bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRPV1 receptor antagonist blunts cholinergic‐mediated sweating
Authors: Mack Gary W. , Kunz Kevin R. 
Published: June 2021

Cholinergic‐mediated primary sweat production requires an increase in Ca++ influx across the epithelial cell membrane of the sweat gland. Several Ca++ channels have been proposed to contribute to the increase in Ca++ influx. We tested the hypothesis that the nonspecific cation channel associated with the TRPV1 receptor, which are located on sweat gland epithelial cells, contributes to the Ca++ influx and thereby local sweat production. We measured local sweat rate (SR) with a 0.7 cm2 capsule placed on the skin overlaying an intradermal microdialysis probe used to deliver 20 mM capsazepine, a TRPV1 receptor antagonist, to the skin in 12 healthy young adults. Two small stainless steel needles were place into the skin (7 mm apart, 2 mm deep) and stimulated at a constant current intensity of 2.5 mA for 30 s at frequencies of 0.2, 1, 2, 4, 8, 16, 32, and 64 Hz to generate a sigmoidal shaped stimulus‐response curve of the area under the SR‐time curve versus log10 of the stimulus frequency before (vehicle control) and following 60 min of 20 mM capsazepine perfusion. The AUC data were normalized to the peak SR response during the control trial. The plateau of the area under the SR‐time curve was higher during control (101 ± 12 % max) than during capsazepine treatment (73 ± 18 % max, p =0.0045) while the EC50 was similar for both trials averaging 10.8 ± 2.1 Hz. The marked reduction in the plateau local sweat rate response supports the hypothesis that the TRPV1 receptor cation channel contributes to Ca++ influx during cholinergic‐mediated sweating.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Neurons in the Ventral Lateral Preoptic (vLPO) Area Inhibit Brown Adipose Tissue (BAT) Thermogenesis
Authors: Conceição Ellen P. , Madden Christopher J. , Morrison Shaun F. 
Published: June 2021

Neurons in the preoptic area of the hypothalamus play important roles in thermoregulation. However, the subregions of the preoptic hypothalamus are heterogeneous, such that neuronal activation at some sites elicits hyperthermia, while others evoke hypothermia. Here we show that in urethane/chloralose‐anesthetized, artificially‐ventilated rats, neurons in the vLPO (0.0 to −1.44 mm caudal to bregma, 0.8 to 1.5 mm lateral to the midline, and −8.0 to 9.8 mm below the dura surface, incisor bar in flat skull position) have a hypothermic effect mediated by inhibition of sympathetic nerve activity (SNA) and BAT thermogenesis. The activation of cvLPO neurons with nanoinjections of NMDA (0.2 mM, 60 nl) evoked a complete inhibition of cold‐evoked BAT thermogenesis: BAT SNA (−97 %, p = 0.01), BAT temperature (TBAT, −0.4 °C, p = 0.01), expired CO2, (Exp CO2, −0.4 %, p = 0.0004), mean arterial pressure (MAP, −9 mmHg, p = 0.01) and heart rate (HR, −53 bpm, p = 0.0005). Similar BAT sympathoinhibitory responses were obtained with nanoinjections of bicuculline (BIC, 1.0 mM, 60 nl) in the vLPO. Under thermoneutral conditions, the inhibition of cvLPO neurons by activation of local GABAA receptors (muscimol, 1.2 mM, 60 nl) increased BAT SNA (+99 % p = 0.0001), TBAT (+2.2 °C, p = 0.0001), Exp CO2 (+1.0 %, p = 0.00003), and HR (+58 bpm, p = 0.007), with no change in MAP (p = 0.5). Nanoinjections of muscimol, or the glutamate receptor antagonists, AP5/CNQX, in the dorsomedial hypothalamus (DMH), or in the rostral raphe pallidus (rRPa), reversed the activation of BAT thermogenesis evoked by inhibition of vLPO neurons. Activation of neurons in vLPO inhibited the BAT thermogenesis evoked by BIC nanoinjections in the DMH, but not the increase in BAT SNA evoked by BIC nanoinjections in the rRPa. We conclude that vLPO contains BAT sympathoinhibitory neurons that mediate the warm ambient‐evoked inhibition of BAT thermogenesis through a direct or indirect GABAergic input to rRPa. Similarly to the cold‐evoked activation of BAT thermogenesis, that following inhibition of vLPO neurons requires the glutamatergic, BAT sympathoexcitatory pathway from DMH to BAT sympathetic premotor neurons in rRPa. These novel findings a key population of BAT sympathoinhibitory neurons in the central pathway mediating the skin warming‐evoked inhibition of BAT thermogenesis, requiring the addition of a BAT sympathoinhibitory pathway between vLPO and rRPa to the current model of central autonomic thermoregulation.Support or Funding InformationThis work was supported by NIH R01‐NS091066 (S.F.M.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ventral Lateral Preoptic (vLPO) Neurons Inhibit Brown Adipose Tissue Thermogenesis during Warming of the Preoptic Area
Authors: Mohammed Mazher , Madden Christopher J. , Morrison Shaun F. 
Published: June 2021

