bluuebunny/crossref_metadata_2025_split huggingface dataset:
How do the Carotid Chemoreceptors Modulate Ventilatory Control and Cardiovascular Regulation at Rest and During Exercise in COPD?
Authors: Phillips Devin , Collins Sophie , Steinback Craig , Bryan Tracey , Wong Eric , McMurtry Michael Sean , Bhutani Mohit , Stickland Michael 
Published: June 2021

RATIONALEWe have recently demonstrated elevated activity and sensitivity of the carotid chemoreceptor (CC) in COPD, which may alter ventilatory and cardiovascular regulation at rest and during exercise. Accordingly, we sought to examine whether CC inhibition modifies ventilation and cardiovascular regulation at rest and during exercise in COPD.METHODSIn a randomized double blind crossover study, thirteen COPD patients (FEV1 predicted ± SD: 82 ± 19%) and thirteen healthy controls completed resting cardiovascular function measurements while receiving either intravenous (I.V.) saline or I.V. dopamine (2 mg/kg/min) while inspiring either room air or 100% O2 (order randomized). Participants then completed two time to symptom limitation constant load exercise tests at 75% peak power output, on separate days, while receiving either I.V. saline or dopamine (order randomized). At rest, arterial stiffness was determined by pulse‐wave velocity (PWV) and muscle sympathetic nerve activity (MSNA) was measured by microneurography. Ventilatory responses were evaluated using expired gas data and cardiac output (impedance cardiography) was collected to calculate vascular conductance (cardiac output/mean arterial pressure (MAP)). Exertional dyspnea was evaluated using a modified Borg scale and inspiratory capacity maneuvers were performed to determine operating lung volumes.RESULTSAt rest, CC inhibition with dopamine decreased central and peripheral PWV, ventilation and MAP (p<0.05) while increasing vascular conductance in COPD. No change in CV function was observed with dopamine in controls. CC inhibition with hyperoxia decreased peripheral PWV and MSNA (p<0.05) in COPD, while no change was observed in controls. At a standardized exercise time (isotime) of 4 minutes and at symptom limitation, minute ventilation was not different between saline and dopamine conditions in COPD or controls. Operating lung volumes and exertional dyspnea were not different between conditions within either group. Vascular conductance was increased (p<0.05) during exercise with dopamine in COPD, secondary to reduced MAP, while no change was observed in controls. There was no change in time‐to‐exhaustion in either group with dopamine.CONCLUSIONResults from the current study suggest that the CC plays a role in cardiovascular regulation at rest and during exercise in COPD; however, exercise ventilation, dyspnea and exercise tolerance were unaffected by CC inhibition in COPD patients. Interventions aimed at chronically reducing CC activity may be beneficial to reduce cardiovascular risk in COPD.Support or Funding InformationLung Association of Alberta/NWTCanadian Institute of Health ResearchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
High Intensity Muscle Metaboreflex Activation Blunts Cardiopulmonary Baroreflex Control of Sympathetic Vasomotor Outflow
Authors: Katayama Keisho , Kaur Jasdeep , Young Benjamin E. , Barbosa Thales C. , Ogoh Shigehiko , Fadel Paul J. 
