGs are upregulated after SCI as a neuroprotective response that attenuates excitotoxicity by acting as a buffer for Ca2+. To test our hypothesis, we induced excitotoxicity by injecting rats with a threshold dose of NMDA with or without ChABC utilizing the well defined spinal respiratory motor system. 59% of SCI occurs at the cervical level, and mechanical ventilation is the leading cause of death and restriction of independence in these cases. Therefore, we administered the dose instraspinally at the C4 level and paired treatment with intrapleural injection of cholera toxin‐B to retrogradely label the phrenic motor neuron pool, which innervates the diaphragm. Preliminary findings suggest that animals lacking the PNN have exacerbated cell death versus control. This implies that, following SCI, the body's main focus is to survive and not necessarily to preserve function. PNN upregulation after injury could be a conserved mechanism which promotes survival and CNS tissue preservation at the expense of plasticity and functional regeneration. The next steps are to detail the spread of ChABC and how long it takes for the PNN to regenerate. Future directions will investigate the optimal timing of ChABC administration to balance preserving cell survival with promoting functional recovery.Support or Funding InformationNINDS R01NS101105 (WJA)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Re‐Examining the Measurement of Sympathetic Baroreflex Sensitivity at Rest and During Stress
Authors: Duplea Sergiu‐Gabriel , Incognito Anthony V , Sussman Jess , Shepherd Andrew D , Doherty Connor J , Lee Jordan B , Cacoilo Joseph A , Notay Karam , Millar Philip J 
Published: June 2021

The sympathetic arterial baroreflex regulates blood pressure through negative feedback changes in vasoconstrictor muscle sympathetic nerve activity (MSNA). Spontaneous sympathetic baroreflex sensitivity (BRS) is quantified using a weighted linear regression relating absolute diastolic blood pressure (DBP) with occurrence (burst incidence [BI]) or strength (burst amplitude [BA]) of a multi‐unit MSNA burst. Such as assessment generally produces strong negative linear relationships between DBP and MSNA at rest, but are often weakened or absent during sympathoexcitatory stimuli, such as exercise or mental stress. We hypothesized that sympathetic BRS would be better represented during stress by using the change in DBP between two subsequent cardiac cycles (DBP change) rather than the absolute DBP value (absolute DBP). We retrospectively examined 64 participants whom underwent continuous recordings of heart (ECG), blood pressure (Finometer), and MSNA (microneurography). Each participant completed a 2–5 min resting baseline followed by one or more of the following protocols: rhythmic handgrip (RHG; n=24; 3 min at 40% maximal voluntary contraction [MVC]), static handgrip (SHG; n=16; 2 min at 30% MVC), mental stress (MS; n=28; 2 min serial subtraction). At rest, we observed a similar number of strong negative linear relationships (r>0.6) with BI (52/64 vs. 59/64, p=0.12) and BA (41/64 vs. 49/64, p=0.18) using the absolute and change methods. In participants possessing strong relationships across both methods (BI: n=49; BA: n=32), we observed differences in sympathetic BRS of BI (−4.7±1.8 bursts/100 heartbeats/mmHg vs. −5.4±2.0 bursts/100 heartbeats/ΔmmHg, p=0.03) and BA (−2.9±1.0 AU/mmHg vs. −2.5±1.3 AU/ΔmmHg, p=0.06), and modest correlations between methods for BRS of BI (r=0.32) and for BRS of BA (r=0.42). During stress, the absolute and change methods yielded a similar proportion of strong negative linear relationships with BI during RHG (6/24 vs. 10/24, p=0.36), but a higher number using the DBP change method during SHG (7/16 vs. 15/16, p=0.006) and MS (16/28 vs. 24/28, p=0.04). Similarly, the change method identified a greater proportion of strong negative linear relationships with BA during RHG (0/24 vs. 12/24, p<0.001), SHG (0/16 vs. 14/16, p<0.001), and MS (9/28 vs. 20/28, p=0.007). The DBP change method more consistently identified strong negative linear relationships with MSNA BI and BA. The modest relationships between methods at rest may highlight the importance of beat‐to‐beat DBP changes in arterial baroreflex regulation of muscle sympathetic outflow.Support or Funding InformationNatural Sciences and Engineering Research Council of Canada (NSERC); NSERC Discovery Grant; Canada Foundation for InnovationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Dopaminergic Projections to Raphe Pallidus Inhibit Brown Adipose Tissue Thermogenesis
Authors: da Conceição Ellen Paula Santos , Madden Christopher J , Morrison Shaun F. 
Published: June 2021

