bluuebunny/crossref_metadata_2025 huggingface dataset:
Unrestrained Barometric Plethysmography During Air and Hypoxic Exposures in Old Mice Fed a Capsaicin Rich or Control Diet
Authors: Russell Jacob D , Receno Candace N , Cunningham Caitlin M , Deruisseau Keith C , Deruisseau Lara R
Published: June 2021

Capsaicin is the primary active ingredient in chili peppers and is an agonist for transient receptor potential vanilloid 1 (TRPV1). TRPV1 receptors are found in mammalian respiratory airways and pleural afferents (Takemura, 2008). The stimulation of these receptors by capsaicin augments respiratory responses in anesthetized mice with low doses (Roy, 2012) and increases breathing frequency of anesthetized mice upon intracarotid injection (Wang, 2006). Because pulmonary functions tend to deteriorate with age, our study aimed to examine the effects of dietary capsaicin on the respiratory response of aged mice. We hypothesized old mice fed capsaicin would display maintained ventilation compared to mice fed a control diet. Unrestrained barometric plethysmography (UBP) was used to quantify breathing frequency (F, breaths/min), tidal volume (VT, mL/breath), minute ventilation (VE, mL/min), ratio of VT to inspiration time (VT/IT, mL/sec), and the ratio of VE to expired carbon dioxide (VE/VCO2) in mice breathing air (20.93% O2 and .05% CO2) and exposed to hypoxic conditions (10 % O2, 0 % oxygen) for 15 minutes. C57BL/6J male mice were tested at 22 months of age prior to any dietary intervention and again at 23 months of age after one month of a lecithin control diet (CON; 50mg/kg per food weight; n=12) or a capsaicin rich diet (CAP; 50mg/kg per food weight; n=10). Data are presented as % change from pre‐values at 22 months of age; mean±SD. There were no differences between groups (p>0.05) with air exposure for F (CON: −3.7 ± 26.9% vs CAP: 19.5 ± 51.7% breaths/min), VT ( CON: 13.8 ± 40.9% vs. CAP: −3.7% ± 22.4% mL/breath), VE (CON: 3.1 ± 35.6% vs. CAP: 16.0 ± 53.2% mL/min), VT/IT (CON: 55.6 ± 89.6%vs. CAP: 37.8 ± 109.1% mL/sec), or VE/VCO2 (CON: −13.7 ± 45.4% vs. CAP: 11.0 ± 72.1%). Hypoxic exposure revealed no differences (p>0.05) between groups for F (CON: −1.0 ± 23.0% vs. CAP: 6.3 ± 24.9% BPM), VT (CON: 29.0 ± 60.5% vs. CAP: 28.1 ± 49.8% mL/breath), VE (CON: 13.4 ± 33.2% vs. CAP: 17.8 ± 36.6% mL/min), VT/IT (CON: 11.4 ± 29.6% vs. CAP: 12.7 ± 48.3% mL/sec), or VE/VCO2 (CON: −15.1 ± 38.6% vs. CAP: 10.5 ± 65.6%). Therefore, our hypothesis was not supported as there were no differences between CON and CAP respiratory responses. We conclude that 50mg/kg of capsaicin in the diet does not alter ventilation in old mice.

Support or Funding Information

JDR supported by the McDevitt Undergraduate Research Fellowship in Natural Science and CNR supported by 1 R15 HD076379‐01A1S1

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Involvement of the opioid system in the 17β‐estradiol‐induced enhancement of sucrose intake in ovariectomized rats
Authors: Iida Kurumi , Kanamori Konomi , Kondo Sayaka , Izumi Ayana , Morimoto Keiko , Takamata Akira
Published: June 2021

We previously found that 17β‐estradiol (E2) replacement in ovariectomized rats enhanced progressive increase in 10% sucrose solution intake. In the present study, we hypothesized that the E2‐induced enhancement of sucrose intake is mediated by the opioid system, which is known to play an important role in excessive intake of highly palatable foods. Female Wistar rats were ovariectomized and those rats were assigned to the E2‐treated group (E2 group) or cholesterol‐treated group (Veh group). In the experiment 1, we examined the effect of naltrexone (NTX), an opioid receptor antagonist, on intake of sucrose solution. In this experiment, rats were continuously infused with NTX or saline by an osmotic minipump, and intake of 10% sucrose solution was measured for 14 days. The NTX treatment reversed E2‐induced enhancement of sucrose solution intake. In the experiment 2, we investigated whether the μ‐opioid receptors in the nucleus accumbens (NAc) is involved in the effect of E2‐induced enhancement of sucrose intake. We performed microinjections of a μ‐opioid receptor agonist D‐Ala2, NMe‐Phe4, Glyol5‐enkephalin (DAMGO), NTX or saline into the nucleus accumbens (NAc) in each rat. After microinjections, rats were tested the two‐bottle choice paradigm with 10% sucrose solution and water. Injection of NTX in the NAc reduced sucrose intake in the both groups, and the intake was not different between the groups. These results suggest that the E2‐induced enhancement of sucrose intake is possibly mediated by the opioid system. Also, the opioid receptors in the NAc is a potential site of the action of the E2‐induced enhancement of sucrose intake.