Published: June 2021

Muscle sympathetic nerve activity (MSNA) is reduced during low intensity dynamic leg exercise. This reduction in MSNA has been attributed to loading of the cardiopulmonary baroreflex with increased venous return and it has been suggested that such inhibition is overridden with higher intensity exercise due to muscle metaboreflex activation. However, limited data are available regarding the interaction between the cardiopulmonary baroreflex and the muscle metaboreflex. Herein, we tested the hypothesis that cardiopulmonary baroreflex control of MSNA is attenuated when the muscle metaboreflex is strongly activated. In eight healthy young men, MSNA (right peroneal nerve), mean arterial blood pressure (MAP, Finometer), heart rate (ECG), and thoracic impedance were recorded. Graded isolation of the muscle metaboreflex was achieved by post‐exercise ischemia (PEI) following low‐ (PEI‐L), moderate‐ (PEI‐M) and high‐ (PEI‐H) intensity isometric handgrip performed at 20%, 30% and 40% maximum voluntary contraction, respectively. Lower‐body positive pressure (LBPP, +10 mmHg), to load the cardiopulmonary baroreflex, was applied at rest and during PEI. Handgrip exercise elicited intensity‐dependent increases in MSNA and MAP that were maintained during PEI indicating a graded muscle metaboreflex activation. LBPP at rest significantly decreased MSNA burst frequency and total activity (total activity: −39.5 ± 5.7%, mean ± SE, P < 0.05), while MAP was unchanged. When LBPP was applied during PEI, MSNA burst frequency and total activity decreased significantly at PEI‐L (total activity: −41.8 ± 10.6%, P < 0.05) and PEI‐M (total activity: −34.7 ± 8.6%, P < 0.05), but not at PEI‐H (total activity: −11.8 ± 8.6%, n.s., one‐way repeated measures ANOVA: F = 5.07, P < 0.05). Thoracic admittance, which was calculated from thoracic impedance as an index of central blood volume, was not changed during handgrip or PEI alone, whereas LBPP evoked similar increases in thoracic admittance during all conditions (rest: +5.4±0.8, PEI‐L: +5.8±0.5, +PEI‐M: +5.4±0.5, PEI‐H: +5.8±0.5 S·10−4, one‐way repeated measures ANOVA: F = 0.38, n.s.). These preliminary findings suggest that high intensity muscle metaboreflex activation attenuates cardiopulmonary baroreflex control of sympathetic vasomotor outflow.Support or Funding InformationNIH R01 HL127071 JSPS KAKENHI Grant Number JP16KK0201This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Intermittent Hypoxia (IH) modulates the effects of Corticotropin‐Releasing Hormone (CRH) on NTS neuronal synaptic transmission
Authors: Jia Shuping , Mifflin Steve 
Published: June 2021

We examined if exposure to IH, a model of the arterial hypoxemia that occurs during sleep apnea, modulates the effects of activation of CRH receptors (CHRRs) on NTS neuronal synaptic transmission. Whole‐cell recordings from NTS second‐order arterial chemoreceptor neurons, identified by DiA labeling of carotid bodies, were obtained in a caudal NTS slices (250μM thick). Slices were incubated with 100nM of the CRHR1 selective agonist stressin I or 100nM of the CRHR2 selective agonist urocortin II in aCSF for 20 minutes and slices studies 0.5–2.0 hrs later. Spontaneous miniature excitatory postsynaptic currents (mEPSCs) and inhibitory postsynaptic currents (mIPSCs) were recorded in separate slices under voltage clamp 0.5–2 hours after the 20min agonist incubation from both normoxic controls and slices obtained from rats exposed to IH for 7 days. The CRHR1 selective agonist and antagonist had no any effect on mEPSC amplitude or frequency. The CRHR2 selective agonist urocortin II significantly increased mEPSC amplitude (21.60 ± 1.03pA, n=13 vs 26.74 ± 1.13pA, n=11, p<0.01) in normoxic rats but did not alter mEPSC frequency. Exposure to IH increased mEPSC amplitude and in IH exposed rats urocortin II prevented the IH‐induced increase in mEPSC amplitude (27.42 ± 1.32pA, n=15 vs 22.35 ± 0.82pA, n=14, p<0.01). On the other hand, the CRHR1 agonist stressin I significantly enhanced mIPSC amplitude in slices from control, normoxic rats (32.57 ± 2.31pA, n=10 vs 38.14 ± 1.4pA, n=12, p<0.05), but neither IH nor stressin I altered mIPSC amplitudes and frequency in slices from IH exposed rats. The CRHR2 agonist did not alter mIPSC frequency or amplitude. In separate experiments, 10min prior to incubation of the slice with the CRHR selective agonist, the slice was pre‐treated with either CRHR1 antagonist NBI35965 (1μM) or CRHR2 antagonist K41498 (100nM). The CRHR2 selective antagonist K41498 attenuated the urocortin II effect on mEPSCs and the CRHR1 antagonist NBI35965 attenuated the stressin 1 effect on mIPSCs. Our findings provide evidence that CRH can modulate NTS neuronal glutamatergic transmission and GABAergic transmission through different CRHR subtypes. After IH, CRHR2 receptor activation reverses IH‐inudced increases in mEPSC amplitude, whereas after IH CRHR1 receptor activation no longer increases mIPSC amplitude. These changes appear to be primarily mediated by alterations in the post‐synaptic neuron.Support or Funding InformationNIH HL088052This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Corticotropin‐Releasing Hormone Receptor 2 in the Nucleus of the Solitary Tract Contributes to the Intermittent Hypoxia Induced Hypertension