BackgroundThe observations that patients with Parkinson's disease experience weight loss, while dopamine (DA) replacement therapy causes body weight gain, suggest that suppressing the DA system could stimulate energy expenditure. Peripheral administration of dopaminergic drugs decreases heat production by inhibition of brown adipose tissue (BAT) thermogenesis and by an increase in the threshold for muscular shivering. However, the exact neuroregulatory site through which DA modulates the activity of thermogenic thermoeffectors remains undefined.ResultsIn urethane/chloralose‐anesthetized, artificially‐ventilated rats, activation of type 2 or 3 dopamine receptors in the rostral raphe pallidus (rRPa) inhibits cold‐evoked BAT sympathetic activity, reduced BAT temperature and expired CO2, and produced hypotension and bradycardia. Anatomic evidence shows the co‐localization of TH and CTb immunoreactivities in neurons in the in the periventricular gray zona following injection of the retrograde tracer in the rRPa. These data indicate that this dopaminergic cell group projects to rRPa and is the likely source of the dopaminergic inhibition of BAT sympathetic activity.ConclusionOur data provide the first evidence that a DA input to the rRPa from periventricular gray zona modulates BAT thermogenesis and cardiovascular function. Modulating the dopaminergic input to rRPa could provide a novel therapeutic approach to promote fat oxidation, favor better glycaemic control, and accelerate weight loss.Support or Funding InformationNIH R01‐NS091066This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Comparative Assessment of Central and Peripheral Chemoreceptor Reflex Regulation of Muscle Sympathetic Nerve Activity and Ventilation
Authors: Keir Daniel A , Millar Philip J , Duffin James , Floras John S 
Published: June 2021

We tested the hypothesis that central and peripheral chemoreceptor‐mediated sympathetic activation elicited by increases in CO2 tension (PCO2) mirror concurrent ventilatory responses. Twelve healthy young men (mean±SD; age: 24±4 yr; BMI: 24.5±1.3 kg·m−2) performed a modified rebreathing protocol designed to equilibrate central and peripheral chemoreceptor PCO2 tensions with end‐tidal PCO2 (PETCO2) at two isoxic end‐tidal PO2 (PETO2) tensions such that central chemoreceptor reflex responses (hyperoxia) can be isolated from additive peripheral responses (i.e., hypoxia minus hyperoxia). Subject's ventilation (volume turbine) and muscle sympathetic nerve activity (MSNA; microneurography, right fibular nerve) responses to rebreathing at isoxic PETO2 tensions of 150 mmHg (hyperoxia) and 50 mmHg (hypoxia) were recorded continuously. During rebreathing, the PETCO2 (mmHg) at which ventilation (L·min−1) and total MSNA (au) began to rise were identified as the PETCO2 recruitment thresholds (RT). Slopes of these responses above RT also were determined. In hyperoxic rebreathing (i.e., the central chemoreflex response), the mean RT for ventilation (46±3 mmHg) and MSNA (45±4 mmHg) did not differ (p>0.05). Mean slopes were 2.3±0.9 L·min−1·mmHg−1 and 2.1±1.5 au·mmHg−1, respectively. In hypoxic rebreathing (i.e., the summed central and peripheral chemoreflex response), the RT for both ventilation and MSNA were not different (41±3 mmHg vs 41±3 mmHg, p>0.05) but were lower (p<0.05) compared to hyperoxia. Mean slopes for ventilation (4.0±1.8 L·min−1·mmHg−1) and MSNA (5.1±3.4 au·mmHg−1) in hypoxia were greater than in hyperoxia yielding a mean peripheral chemoreflex sensitivity (hypoxic slope minus hyperoxic slope) of 1.7±0.1 L·min−1·mmHg−1 for ventilation and 3.0±2.6 au·mmHg−1 for MSNA. The 95% limits of agreement of RT between ventilation and MSNA for the central chemoreflex were −7 to 6 mmHg (bias=−1 mmHg, p>0.05) and −5 to 5 mmHg (bias=0 mmHg, p>0.05) for the peripheral chemoreflex. There was no relationship (p>0.05) between the ventilatory and MSNA sensitivity for either the central (r2=0.16) or peripheral (r2=0.01) chemoreceptor reflexes. These data highlight two novel findings: 1) ventilatory and sympathetic arms of the central and peripheral chemoreceptor reflexes are initiated at similar PETCO2 recruitment thresholds and 2) sympathetic responsiveness cannot be predicted from the sensitivities of the ventilatory central and peripheral chemoreceptor reflexes.Support or Funding InformationExperiments were funded by a Project Grant from the Canadian Institutes of Health Research (PJT 159491). Dr. Floras holds the Canada Research Chair in Integrative Cardiovascular Biology.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Selective Reductions in Pulmonary Artery Pressure Lowers Sympathetic Neural Activity in Healthy Humans at High Altitude
Authors: Simpson Lydia L , Steele Andrew , Meah Victoria L , Thapamagar Suman , Gasho Christopher , Drane Aimee , Oliver Samuel J , Tymko Michael M , Ainslie Philip N , Steinback Craig D , Stembridge Mike , Moore Jonathan P 
Published: June 2021