Support or Funding Information

JPSP KAKENHI #15K12355 and 24500975 to Akira Takamata

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Obesity by High Fat Diet Decreases the Abundance of MC4R Protein in the Paraventricular Nucleus of the Hypothalamus without Reducing the Number of MC4R Neurons
Authors: Nyamugenda Eugene , Russell Susan , Cooney Kimberly , Griffin Haven , Hoang Vincent Ngoc , Phelan Kevin D. , Baldini Giulia
Published: June 2021

The hypothalamus plays a central role in maintaining normal energy homeostasis. The arcuate nucleus (ARC) of the hypothalamus receives anorexigenic signals from the periphery mediated by increased circulating leptin and insulin, which bind to receptors expressed by proopiomelanocortin (POMC) neurons in the ARC. When activated, POMC neurons projecting to the paraventricular nucleus (PVN) of the hypothalamus release α‐Melanocyte‐stimulating hormone (α‐MSH) at this location. In the PVN, α‐MSH binding to the melanocortin 4 receptor (MC4R) signals to decrease food intake and increase energy expenditure. Exposure to HF diet induces, in male, but not female mice, injury to POMC neurons with neuronal loss and loss of α‐MSH abundance. It remains unclear whether other types of hypothalamic neurons are also being affected by exposure to HF diet. In this respect, we have found that exposure to HF diet induces loss of Single‐Minded Family BHLH Transcription Factor 1 (Sim1) neurons in the PVN of male and female mice. Sim1 neurons in the PVN include the population of MC4R neurons. Here we asked whether in the PVN of mice exposed to HF diet there is a loss of MC4R neurons and/or decreased abundance of MC4R protein. When exposed to HF diet, male and female Sapphire mice expressing GFP under the MC4R have increased body weight as compared to the control mice fed low fat (LF) diet (by 39.03 ± 5.37% and 24.19 ±4.18%, respectively). Both male and female Sapphire mice exposed to HF diet have the same number of MC4R neurons as compare to controls exposed to LF diet. These data indicate that MC4R neurons are resistant to HF diet. To test whether exposure to HF diet reduces the abundance of MC4R protein, we generated knock‐in mice with human influenza hemagglutinin (HA) epitope tag at the C‐terminus of endogenous MC4R (MC4R‐HA mice). As compared to control, male and female MC4R‐HA mice exposed to HF diet had increased body weight (by 53.84 ± 7.00% and 45.57 ± 6.23% respectively), increased caloric intake by (39.28 ± 16% and 37.52 ± 10.85%, respectively) and reduced MC4R protein abundance in the PVN (by 63.27 ± 18.54 % and 67.77 ± 18.00 %). The data indicate that loss of MC4R protein, rather than of MC4R neurons, is a feature of male and female mice exposed to HF diet, thereby suggesting expression of MC4R as a target for anti‐obesity therapy.

Support or Funding Information

This work was supported by National Institutes of Health Grants R01‐DK102206 (to G.B.), by UL1TR000039, and by Intramural Funding Support from the University of Arkansas for Medical Sciences College of Medicine Research Council.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mechanism of action of catestatin as an autocrine modulator regulating catecholamine secretion from chromaffin cells at the of splanchnicoadrenomedullary synapse
Authors: Mahata Sushil Kumar , Sahu Bhavani Shankar , Mahata Sumana , Bandyopadhyay Keya , Mahata Manjula , Webster Nicholas J.G. , Eiden Lee E
Published: June 2021

Objective

The chromogranin A (CgA)‐derived peptide catestatin (CST: human CgA352–372) is thought to act as an autocrine modulator of catecholamine secretion from the adrenal medulla in vivo. Here, we examined how CST affects nicotine‐ and PACAP‐induced secretion from, and protein resynthesis within, dense core (DC) vesicle (DCV) quanta containing catecholamines and chromogranin/secretogranin proteins in PC12 cells.

Methods and Results

Depletion of norepinephrine (NE) from PC12 cells treated acutely (0.5 hours) with either nicotine (60 μM)‐ or PACAP (0.1 μM) was reversed by CST (2 μM), as was 3H‐NE release elicited by both secretagogues. DCV and DC area and diameter, evaluated by Transmission Electron Microscopy, were both decreased after treatment with either nicotine or PACAP, and this morphological effect was likewise reversed by CST. Nicotine or CST alone increased expression of CgA protein (but not CgB), and, in combination, elicited an additional increase in CgA protein, implying that nicotine and CST utilize separate signaling pathways to activate expression of CgA. In contrast, PACAP increased expression of CgB protein (but not CgA), indicating differential regulation of CgA and CgB proteins by cholinergic and peptidergic stimulation. Although CST augmented expression of tyrosine hydroxylase (TH) protein, it did not induce synthesis of catecholamines, presumably due to its inability to cause post‐translation activation of TH via serine phosphorylation. Increased area and diameter of DCVs, and their DCs after CST, CST+nicotine and CST+PACAP are consistent with increased quantal size. Decreased quantal size is possibly mediated by increased synthesis of granulogenic proteins: CgA after CST treatment; CgA after CST+nicotine treatment; and CgB after CST+PACAP treatment.

Conclusion

Based on our results obtained in PC12 cells, we suggest that the CgA‐derived peptide CST acts as a paracrine factor during ACh or PACAP stimulation of secretion from chromaffin cells of the adrenal medulla, modulating both the extent of secretory stimulation by splanchnic nerve firing, and the repletion of secretory granule content after bouts of secretory activity.

Support or Funding Information

Supported by grants from the VA (I01BX000323 to S.K.M.; I01BX002709 to N.J.G.W), and the NIH (MH002386 to L.E.E.).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Progesterone Induces Neuroprotection in a Model of Neonatal Hypoxic‐Ischemic Brain Injury
Authors: Tassinari Isadora D’Ávila , Fabres Rafael Bandeira , de Menezes Camboim Yahi , de Araujo Elcyus Boff Marques , Nunes Ricardo Ribeiro , Andrade Mirella Kielek Galvan , Rodrigues Thais Lopes , Netto Carlos Alexandre , Ribeiro Maria Flavia Marques , de Fraga Luciano Stürmer
Published: June 2021

Neonatal hypoxic‐ischemic encephalopathy (HI) is a major cause of neurologic deficits in newborns. Since administration of progesterone (PROG) has shown neuroprotective effects in adult models of nervous system injury, we evaluated the effects of PROG in a model of neonatal HI.