Authors: Wang Lei , Nguyen Dianna , Cross Stephanie , Mifflin Steve 
Published: June 2021

Our previous study in rats suggested that Corticotropin‐Releasing Hormone (CRH) Receptor 2 (CRHR2) is the predominant CRH receptor in the nucleus of the solitary tract (NTS), a key nucleus that regulates autonomic and cardiovascular functions; exposure to intermittent hypoxia (IH), a model of the arterial hypoxemias that occur during sleep apnea, significantly decreased CRHR2 mRNA levels in the NTS. To study the CRHR2 signaling pathway in the NTS, we performed calcium imaging on NTS slice preparations using Fura‐2‐acetoxymethyl ester. CRH induced a transient increase of intracellular calcium level in NTS neurons that was abolished by the voltage‐dependent calcium channel blocker nifedipine. Calcium influx was attenuated by the CRHR2 antagonist K41498 but not by NBI‐35965, an antagonist for CRH receptor 1 (CRHR1). Calcium influx can be induced by the CRHR2 agonist Urocortin II but not by the CRHR1 agonist Stressin I. More importantly, consistent with the down‐regulation of CRHR2 mRNA after IH exposure, IH exposure also attenuated the CRH‐induced calcium influx in the NTS. Further in vivo pharmacological studies revealed that intra‐4th ventricle infusion of the CRHR2 agonist Urocortin II significantly increased basal blood pressure and exacerbated the IH‐induced hypertension in rats; intra‐4th ventricle infusion of the CRHR2 antagonist K41498 did not affect the basal blood pressure but significantly delayed the onset of IH‐induced hypertension. Considering that the NTS is the major CRHR2‐expressing nucleus in the brain stem that regulates sympathetic activity and blood pressure, these results indicate that activation of CRHR2 in the NTS contributes to the hypertension during IH. To study the source of CRH in the NTS that regulates blood pressure, we expressed Channelrhodopsin 2 (ChR2) specifically into the CRH‐producing neurons in the paraventricular nucleus of the hypothalamus (PVN) by injecting Cre‐inducible viral constructs expressing ChR2 into the PVN of CRH‐Cre mice. We observed significant pressor responses after optogenetic stimulation of CRH somas in the PVN (12.3 ± 1.13 mmHg) or CRH fibers in the NTS that originated from the PVN (3.54 ± 0.69 mmHg), suggesting that activation of CRH projections from the PVN to the NTS increases blood pressure. Collectively, these results suggest that CRH derived from the PVN activates CRHR2 in the NTS, which may contribute to the IH‐induced hypertension; down‐regulation of CRHR2 and CRHR2‐mediated calcium influx in the NTS may serve as compensatory responses to protect against the IH‐induced hypertension.Support or Funding InformationThis study was supported by National Institute of Health HL088052This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Resting regional brain activity and functional connectivity varies with resting blood pressure but not muscle sympathetic nerve activity in normotensive humans
Authors: Macefield Vaughan Gary , Kobuch Sophie , Henderson Luke Anthony 
Published: June 2021

IntroductionMean arterial pressure (MAP) is tightly controlled by the brain, with the rostroventrolateral medulla (RVLM) ‐ the final output nucleus for muscle sympathetic nerve activity (MSNA) ‐ playing a particularly important role. The aim of this study was to investigate the relationships between regional cerebral blood flow (rCBF) ‐ a proxy marker of neural activity ‐ and MAP and MSNA in young, healthy normotensive subjects.MethodsPseudocontinuous arterial spin labeling (pCASL) and functional magnetic resonance imaging (fMRI) of the brain were performed immediately following a recording of MSNA and BP in 31 normotensive subjects (13 females, 18 males; mean±SE age: 23.3±3.8 y). Subjects were divided into groups with lower (78.8±1.1 mmHg, n=15) and higher (95.9±1.6 mmHg, n=16) MAP, as well as lower (7.5±0.8 bursts/min, n=16) and higher (22.3±1.9 bursts/min, n=15) MSNA.ResultsRegional cerebral blood flow correlated positively with resting MAP in the RVLM and dorsolateral pons, as well as in the insular, prefrontal and cingulate cortices. Furthermore, functional connectivity analysis revealed that the insular and prefrontal cortices displayed greater resting connectivity within the RVLM in the group with lower MAP, but not in the group with higher MAP. However, no significant differences in rCBF were found when subjects were divided on the basis of MSNA.ConclusionsThese results suggest that small differences in resting MAP are associated with significant differences in resting activity and functional connectivity within brain regions known to contribute to cardiovascular control. It remains to be seen how these relationships are affected in hypertensive individuals.Support or Funding InformationNational Health & Medical Research Council of Australia (GTN1100040)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Estrogen Receptor Beta and G‐Protein Coupled Estrogen Receptor are Located and Activated on Microglia by Estrogen
Authors: Dvorak Katherine , Boyer Michael , Barnes Maria J. , Clayton Sarah C. 