Brown adipose tissue (BAT) and shivering thermogenesis and cutaneous vasoconstriction are inhibited in warm climatic conditions to reduce heat production and increase heat dissipation, thereby maintaining core body temperature homeostasis. We tested the hypothesis that the hypothalamic preoptic area (POA) contains warm sensitive neurons (WSNs) that are activated by local warming to produce inhibition of BAT activity. In urethane/α‐chloralose‐anesthetized, artificially‐ventilated rats, warming the POA bilaterally with a thermode (two silver rods connected to a peltier device) increased POA temperature from 35 to 40°C and promptly inhibited skin cooling (35–36°C)‐evoked BAT sympathetic nerve activity (SNA) (from 1061±2.7 to 102±0.1 that corresponds to 100% reduction, p<0.001) and reduced BAT temperature (1.7±0.2, p<0.001), core temperature (0.3±0.1, p<0.05), expired CO2 (0.7±0.1%, p<0.001), heart rate (61±10, p<0.001) and mean arterial pressure (14±6, p<0.05). Bilateral nanoinjections of the GABAA‐agonist, muscimol (500 mM, 100 nl), into the ventral lateral preoptic area (vLPO) prevented (p<0.001) the local POA warming‐induced inhibition of BAT SNA and the reductions in BAT and core temperatures. Blockade of ionotropic glutamate receptors in vLPO with nanoinjections of AP5/CNQX also prevented (p<0.001) the local POA warming‐induced inhibitions of BAT thermogenesis. POA warming failed (p>0.05) to inhibit the elevated BAT SNA following blockade of local GABAA receptors with nanoinjections of bicuculline (BIC) in the rostral raphe pallidus (rRPa), but still effectively inhibited the elevated BAT SNA following BIC nanoinjections in the dorsomedial hypothalamus (DMH). Our results demonstrate that the POA warming‐evoked inhibition of BAT thermogenesis requires activation of GABAA receptors in rRPa, but not those in DMH. In addition, the finding that glutamate receptor blockade in vLPO prevents the POA warming‐induced inhibition of BAT activity, is consistent with WSNs glutamatergically exciting BAT sympathoinhibitory neurons in vLPO to produce the POA warming‐induced inhibition of BAT thermogenesis. These novel findings elucidate the central pathway mediating POA warming‐evoked inhibition of BAT thermogenesis and require the addition of a BAT sympathoinhibitory pathway between vLPO and rRPa to the current model of central autonomic thermoregulation.Support or Funding InformationSupported by NIH R01091066 (SFM).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sympathetic Nerve Fibers within the Cervical Vagus Nerve Do Not Innervate the Heart
Authors: Migirov Allan , Siano John , Dedkov Eduard I. , Zhang Youhua 
Published: June 2021