Seven‐days‐old rats (n=6) were subjected to a surgery for ligation of the common right carotid artery followed by exposure to an hypoxic atmosphere (8% of oxygen) for 60 min. PROG (10 mg/kg) was administered before and/or after HI. Rats were euthanized one week after HI and their brains were processed for histology or Western blot analysis. Hemispheric and hippocampal volumes were measured and apoptotic cells were counted in the CA1 and CA3 areas of the hippocampus. Proteins involved in cell death and survival (caspase‐3 and Akt) were also analyzed. This study was approved by the local Institutional Animal Care and Use Committee (UFRGS #26669; HCPA #140578).

The hemispheric and hippocampal lesion caused by HI was reduced by PROG treatment. The number of apoptotic cells in CA1 and CA3 areas was also decreased by PROG administration. Expression of p‐Akt was unaffected by HI but was significantly increased in the hippocampus of PROG‐treated animals. Moreover, administration of PROG reduced hippocampal cleaved caspase‐3 expression.

In summary, PROG administration reduced brain damage and neuronal apoptosis in neonatal animals submitted to HI. This neuroprotective effect is probably related to the capability of PROG in regulating caspase‐3 and Akt signaling pathways.

Support or Funding Information

This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq‐Brazil), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES‐Brazil), Pró‐Reitoria de Pesquisa (PROPESQ/UFRGS‐Brazil), and Fundo de Incentivo à Pesquisa e Eventos do Hospital de Clínicas de Porto Alegre (FIPE/HCPA‐Brazil).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Exposure to environmentally relevant concentration of second hand smoke increased blood pressure and decreased baroreflex sensitivity in mice
Authors: Pan Shiyue , Karey Emma , Chen Yi‐Je , Nieves‐Cintron Madeline , Pinkerton Kent E , Chen Chao
Published: June 2021

BACKGROUND

Second hand smoke (SHS), a main indoor air pollution, is a significant risk factor for cardiovascular morbidity and mortality. Epidemiological studies link SHS exposure to increased sympathetic nerve activity (SNA) and blood pressure (BP), suggesting a central component in SHS‐induced cardiovascular dysregulation. However, we have limited information on effects of SHS on baroreflex sensitivity (BRS), an indicator of central regulation of BP and a stronger link to cardiovascular morbidity and mortality than the elevated BP. Additionally, we lack information on whether exposure to environmentally relevant levels of SHS affects BP regulation. Here we sought to test the hypothesis that chronic exposure to an environmentally relevant level of SHS elevates BP and reduces BRS.

METHODS

Adult male C57BL/6J mice (11 wk old) were implanted with BP/ECG telemetry devices. After two weeks of recovery from surgery, mice were randomly assigned to either filtered air (FA, n=18) or SHS (n=14) for up to 12 weeks. The SHS exposure level was similar to that of a smoky bar (3 mg/m3, 6 hr/d, 5 d/wk). 36 hours of continuous BP and ECG recordings were performed after the 5th day of exposure each week. Data were divided into three 12‐hr periods based on light cycle: dark 1, light and dark 2. Standard deviation of beat‐to‐beat BP was taken as the BP variability (BPV). BRS was determined with the sequence method using systolic BP.

RESULTS

There was no difference in body weight between FA‐ and SHS‐exposed mice over the 12‐wk period. SHS exposure had no effect on dark‐light difference in BP, BPV, and BRS. Comparing to FA mice, SHS mice had higher systolic BP (~2.4 mmHg, p < 0.05), mean BP (~3 mmHg, p <0.05), and diastolic BP (~4 mmHg, p < 0.05) by 4 weeks of exposure. SHS reduced pulse pressure (PP, ~2 mmHg, p < 0.05), although the magnitude of the reduction diminished over time. In contrast, the SHS‐induced reduction in BRS was time dependent and accumulative, having a slower onset than changes in BP and PP, and becoming more severe with increasing exposure duration (−0.8%, −6.2%, and −12.3% for 4, 8, and 12 wk, respectively). SHS did not change BP variability, regardless of exposure duration.

CONCLUSIONS

The effect of SHS on increased BP was observed after 4 wk of exposure and sustained through 12 wk of exposure. In contrast, SHS‐induced reductions in BRS showed a delayed onset that accumulates with prolonged exposures. The data suggest that SHS may activate multiple mechanisms resulting in BP dysregulation.

Support or Funding Information

R01 ES025229

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of Sex on Cardiovascular Responses to Acute Sympathoexcitatory Stressors
Authors: Coovadia Yasmine , Adler Tessa Evangeline , Usselman Charlotte Willemina
Published: June 2021