Published: June 2021

Upon menopause, women have an increased risk of cardiovascular disease, in part due to the decrease in estrogen production that occurs. While estrogen's cardioprotective effects have been known for many years, the exact mechanism of this protection is still under investigation. Estrogen receptors have been detected in locales in the central nervous system that are critical in the regulation of arterial pressure and sympathetic nervous activity, particularly the rostral ventrolateral medulla (RVLM) and paraventricular nucleus (PVN) of the hypothalamus. Animal models of menopause implicate over activity of the sympathetic nervous system contributes to hypertension. Microglia are believed to be the resident immune cells of the brain. In previous studies, activated glia have been shown to contribute to increased neuronal tone and excitability in the PVN and RVLM and increased sympathetic activity, potentially through the release of pro‐inflammatory cytokines. The role of microglia in hypertension is not clear. The overall objective of these studies is to investigate if estrogen can regulate the activity of microglia. We sought to evaluate how estrogen regulates its cognate receptors using an immortalized microglia 10‐day old female mouse cell line (EOC2). Utilizing immunohistochemical and western blot techniques, our data demonstrate that the microglia cell line expressed estrogen receptor beta (ERβ) and G‐Protein coupled Estrogen Receptor (GPER). Exposing the cells to 10nM of estrogen for 15 minutes demonstrated that estrogen activates the microglia and initiates ERβ translocation from the membrane to the cytosol. We found a dose (1, 10 and 100 nM) and time (5, 15, 30 and 60 minute) dependent change in the protein level of GPER and ERβ. These results demonstrate that estrogen exposure can activate microglial cells and increase expression of estrogen receptors. Future studies will examine if the activation of microglia by estrogen alters the release of cytokines and thus may modulate neuronal function. These findings will contribute to the pivotal role estrogen plays in central blood pressure regulation and will undoubtedly shed light on possible mechanisms of menopause‐induced hypertension.Support or Funding InformationS Clayton DMU IOERM Barnes DMU IOERThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of Chronic Vagal Nerve Stimulation on Glucose Tolerance in Conscious Rats
Authors: Stauss Harald M. , Stangl Hubert 
Published: June 2021

Previously, we demonstrated that cervical vagal nerve stimulation (VNS) inhibits insulin secretion and markedly increases resting blood glucose levels in anesthetized rats. Based on these findings, we hypothesized that chronic cervical VNS induces impaired glucose tolerance in conscious rats.All animal experiments were approved by the Institutional Animal Care and Use Committee of The University of Iowa. Rats were chronically instrumented with telemetric blood pressure sensors inserted into the aorta through the femoral artery and right‐sided cervical vagal nerve stimulators. Three and six days following surgery, repeated glucose tolerance tests (1.5 g dextrose/kg BW, i.p.) were performed after overnight fasting with the vagal nerve stimulators on or off (sham stimulation) in randomized order. VNS (3V, 5Hz, 1ms pulse duration, 1h on 1h off) or sham stimulation was started on the day before the glucose tolerance test. The stimulators were switched to a continuous stimulation mode (instead of 1 h on, 1 h off) for the entire duration of the glucose tolerance tests (2–3 hours) and switched off thereafter. Effectiveness of VNS was confirmed in all animals by the heart rate response to VNS (assessed through the telemetric blood pressure sensors).The study is still ongoing at the time of this writing. Preliminary results from three animals that completed the study so far indicate that baseline blood glucose levels were elevated in animals that received overnight VNS (168±16 mg/dL, n=3) compared to sham stimulated animals (123±15 mg/dL, n=3, P=0.11). The maximal increase in blood glucose levels during the oral glucose tolerance tests (time point 30 min) was greater in rats with VNS (+412±23 mg/dL, n=3) compared to sham stimulated animals (+233±41 mg/dL, n=3, P=0.11). Furthermore, two‐way Analysis of Variance revealed that glucose levels were significantly elevated throughout the 120 min of the glucose tolerance tests in rats with VNS compared to sham‐stimulated animals (P<0.01).These preliminary results suggest that cervical VNS impairs glucose tolerance in conscious rats. It remains to be determined if human patients treated with VNS are at greater risk to develop type 2 diabetes.Support or Funding InformationSupported by a pilot grant from the University of Iowa Hospitals and Clinics Center for Hypertension Research and the German Research Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Thoracic TRPV1 Receptor Spinal Afferent Ablation Prevents the Development and Progression of Hypertension in SHR but Not in Ang II‐infused Rats
Authors: Shanks Julia A. , de Morais Sharon Del Bem Velloso , Wang Hanjun , Zucker Irving H. 
Published: June 2021

Sympatho‐excitation is well described in the pathogenesis of hypertension in both clinical and animal models. Increased sympathetic drive to the heart and alerted cardiac spinal afferent signaling have previously been implicated in contributing to the development and progression of hypertension via the cardiac sympathetic afferent reflex (CSAR). However, the role cardiac spinal afferents play in modulating this response is unknown. To address this, we utilized two rat models of hypertension that have previously been described to have a neurogenic component to their phenotype, the spontaneously hypertension rat (SHR) and angiotensin II (Ang II; 240 ng/kg/min) infusion model. To selectively and chronically ablate the CSAR, the afferent specific neurotoxin, a potent TRPV1 receptor agonist, Resiniferatoxin (RTX) was given epidurally at the level of the T1–T4 dorsal root ganglia (DRG; 6 μg/ml, 10 μl/per ganglion). Blood pressure (BP) was monitored using radiotelemetry in the conscious state before and for 1–2 months post RTX. Echocardiograms were performed on all animals, under 2% isoflurane anesthesia, pre‐treatment and at the end of the study to monitor any changes spinal nerve ablation had on cardiac function. Selective ablation of TRPV1 expressing neurons in the DRG was confirmed by immunohistochemistry. In young (8 week) SHR, T1–T4 RTX abolished the increase in blood pressure (BP) observed in vehicle control animals (n = 6, both groups). Thoracic TRPV1 ablation with RTX in older (16 week) SHR with established hypertension significantly reduced BP compared to control (n = 7, both groups). No change in BP to thoracic RTX was observed in Wistar Kyoto rats (n = 5, RTX and control), RTX had no effect on heart rate in any group. To confirm the BP lowering action of RTX in the SHR was site specific to the T1–T4 thoracic (cardiac) DRG, RTX was administered into the lumbar region of the spinal cord (L2–L5) in 16‐week‐old SHR; no change in BP was observed (n = 5, RTX and control). Epicardial application of RTX in 16 week‐old SHR also failed to significantly reduce BP compared to control (n = 6, both groups). RTX treatment 1 week before (n = 3) or 1 week after (n = 5) Ang II infusion did not alter Ang II‐induced hypertension compared to controls (n=3; n=8, respectively). These data suggest that thoracic spinal afferents contribute to the hypertensive process in SHR. We speculate that the SHR exhibit higher levels of sympatho‐excitation compared to Ang II‐hypertension, thereby responding more effectively to elimination of a sympatho‐excitatory input. From these data, the origin of the afferents is inconclusive.Support or Funding InformationSupported by NIH grant HL 126796 and Sorrento Therapeutics, Inc.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.