IntroductionChronic cervical vagus nerve stimulation has been introduced as a novel therapy for various diseases, including refractory epilepsy and chronic heart failure. Although it has been shown that the cervical vagus nerve contains sympathetic fibers, whether or not these sympathetic fibers innervate the heart is a subject of debate.MethodsDiI, a plasma membrane lipophilic fluorescent dye (neuronal tracer) was applied on the epicardial surface of the heart at the right atrium‐right pulmonary vein junction and at the inferior vena cava and left atrium junction (these locations are known to have epicardial ganglia) in 4 rats to trace the nerve fibers innervating the heart. Two rats without DiI application served as controls. Right cervical vagus nerves were harvested 1 week after DiI application or sham surgery and processed for frozen histological sections. All sympathetic fibers in the cervical vagus nerve were visualized by immunostaining with anti‐tyrosine hydroxylase antibody, whereas those nerve fibers innervating the heart were expected to carry a fluorescent DiI dye.ResultsAs shown in the figure, there were a few fibers stained with DiI (red color) in the cervical vagus nerve, which were not detected in controls. Sympathetic fibers in the vagus nerve (green color) were present in all animals. However, there was no overlap of the sympathetic fibers and DiI labeled nerve fibers in the vagus nerve.ConclusionsCervical vagus nerve contains sympathetic nerve fibers, however, these fibers do not innervate the heart.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Greater Beat‐To‐Beat Resting Blood Pressure Variability in Young Healthy African American Men
Authors: Young Benjamin E. , Vranish Jennifer R. , Peper Sara E. , Wang Jing , Keller David M. , Fadel Paul J. 
Published: June 2021

It is well documented that African Americans (AA) are at a greater risk for the development of hypertension than Caucasian Americans (CA). Our laboratory has recently demonstrated exaggerated transduction of sympathetic nerve activity to blood pressure (BP) in young, healthy AA men compared to CA men. The influence of this greater sympathetic vascular transduction on BP variability is unclear. Although previous studies have reported greater BP variability in AA than CA based on 24‐hr ambulatory BP measurements, to date, no studies have investigated resting BP variability on a beat‐to‐beat basis in AA. Thus, we tested the hypothesis that young AA men would exhibit greater beat‐to‐beat BP variability in comparison to CA men. Heart rate (ECG), and beat‐to‐beat arterial BP (finger photoplethysmography) were continuously measured during a 20‐minute resting period in young, healthy CA (n=15) and AA (n=14) men. The arterial BP waveform was analyzed via Modelflow to estimate stroke volume, and used to calculate cardiac output (CO) and total peripheral resistance [TPR: mean arterial pressure (MAP) divided by CO]. Variance, range, and interquartile range were calculated for MAP, CO and TPR. Data are presented as mean ± standard error (SE). Despite similar average absolute resting systolic BP, diastolic BP, and MAP, compared to CA, AA exhibited larger MAP variance (CA: 19.2±2.6 mmHg2, AA: 32.3±4.0 mmHg2, p=0.009). In addition, the range (CA: 26.9±2.0 mmHg; AA: 33.2±1.8 mmHg, p=0.03) and interquartile range (CA: 5.7±0.4 mmHg; AA: 7.6±0.5 mmHg, p=0.007) of MAP were greater in AA than CA. Similar results were found for both systolic BP and diastolic BP. Interestingly, the variance of CO was not significantly different between groups (P=0.63), whereas the variance of TPR was significantly greater in AA than CA (P=0.03). Likewise, the TPR (but not CO) range, and interquartile range were greater in AA than CA. These findings demonstrate that, relative to CA, AA exhibit greater beat‐to‐beat BP variability which appears to be related to greater variability in TPR. Overall, these greater fluctuations in resting BP may constitute a source of future cardiovascular risk in AA men, and predispose them to the development of hypertension.Support or Funding InformationSupported by NIH R15 HL130906.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Differential effects of osmotic stress on synaptic vs. paracrine signaling mechanisms in oxytocinergic magnocellular neurons.
Authors: Frazier Charles Jason , Sheng Wanhui , Harden Scott W. 
Published: June 2021