Over the past twenty years, an increasing number of studies have compared baseline cardiovascular regulation between men and women. These studies have provided strong support for an effect of sex on cardiovascular outcomes, and implicate the sympathetic nervous system as a mediator of many of these differences. However, many of these studies have been conducted under baseline conditions, despite the fact that humans are seldom in a true “baseline” state (i.e., quiet, supine rest). Therefore, the purpose of this study was to investigate the effect of sex on cardiovascular responses to sympatho‐excitatory stimuli in young healthy individuals. We examined cardiovascular responses to the cold pressor test (CPT) and a voluntary end‐expiratory apnea (APN) in 5 women and 4 men. We hypothesized that women would demonstrate a reduced change in total peripheral resistance (TPR) and therefore blood pressure (BP) responses to these stimuli compared with men. Men and women were of similar age (men: 24 ± 2 y, women: 24 ± 1; p=0.8) and BMI (men: 26 ± 6 kg/m2, women: 22 ± 1; p=0.2). Baseline mean arterial pressure (MAP) was higher in men than women (87 ± 7 vs77 ± 4 mmHg, respectively; p=0.03), while baseline TPR (men: 25.7 ± 2.7 vs women: 23.2 ± 6.6 mmHg/L/min; p=0.5) and cardiac output (3.4 ± 0.4 vs 3.5 ± 0.9 L/min; p=0.9) were similar between the sexes. CPT was associated with a significant increase in MAP from baseline which was not different between the sexes (men: 90 ± 3 vs women: 92 ± 13mmHg; main effect of condition: p=0.03, effect of sex: p=0.7). Likewise, TPR increased in response to CPT, but again this response did not differ between the sexes (men: 27.0 ± 7.1, vs women: 25.8 ± 5.4 mmHg/L/min; main effect of condition: p=0.04, effect of sex: p=0.3). APN‐EX was associated with a similar increase in DBP (men: 83 ± 6 vs women: 69 ± 25 mmHg; main effect of condition: p=0.03, effect of sex: p=0.3) as well as TPR (men: 33.0 ± 4.8 vs women: 29.0 ± 13.9 mmHg/L/min; main effect of condition: p=0.01, effect of sex: p=0.6). In conclusion, cardiovascular responses to the CPT, a generalized sympathetic stressor, as well as to APN, which activates the chemoreflex, were similar between the young healthy men and women. These data refute our hypothesis, and suggest that cardiovascular responsiveness during these sympatho‐excitatory stimuli does not differ between the sexes.

Support or Funding Information

This project was supported by a Natural Sciences and Engineering Research Council Discovery Grant (CWU). TEA and YC were supported by the McGill Department of Kinesiology and Physical Education Graduate Excellence Fellowship.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Muscle Sympathetic Nerve Activity Responses to Hypercapnia in Exercise Trained and Sedentary Adults
Authors: Eisenmann Nicole A , Howery Anna J , Harvey Ronee E , Barnes Jill N
Published: June 2021

Elevated activity of the sympathetic nervous system at rest and sympathetic hyperreactivity to stress have been shown to be predictors for the development of cardiovascular diseases, such as hypertension. Previous studies have shown that there is no difference in resting muscle sympathetic nerve activity (MSNA) with exercise in young adults; however, the effects of exercise on the sympathoexcitatory response to chemical stimuli, such as hypercapnia, have not been studied. The purpose of this study was to compare MSNA responses to hypercapnia in young exercise trained and sedentary adults. Twenty‐nine young healthy adults were evaluated including 16 exercise trained (EX: M/F = 7/9; age = 27 ± 5 years; BMI = 23 ± 2 kg/m2) and 13 sedentary controls (CON: M/F = 7/6; age = 28 ± 4 years; BMI = 25 ± 2 kg/m2). Mean arterial pressure (MAP), heart rate (HR) and MSNA were measured continuously throughout the protocol. After baseline measurements were recorded, participants underwent a stepped hypercapnic protocol increasing to 6% CO2. Results are reported as mean ± SE. MAP was not different between groups at baseline (EX: 95 ± 4 mmHg vs. CON: 91 ± 5 mmHg; p>0.05) and during 6% CO2 (EX: 96 ± 4 mmHg vs. CON: 101 ± 5 mmHg; p>0.05). Both the change in MAP (EX: 1 ± 4 mmHg vs. CON: 11 ± 5 mmHg; p<0.05) and % change in MAP (EX: 2 ± 4 % vs. CON: 13 ± 5 %; p<0.05) were greater in the CON group compared with the EX group. HR was greater in the CON group compared with the EX group at baseline (EX: 50 ± 1 bpm vs. CON: 59 ± 3 mmHg; p<0.05) and during 6% CO2 (EX: 57 ± 2 bpm vs. CON: 68 ± 3 bpm; p<0.05). Both the change in HR (EX: 8 ± 1 bpm vs. CON: 9 ± 2 mmHg; p>0.05) and % change in HR (EX: 16 ± 3 % vs. CON: 16 ± 4 %; p>0.05) were not different between groups. MSNA was not different at baseline (EX: 16 ± 1 bursts/min vs. CON: 18 ± 2 bursts/min; p>0.05) and during 6% CO2 (EX: 17 ± 2 bursts/min vs. CON: 20 ± 2 bursts/min; p>0.05). The change in MSNA was greater in the CON group compared with the EX group (EX: 0.5 ± 0.4 bursts/min vs. CON: 2.4 ± 0.9 bursts/min; p<0.05) and the percent change in MSNA was non‐significant but tended to be higher in the CON group compared with the EX group (EX: 4 ± 2 % vs. CON: 16 ± 6 %; p=0.057). The sympathetic response to hypercapnia was lower in young exercise‐trained adults compared with sedentary adults. Taken together, these results suggest that hypercapnia‐induced sympathoexcitation may be altered with exercise training status, even in young healthy adults.

Support or Funding Information

NIH HL118154

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Global REACH Expedition: Chronic Hypoxia Attenuates the Contribution α‐Adrenergic Receptors to Sympathetic Transduction in Exercising Humans
Authors: Hearon Christopher M , Hansen Alex B , Moralez Gilbert , Romero Steven A , Levine Benjamin D , Lawley Justin S
Published: June 2021

Introduction

Acute exposure to hypoxia causes a rise in sympathetic nervous system activity (SNA) that restrains peripheral vasodilation. In normoxia, α‐adrenergic receptors are the primary mechanism eliciting vasoconstriction in response to increased SNA at rest and during exercise. However, exposure to chronic hypoxia (CH) causes a sustained and marked increase in SNA that is offset by reduced neurovascular transduction (vasoconstriction). Data from animal models indicate that CH blunts α‐adrenergic vasoconstrictor signaling, termed ‘hypoxic sympatholysis’. In humans it is unknown how CH alters α‐adrenergic restraint of skeletal muscle vascular tone at rest and during exercise.