Chronically elevated sympathetic neural activity is a characteristic of many disease states. Tonic chemoreflex activation has been implicated in the development of sympathetic overactivity; however, other reflexes may also contribute. For example, in an animal model, stimulation of pulmonary baroreceptors induces a reflex increase in sympathetic neural activity. In humans, pulmonary pressure has been shown to be related to basal sympathetic activity in pulmonary hypertension; however a critical step in determining a causal link is to establish whether changing pulmonary pressure alters sympathetic outflow. In this pilot study, we exposed thirteen healthy humans (5 females, 28 [ ± 7] years) to high altitude hypoxia (HA; 4383m), a setting known to increase both pulmonary pressure and sympathetic activation, before selectively lowering pulmonary pressure via inhalation of the pulmonary vasodilator nitric oxide. Muscle sympathetic nerve activity (MSNA; Microneurography), blood pressure (BP; Photoplethysmography), heart rate (HR; Electrocardiogram), and peripheral oxygen saturation (SPO2; Pulse oximetry) were continually measured during ambient air breathing (Amb) and during a 6‐minute inhalation of nitric oxide (iNO; 40ppm in 21% O2). Pulmonary artery systolic pressure (PASP), pulmonary vascular resistance (PVR) and stroke volume (SV) were determined via cardiac ultrasound. iNO reduced PASP (−23 ± 12%) and PVR (−21 ± 16%) compared to Amb (Table 1). iNO also reduced MSNA burst frequency (−18 ± 18%), burst incidence (−16 ± 17%) and total activity (−21 ± 20%) compared to Amb. MSNA changes during iNO were not related to changes in SPO2 (r = −0.16, P = 0.61) or MAP (r = −0.28, P = 0.35). Our data demonstrate that selectively reducing pulmonary pressure reduces sympathetic nerve activity in healthy humans; therefore, this provides evidence for a causal link in the relationship between pulmonary pressure and basal sympathetic activity. Further investigation is warranted to establish whether elevated pulmonary pressure is a mechanism contributing to chronically elevated sympathetic outflow in disease.Support or Funding InformationThis study was supported by the Natural Sciences and Engineering Research Council of Canada and a Canada Research Chair in Cerebrovascular Physiology grant.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Nrf2 Dysfunction in the RVLM is Associated with Obesity‐Induced Sympathoexcitation
Authors: Hall Delton , Asirvatham‐Jeyaraj Ninitha , Balasubramanian Priya , Subramanian Madhan 
Published: June 2021

Sympathetic overactivity contributes to the pathogenesis of obesity‐induced hypertension. The rostral ventrolateral medulla (RVLM) is an important brainstem region that regulates sympathetic nerve activity (SNA) to peripheral tissues. Oxidative stress and neuroinflammation in the RVLM are believed to be important contributors for augmented SNA in obesity, however, the molecular mechanisms that initiate and sustain the pro‐inflammatory milieu in the RVLM during obesity are not clear. Nuclear factor erythroid 2‐related factor (Nrf2) is a master transcriptional factor that regulates the expression of anti‐oxidant and anti‐inflammatory genes. We hypothesized that obesity impairs Nrf2 signaling to increase oxidative stress in the RVLM leading to increases in SNA and hypertension. To test this, 2 months‐old male C57BL/6J mice were fed a high‐fat diet (HFD; 60% fat) or normal chow diet (10% fat for 16 weeks and were instrumented with radiotelemeters in the last 2 weeks for measuring blood pressure and SNA. Heart rate variability and depressor response to ganglionic blockade were used to assess SNA. At the end of 16 weeks, animals were sacrificed, brainstem was isolated and sectioned. Superoxide levels were assessed in the frozen sections by dihydroethidium staining (DHE). RVLM was microdissected for gene expression analysis. Data were analyzed by students t‐test and p<0.05 was considered statistically significant. HFD feeding resulted in a mild but significant increase in mean arterial pressure (103.7 ± 0.9 vs 108.6 ± 0.73 mmHg, normal chow diet vs HFD; P<0.05; n=4) and systolic blood pressure (121.2 ± 1.2 vs 129 ± 0.67 mmHg, p<0.05; n=4) compared to normal chow‐fed animals. Ganglionic blockade using hexamethonium showed greater depressor response (−0.21 ± 2.9 vs 13.13 ± 1.3 mmHg, normal chow diet vs HFD; p<0.05; n=4) to HFD feeding. Furthermore, low‐frequency blood pressure variability and the ratio of low‐frequency to high‐frequency heart rate variability in HFD mice were significantly higher than in the control mice suggesting HFD upregulated SNA. In addition, obesity‐induced sympathoexcitation was associated with increased superoxide levels (DHE staining) and decreased mRNA levels of Nrf2 (1.05 ± 0.16 vs 0.48 ± 0.06 fold, normal diet vs HFD; p<0.05) and its target genes (e.g. NQO1 1.08 ± 0.22 vs 0.51 ± 0.08 fold, p<0.05 and SOD2 1.03 ± 0.13 vs 0.48 ± 0.05 fold; p<0.05) in the RVLM of HFD mice. Collectively, our results show for the first time, evidence for obesity‐associated Nrf2 dysfunction in the RVLM. Future studies will investigate the mechanistic role of Nrf2 signaling in the RVLM in obesity‐induced sympathoexcitation.Support or Funding InformationRAC fund, CVHS, Oklahoma State UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.