Acute hypernatremia promotes natriuresis in part by increasing activity of oxytocinergic magnocellular neurons in the hypothalamus that promote synaptic release of oxytocin (OT) from axon terminals in the neurohypophysis. Acute hypernatremia also blunts stress‐induced activation of the hypothalamic‐pituitary‐adrenal axis via a mechanism that we believe is likely to depend on central paracrine (rather than synaptic) release of OT from magnocellular dendrites. Interestingly, prior work from other groups indicates that acute hypernatremia produces an increase in the concentration of circulating OT significantly more rapidly than it creates an increase in the concentration of central OT. The current project was designed to develop a better understanding of the underlying cellular mechanisms through which osmotic stressors may plausibly promote both synaptic and paracrine release of OT from the same population of osmosensitive hypothalamic neurons, but with distinctly different temporal dynamics. Towards that end, we used the Cre‐LoxP system to generate OT‐reporter mice that express tdTomato in neurons that synthesize OT. Initial studies indicated a strong colocalization of tdTomato with OT/neurophysin1 throughout the hypothalamus. Whole‐cell patch clamp recordings from tdTomato positive magnocellular neurons in the paraventricular nucleus of the hypothalamus revealed expected intrinsic properties, including transient outward rectification produced by a prominent A‐type K+ current (IA). Initial imaging studies revealed that the dendrites of OT positive magnocellular neurons are passive conductors, with robust activity dependent dendritic calcium influx that diminishes substantially with increasing distance from the soma. Bath application of an external osmolyte (15 mM mannitol) produced a clear increase in the frequency of spontaneous action potentials observed in OT positive magnocellular neurons, and yet intriguingly, also produced a clear decrease in activity dependent dendritic calcium influx. This effect was also much more prominent in distal dendrites than in proximal dendrites, consistent with a mechanism that depends on decreased dendritic input resistance. Also consistent with that interpretation, we found that acute application of 15 mM mannitol significantly reduces the amplitude of evoked glutamatergic EPSCs recorded at the soma, as produced by a small theta glass stimulator placed near the distal dendrites. Interestingly, preliminary data suggest that parvocellular OT neurons lack similar osmosensitivty. Collectively, these results provide a partial mechanistic explanation for why acute osmotic stress is likely to initially favor synaptic over paracrine release of OT from osmosensitive hypothalamic magnocellular neurons.Support or Funding InformationSupported by NIMH R0104641This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Presynaptic large‐conductance calcium‐activated potassium channels modulate GABAergic inhibitory synaptic transmission in the superficial dorsal horn of the mouse
Authors: Fukushima Teruyuki , Hori Yuuichi 
Published: June 2021

Large‐conductance calcium‐dependent potassium (BK) channels are found in various tissues, including nerve, smooth and skeletal muscles, and other cell types. They are potassium‐selective ion channels that are activated in response to increased intracellular calcium concentrations and transmembrane voltages.We previously reported that the BK channels that are located in presynaptic terminals control excitatory synaptic transmission in the superficial dorsal horn (SDH), and that functional downregulation of BK channels accompanies the neuropathic pain induced by peripheral nerve injury.In the present experiments, we attempted to clarify the physiological significance of BK channels in the modulation of GABAergic inhibitory synaptic transmission in the SDH where nociceptive information is processed.Spontaneously occurring GABAergic miniature inhibitory postsynaptic currents (mIPSCs) were recorded from the GFP‐negative neurons located in the SDH of a mouse spinal cord slice by using slice preparations from adult glutamate decarboxylase 67‐green fluorescent protein (GAD67‐GFP) knock‐in mice, and the effects of Iberiotoxin, a BK channel blocker, on the GABAergic mIPSCs were analyzed.Iberiotoxin increased the frequency of GABAergic mIPSCs without affecting the amplitude of GABAergic mIPSCs, suggesting that the activation of BK channels attenuates GABAergic synaptic transmission via presynaptic mechanisms.In order to clarify the role of BK channels in the nociceptive information processing which is modulated by GABAergic transmission, we are currently doing the similar experiments using peripheral nerve‐ligated neuropathic mice.Those results may provide clues for the underlying mechanisms of the nociceptive actions of BK channels in the SDH.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Leptin Activates Transient Receptor Potential Melastatin 7 (TRPM7) Channels in Mouse Glomus Cells and Leptin‐Receptor Expressing Pheochromocytoma Cells
Authors: Mu Yun‐Ping , Caballero‐Eraso Candelaria , Liu Xiao‐Ru , Shin Mi‐Kyung , Paudel Omkar , Yeung Bonnie , Tang Wan‐Yee , Shirahata Machiko , Polotsky Vsevolod , Sham James 
Published: June 2021