Purpose

To test the hypothesis that CH reduces α‐adrenergic restraint of forearm skeletal muscle vascular tone at rest and during sympathoexcitation in response to cycle exercise.

Method

In 9 healthy lowland natives, we measured forearm blood flow (Doppler ultrasound), mean arterial pressure (MAP, intra‐arterial catheter), heart rate (HR, ECG) and calculated changes in vascular conductance (ΔFVC) during semi‐recumbent cycle exercise (60% VO2 max) at baseline (BL: 344m) and after three weeks sojourn at high‐altitude (CH: 4,380m). Sympathetic α‐adrenergic restraint of vascular tone was assessed via intra‐arterial infusion of phentolamine (PHT, α‐adrenergic antagonist) to achieve local forearm α‐adrenoceptor blockade. All data are quantified as mean ± SD.

Results

At rest, FVC was not lower in CH (BL: 38.0 ± 9.3 vs. CH: 32.6 ± 15.1 ml/100 mmHg/min; p=0.17). Local α‐adrenergic blockade increased FVC at BL and in CH (ΔFVC during PHT: BL: 70.0 ± 35.5 vs. CH: 87.7 ± 69.2 ml/100mmHg/min; P=0.59), indicative of significant residual basal α‐adrenergic restraint of vascular tone in CH. In contrast, the forearm vasoconstrictor response to 60% cycle exercise was attenuated by ~50% in CH (%ΔFVC during exercise: BL: −42.7 ± 29.6 vs. CH: −21.6 ± 19.4; P<0.05). Local α‐adrenergic blockade attenuated the vasoconstrictor response to exercise by 80% at BL (%ΔFVC during exercise: BL: −38.7 ± 34.2 vs. PHT: −6.1 ± 26.3; P<0.05). However, local α‐adrenergic blockade had no impact on the vasoconstrictor response to exercise in CH (%ΔFVC during exercise: CH: −21.6 ± 19.4 vs. PHT: −18.9 ± 12.1; P=0.77).

Conclusion

Exposure to CH did not significantly alter basal α‐adrenergic restraint of forearm skeletal muscle vascular tone. However, CH attenuates the forearm vasoconstrictor response to cycle exercise, and the contribution of α‐adrenergic receptor‐mediated vasoconstriction is abolished, indicating a reliance on alternative vasoconstrictor mechanisms.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Response of Neurons in the Rostral Ventrolateral Medulla (RVLM) to Anticipated and Passive Movements
Authors: Bielanin John P , Miller Derek M , Joshi Asmita , Engstrom Isaiah C , Kambouroglos Emmanuel , McCall Andrew A , Barman Susan M , Yates Bill J
Published: June 2021

It is well‐established that the rostral ventrolateral medulla (RVLM) plays a predominant role in regulating the activity of sympathetic outflow to the cardiovascular system. We and others have previously shown that in addition to baroreceptor inputs, RVLM neurons respond to signals from the vestibular system. However, most recordings of RVLM unit activity have occurred in anesthetized or decerebrate preparations, limiting the assessment of cognitive effects on neuronal activity. In this study, felines were instrumented for chronic recordings of the electrocardiogram and/or carotid artery blood flow as well as activity of RVLM neurons during 40° head‐up tilts. RVLM units were identified through stereotaxic coordinates and having activity correlated with changes in blood pressure during the cardiac cycle. Tilts were preceded by a light cue, so animals anticipated the movement. We tested the hypothesis that head‐up tilts elicit an increase in the activity of RVLM neurons that is initiated between the light cue and the onset of movement. We also determined if there is a relationship between RVLM unit activity and heart rate, as would be expected if the changes in firing rate are dictated by baroreceptor signals. Head‐up tilts elicited an increase in firing rate for a third of RVLM units. However, for the majority of these units, there was not a significant change in firing rate following the light cue and prior to head‐up rotations. In addition, linear regression analyses showed that there was no appreciable relationship between unit firing rate and heart rate (R2 values ranged from 0.001–0.29, median of 0.03). These studies suggest that cognitive inputs do not produce feedforward alterations in excitability of RVLM neurons prior to perturbations that can alter blood pressure. In addition, they show that inputs to RVLM neurons are complex such that the firing rate of the units is not simply related to baroreceptor inputs.

Support or Funding Information

NIH grant R01‐DC013788

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Elevated muscle sympathetic nerve activity is independently associated with common carotid artery wall thickness in humans
Authors: Holwerda Seth W. , Luehrs Rachel E. , Pierce Gary L.
Published: June 2021

Aging is characterized by increased wall thickness and stiffening of the large elastic arteries (i.e., aorta and carotid arteries), although the mechanisms involved are incompletely understood. Studies in vitro demonstrate hypertrophy of vascular smooth muscle following chronic sympathetic‐adrenergic stimulation. In addition, higher measures of sympathetic nerve activity, which typically occur with advancing age, are associated with greater intima‐media thickness (IMT) of the large peripheral arteries such as the common femoral arteries. Therefore, we tested the hypothesis that the age‐related increase in large elastic artery (carotid) IMT would be independently associated with higher sympathetic nerve activity. In a cohort of 88 young and middle‐age/older adults (age: 19–73 yr, 52% men) with no history of cardiovascular disease, we performed assessments of muscle sympathetic nerve activity (MSNA, microneurography), common carotid IMT (ultrasonography), and ambulatory 24‐hr mean arterial pressure (MAP). As expected, advancing age was significantly correlated with higher MSNA burst frequency (R=0.54, P<0.001), carotid IMT (R=0.51, P<0.001), and ambulatory 24‐hr MAP (R=0.18, P=0.047). Results from multiple regression analysis that included MSNA burst frequency and traditional cardiovascular disease (CVD) risk factors that were also significantly correlated with carotid IMT (age, BMI, history of hypertension or borderline hypertension, family history of hypertension, and ambulatory 24‐hour MAP) showed that MSNA burst frequency (P=0.031), age (P=0.003), and ambulatory 24‐hour MAP (P=0.003) were independent determinants of carotid IMT (model R2=0.47, P<0.001). When expressing carotid IMT relative to lumen diameter (carotid IMT‐to‐lumen diameter ratio), multiple regression analysis showed that only MSNA burst frequency (P=0.02) was an independent determinant (model R2=0.36, P<0.001). These findings demonstrate an independent association between MSNA and carotid IMT and suggest that the age‐related increase in sympathetic‐adrenergic tone may contribute importantly to increased wall thickness of the large elastic arteries.

Support or Funding Information

AHA (17POST33440101), T32 HL07121, NHLBI (P01HL014388), U54 TR001356 and AHA (13DG143400012).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sympathetic Transduction in Young Women with a Family History of Hypertension
Authors: McGinty Shane J. , Babcock Matthew C. , Matthews Evan L. , Greaney Jody L. , Wenner Megan M.
Published: June 2021

Exaggerated sympathetic transduction has recently been demonstrated in certain populations of young adults at risk for future hypertension. Our laboratory has previously reported that young women with a family history of hypertension (+FH), a population with a greater risk for future hypertension, have exaggerated sympathetic and blood pressure (BP) reactivity compared to women without a family history of hypertension (−FH). However, it is unclear whether resting sympathetic transduction may partially explain the exaggerated BP reactivity in +FH women.

PURPOSE

Therefore, the purpose of this study was to test the hypothesis that +FH young women would display augmented pressor responses following spontaneous bursts of muscle sympathetic nerve activity (MSNA) at rest.

METHODS

We retrospectively examined beat‐by‐beat BP (finger photoplethysmography) and MSNA (peroneal microneurography) in 5 +FH (22 ± 1 yr, 20 ± 2 kg/m2) and 7 −FH young women (24 ± 3 yr, 21 ± 1 kg/m2) during 10 minutes of supine rest. Signal averaging was used to characterize changes in BP for the 10 cardiac cycles following spontaneous MSNA bursts. Resting baseline variables were compared using unpaired t‐tests. A 2‐way repeated measures ANOVA was used to compared BP changes over 10 cardiac cycles following a burst of MSNA, and peak BP changes were compared using unpaired t‐tests. Data are presented as mean ± SD.

RESULTS

Resting mean arterial pressure (MAP) (+FH: 76 ± 12 vs. −FH: 83 ± 19 mmHg, p=0.72), MSNA (+FH: 8 ± 2 vs. −FH: 8 ± 5 bursts/min, p=0.89), heart rate (+FH: 70 ± 13 vs. −FH: 61 ± 4 bpm, p=0.12), and total peripheral resistance (+FH: 1811 ± 683 vs. −FH: 1432 ± 293 mmHg·min/mL, p=0.77) were not different between groups. Following spontaneous bursts of MSNA, the increase in MAP over the subsequent 10 cardiac cycles was not different between groups (time: p<0.01, group: p=0.16, interaction: p=0.89). Additionally, the peak change in MAP (+FH: Δ 1.5 ± 0.9 vs. −FH: Δ 2.4 ± 1.8 mmHg, p=0.35) systolic BP (+FH: Δ 1.6 ± 1.2 vs. −FH: Δ 3.7 ± 2.2 mmHg, p=0.18) and diastolic BP (+FH: Δ 2.2 ± 0.9 vs. −FH: Δ 3.5 ± 2.9 mmHg, p=0.73) were not different between groups.

CONCLUSIONS

These preliminary data suggest that sympathetic transduction following a burst of MSNA at rest does not elicit greater increases in BP in +FH young women. Further research is needed in order to more specifically examine whether the degree to which a sympathetic burst influences vascular tone is altered in +FH women.

Support or Funding Information

Supported by NIH Grant P20 GM 113125, P20 GM 103446, U54 GM 104941, and The University of Delaware Research Foundation

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cardio‐Renal Syndrome Type 2: The Role of the Cardiac Spinal Afferent Reflex
Authors: Xia Zhiqiu , Han Li , Schiller Alicia , Pellegrino Peter R. , Lisco Steven J. , Zucker Irving H. , Wang Han‐Jun
Published: June 2021

Background

Cardio‐renal syndrome type II (CRS II) is defined as a chronic abnormality in cardiac function (chronic heart failure, CHF) causing progressive and potentially permanent chronic kidney disease. We hypothesized that the cardiac sympathetic afferent reflex (CSAR, a cardiogenic sympatho‐excitatory reflex mediated by spinal afferents from the heart) plays a critical role in the pathological development of CRS II. Specifically, we proposed that the CSAR control of sympathetic outflow to the kidneys exacerbates renal hypoperfusion and accelerates renal dysfunction including renal tubular damage in CRS II.

Methods

We examined the effects of acute or chronic activation/inhibition of the CSAR on renal blood flow (RBF), renal vascular resistance (RVR) and renal function in sham‐operated and myocardial infarction (MI) rats. Renal function was evaluated by measuring 1) blood creatinine and blood urea nitrogen (BUN) by iSTAT analysis; 2) urinary kidney damage markers such as the kidney injury molecule [KIM]‐1 and 3) RNA sequencing analysis (RNA‐Seq) in renal tissues.