Obesity is a leading cause of high cardiovascular morbidity and mortality. It is characterized by an increased leptin level, which has been implicated in increased sympathetic activity and the pathogenesis of hypertension. However, the mechanism by which leptin enhances sympathetic activity is unclear. Leptin receptors (LEPRs) are expressed in the carotid body, the most important arterial chemoreceptor for the cardio‐respiratory chemoreflex. We have previously demonstrated that leptin enhances carotid sinus nerve activity in response to hypoxia; this effect is abolished by non‐selective blockers of transient receptor potential (TRP) channels; and the TRPM7 channel is the most abundant TRP subtype expressed in CB (Shirahata et al., Adv Exp Med Biol. 2015;860:153–9). Since leptin is known to regulate many different ion channels, we hypothesize that leptin may exert its effects through modulation of TRPM7 channel activity. To test this hypothesis, we used glomus cells isolated from the carotid bodies of C57BL/6 mice and the LEPR (LEPRb) expressing pheochromocytoma (PC12LEPRb) cells, which express a high level of TRPM7 channels, as a cell model. Non‐selective cation channels were recorded under amphotericin‐B perforated‐patch techniques with K+ replaced by Cs+ in the presence of voltage‐gated Ca2+ channel and Cl− channel blockers. In the glomus cells, voltage‐ramp from −100 to 100 mV activated a small outwardly rectifying current. Application of leptin 100 ng/ml caused a significant increase in both the outward and inward component of the current, which was completely reversed by the subsequent addition of the TRPM7 antagonist FTY720. In the PC12LEPRb cells, the specific TRPM7 agonist naltriben caused significant increase of a similar outwardly rectifying current, which was abolished by the TRPM7 antagonists NS8593 and FTY720. Leptin at concentration of 10–100 ng/ml caused concentration‐dependent increase in the current, which again was completely blocked by NS8593 and FTY720. These results for the first time demonstrated that stimulation of leptin receptor in both the native glomus cells and the PC12LEPRb cell is capable of activating TRPM7 channels, and suggest that leptin may exert its effect on the carotid body through modulation of TRPM7 activity.Support or Funding InformationThis work is supported by HL133100This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Influence of Sugar and Artificial Sweeteners on Vascular Health during the Onset and Progression of Diabetes
Authors: Hoffmann Brian Robert , Ronan George , Haspula Dhanush 
Published: June 2021

As diabetes and obesity become a rising worldwide heath concern there has been an increased awareness of environmental factors, such as diet, that are contributing to the problem. The negative implications of consuming high amounts of dietary sugar on overall health have long been linked to diabetes, obesity, cardiovascular disease, and other systemic health problems. However, it was not until recently that the negative impact of consuming non‐caloric artificial sweeteners in the place of sugar had been increasingly recognized as a potential contributor to the dramatic increase in diabetes and obesity, along with the associated complications. This study tested the response of the vascular endothelium in vitro and the in vivo response of a diabetes susceptible BB‐DR rat model to glucose, aspartame, and acesulfame potassium supplementation through the use of high‐throughput ‘omics' analyses coupled with functional testing. We have demonstrated that an acute in vitro treatment of rat microvascular endothelial cells with high glucose (25 mM) results in impairment of through glycosylation as exhibited by a restored function with PNGaseF enzymatic removal of N‐glycosylations (p<0.05). Conversely, artificial sweetener treatments also exhibited endothelial impairment in an in vitro tube formation assay (p<0.05); however, gene expression analyses suggested the mechanisms of dysfunction were through different mechanisms than the glucose treatment. Furthermore, through a site‐specific proteomic analysis we have identified 87 proteins significantly increased in N‐glycosylation and 143 in O‐glycosylation (p<0.05) on the endothelial cell surface following high glucose treatment as compared to normal glucose (4.5 mM); many targets related to vascular homeostasis. Those experiments have been supplemented with a comprehensive metabolomics analysis of plasma from an acute three week study on diabetes susceptible BB‐DR rats fed a high glucose, aspartame, or acesulfame potassium diet. Through this set of experiments we have identified unique signatures of alterations in lipid metabolism, among others, following artificial sweetener consumption. Overall, results of this study suggests that exposure to high glucose and artificial sweetener administration lead to unique mechanisms of vascular impairment and homeostatic alterations that may be important during the onset and progression of diabetes and obesity.Support or Funding InformationSupport for this project has been provided by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (K01‐DK105043 to BRH) and the Department of Biomedical Engineering at the Medical College of Wisconsin and Marquette University, Milwaukee, WI, USA.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.