Results

Acute CSAR activation by epicardial application of bradykinin (BK) in anesthetized, vagotomized rats resulted in an augmented increases in blood pressure, heart rate, and renal sympathetic nerve activity in MI compared to sham rats. CSAR activation also increased renal vascular resistance (RVR) to a greater extent in MI rats compared to sham rats. Chronic CSAR ablation by epicardial application of the highly specific TRPV1 receptor agonist resiniferatoxin (RTX) restored, in part, the decreased RBF and increased RVR in MI rats. Furthermore, epicardial RTX prevented the development of renal dysfunction at 4–5 months post MI as evidenced by decreased blood creatinine and BUN in MI+RTX rats. RNA‐Seq analysis showed that several renal injury and inflammatory gene markers were significantly upregulated by 30–100 fold at 18‐weeks post‐MI. Of those, the gene expression of KIM‐1 (a specific proximal tubular damage marker) was increased by ~70 fold in whole‐kidney tissue of MI rats compared to sham rats, whereas it was only increased by ~4 fold in rats treated with RTX. Compared to sham rats, MI rats exhibited much higher concentration of urinary Kim‐1 18 weeks post MI, which was largely prevented by RTX treatment.

Conclusion

These data suggest that CSAR ablation by RTX may impart a selective protective effect on renal proximal tubular damage in CHF. Considering the fact that renal proximal tubules are located in the renal cortex where the majority of renal blood flow is distributed, it is very likely that chronic CSAR ablation improves renal proximal tubular damage by partially restoring cortical blood flow in CHF.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sympathomodulation in heart failure: A role for stellate ganglia Nrf2
Authors: Shanks Julia , Gao Lie , Zucker Irving H.
Published: June 2021

Nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) is a key transcription factor involved in modulating redox signalling by regulating the expression of a number of antioxidant genes. It is known that both sympathetic hyperactivity and increased oxidative signalling are hallmarks of chronic heart failure (HF). Previous data from our group have shown that site selective deletion of Nrf2 in the rostral ventrolateral medulla (RVLM) increases blood pressure, reduces baroreflex sensitivity and increases renal sympathetic nerve activity (RSNA) in normotensive mice. Moreover, Nrf2 expression is downregulated in the RVLM of HF mice, where its selective viral up regulation improves baroreflex sensitivity and reduces sympathetic tone. In this study we hypothesized that Nrf2 expression is downregulated in all sympathetic neural tissue in HF, and that selective overexpression of Nrf2 in the stellate ganglia would suppress cardiac sympatho‐hyperactivity and arrhythmogenesis in HF. Heart failure was induced by coronary artery ligation in both mice and rats. Terminal experiments were performed 6 weeks post MI. Heart failure was confirmed by echocardiography. Nrf2 protein and message expression were determined by western blot and rt‐PCR, respectively. Markers of oxidative stress within the stellate were determined using a variety of immunofluorescent techniques. Acute terminal experiments (2 % isoflurane) in rats, determined haemodynamic changes to stellate stimulation. Expression of Nrf2 protein and message was significantly down regulated within the stellate ganglia of both male and female mice (Nrf2 Protein: Male‐Sham, 0.65 ± 0.08 (n = 10), Male‐HF, 0.29 ± 0.13 (n = 9), p < 0.01. Female‐Sham, 0.53 ± 0.05 (n = 3), Female‐HF, 0.25 ± 0.04 (n = 3), ratio Nrf2/GAPDH). Nrf2 mRNA: Male‐Sham, 0.98 ± 0.03 (n = 2), Male‐HF, 0.49 ± 0.55 (n = 3), p < 0.05). Increased markers of redox signalling were seen within the stellate ganglia of HF mice, including increased labelling for 3‐Nitrosylation (3‐NT), 4 Hydroxynonenal, 8‐OHdG, and DHE as a marker of superoxide production. We also observed a reduction in Nrf2, and its downstream target NQO1 in the stellate ganglia of HF rats (10 weeks post coronary artery ligation (2% isoflurane), n = 5, sham and HF), a reduction in stellate Nrf2 was correlated with infarct size and ejection fraction. Within the HF group we observed increased haemodynamic changes to stellate stimulation in anaesthetized rats. These data suggest that oxidative signalling is increased and Nrf2 reduced within the stellate ganglia in HF and could open the potential for future therapeutic targets. Upregulation of Nrf2 in the stellate ganglia and the role of stellate ganglia Nrf2 in cardiac sympathetic drive and redox signalling in HF remain to be determined.

Support or Funding Information

Work done with support of the NIH (PO‐1 HL62222) and AHA (18POST34030046).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Glut5‐KD reduces blood pressure via increases phosphorylation of nNOS and decreases NADPH oxidase by AMPK activation in the NTS of fructose‐induced hypertensive rats
Authors: Chen Hsin‐Hung , Cheng Pei‐Wen , Tseng Ching‐Jiunn
Published: June 2021

Glucose transporter5 (GLUT5) is a fructose transporter in enterocytes. Many studies indicated that the mechanisms by which excessive fructose increases blood pressure. GLUT5 immunoreactivity is located in the epithelial cells of the choroid plexus and the ependymal cells, suggesting the possibility of the direct transportation of intravascular fructose into the nucleus tractus solitarii (NTS). The aim of this study was to investigate whether knock‐down GLUT5 in the NTS can improve hypertension in fructose‐fed rats with 10% fructose water. Our in vivo study showed that GLUT1/5 mRNA levels increased in the NTS of fructose‐fed rats at the early stage of 7 days. Our in vitro immunoblotting study found that fructose‐induced GLUT5 up‐regulated lead to AKT‐nNOS signaling pathway significantly decreased in PC12 neuronal cells after fructose treatment. In addition, we injected lentivirus‐delivered GLUT5 shRNA into the NTS of fructose‐induced hypertensive rats for 6 weeks. Two weeks after injection of lentivirus‐delivered GLUT5 shRNA, we fed with 10% fructose water for 4 weeks. Glut5‐knockdown (KD) down‐regulates blood pressure through improved sympathetic hyperactivity and central insulin signaling in the fructose‐induced hypertensive rats. Our data showed that Glut5‐KD restores AMPK‐dependent mechanism, decreases fructose‐induced oxidative stress, which attenuated NADPH oxidase in the NTS of fructose‐induced hypertensive rats. This study suggests that fructose through GLUT5‐RAGE overexpression induces ROS generation in the NTS, which lead to impairment of AKT‐nNOS‐NO signaling pathway and cause hypertension.

Support or Funding Information

MOST104‐2320‐B‐075B‐003‐MY3, 107‐2320‐B‐075B‐002‐MY2

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
DOCA‐salt hypertension and the role of the OVLT‐sympathetic‐gut microbiome axis
Authors: Collister John P. , Nahey David , Hartson Rochelle , Weber Bonnie , Johnson Timothy
Published: June 2021

Limited studies suggest an association of gut microbiome changes with certain forms of hypertension, but a cause/effect relationship has yet to be fully defined. The deoxycorticosterone acetate (DOCA)‐salt model of hypertension in rats is known to have a neurogenic component linked to increased sympathetic nervous system activity. Indeed, we have recently shown the hypertensive response in DOCA‐treated rats requires the organum vasculosum of the lamina terminalis (OVLT), a circumventricular organ that has direct connections to the PVN to increase sympathetic activity. Furthermore, celiac ganglionectomy also supports a role of splanchnic sympathetic innervation to the gut in the hypertensive response to DOCA. Taken together, we hypothesize an OVLT‐sympathetic‐gut (OSG) microbiome axis is involved in the development of hypertension. Having previously reported that the OVLT plays a significant role in the development of DOCA‐salt hypertension, the present study was designed to test the hypothesis that the OVLT mediates changes in the gut microbiome associated with concomitant hypertension. In uninephrectomized OVLT lesioned (OVLTx; n = 5) and SHAM (n = 4) Sprague‐Dawley rats consuming a 2% NaCl diet and 0.9% NaCl drinking solution, 24‐hour mean arterial pressure (MAP) was recorded telemetrically 5 days before and 21 days after DOCA implantation (100 mg/rat; SQ). Microbiome analyses were performed on regional gut samples (jejunum, ileum, cecum, and colon) at the end of the study and compared to normal control rats (n=8). The chronic pressor response to DOCA was attenuated in OVLTx rats such that MAP increased to 157±7 mmHg in SHAM rats by Day 21 of DOCA compared to only 127±5 mmHg in OVLTx rats. Moreover, DOCA hypertension in SHAM rats was associated with decreased levels of Lactobacillus species in the ileum. However, these changes were mitigated and offset by lesion of the OVLT and these bacterial populations in OVLT lesioned rats with attenuated hypertension more closely resembled those in normal control rats. Using Spearman correlation, increasing blood pressure on day 21 correlated with increased Clostridia levels in all tissues, as well as increasing Prevotella and decreasing Bacteroides. We conclude that DOCA‐salt hypertension is associated with specific microbiome changes in the gut, and the attenuated hypertensive effects of DOCA‐salt in OVLT lesioned rats is mediated in part through counteracting changes in these bacterial populations.

Support or Funding Information

Supported by Merial Veterinary Scholars Research Grant and University of Minnesota Grant In Aid

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Prevention of Lipopolysaccharide‐Induced CD11b+ Leukocytes Infiltration in the Kidney: Role of AT2 Receptors
Authors: Patel Sanket Niranjanbhai , Dhande Isha S. , Gray Elizabeth A. , Ali Quaisar , Hussain Tahir
Published: June 2021

Leukocyte infiltration plays a central role in mediating endotoxemic acute kidney injury (AKI). We have recently shown the anti‐inflammatory and reno‐protective role of angiotensin‐II type‐2 receptor (AT2R) activation under chronic low‐grade inflammatory condition using the obese Zucker rat model. The present study tests the hypothesis that prior activation of AT2R attenuates LPS‐mediated early infiltration of leukocytes, inflammation, and AKI. Mice were pre‐treated with AT2R agonist C21 (0.3 mg/kg), with and without AT2R antagonist PD123319 (5 mg/kg) prior to or concurrently with lipopolysaccharide (LPS, 5 mg/kg) challenge. Pre‐treatment with C21, but not concurrent treatment, significantly prevented the LPS‐induced renal infiltration of CD11b+ leukocytes, increase in the levels of circulating and renal chemotactic cytokines, particularly interleukin‐6 (IL‐6) and markers of renal dysfunction (blood urea nitrogen and albuminuria), while preserving anti‐inflammatory interleukin‐10 (IL‐10) production. Moreover, C21 treatment in the absence of LPS increases renal and circulating IL‐10 levels. To investigate the role of IL‐10 in a cross talk between epithelial cells and monocytes, we performed in vitro conditioned media studies in human kidney proximal tubular epithelial (HK‐2) cells and human monocytes (THP‐1 cells). These studies revealed that the conditioned‐media derived from the C21‐treated HK‐2 cells reduced LPS‐induced THP‐1 TNF‐α production via IL‐10 originating from HK‐2 cells. Our findings suggest that activation of AT2R prior to LPS challenge prevents monocyte infiltration and inflammatory renal injury, possibly via an increase in renal IL‐10 production.

Support or Funding Information

This study was supported by NIH grants R01 DK117495 and R01 DK61578.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.