bluuebunny/crossref_metadata_2025 huggingface dataset:
Paraventricular Nucleus in Acupuncture's Inhibition of the Von Bezold Jarsich Reflex
Authors: Tjen‐A‐Looi Stephanie , Guo Zhi‐Ling , Nguyen Ai‐Thuan , Longhurst John
Published: June 2021

Electroacupuncture (EA) stimulates specific somatic sensory nerves underlying P5‐6 acupoints and modulates parasympathoexcitatory reflex responses through actions in the brainstem. Although Bezold Jarisch‐induced decreases in blood pressure and heart rate reflex responses are modulated by acupuncture through actions in nucleus tractus solitarius and nucleus ambiguus, the role of the hypothalamus is unclear. The paraventricular nucleus (PVN) regulates sympathetic outflow and blood pressure. Vagal afferent stimulation activates neurons in the PVN but little is known about cardiopulmonary physiological actions in this nucleus. We therefore hypothesized that the PVN participates in the Bezold Jarisch responses and EA modulation of parasympathoexcitatory cardiovascular responses. Rats were anesthetized, ventilated, and heart rate and mean blood pressures were monitored. Application of phenylbiguanide (PBG) every 10 min close to the right atrium induced consistent depressor and bradycardia reflex responses. Unilateral microinjection of kainic acid or kynurenic acid in the PVN reduced the reflex responses. Thirty min of bilateral EA at P5‐6 acupoints reduced the depressor and bradycardia responses lasted for >60 min. Unilateral inhibition of the PVN with 50 nl of naloxone reversed the EA‐inhibition during repeated PBG‐induced responses. EA‐related c‐Fos PVN neurons were juxtaposed to endorphinergic PVN fibers. Thus, cardiopulmonary PVN responses are important in processing acupuncture modulation of cardiovascular inhibitory reflexes.

Funded by HL‐63313, HL‐72125.
Dynamic Regulation of microRNA Networks in the Brainstem Characterize Hypertension Development
Authors: DeCicco Danielle , Schwaber James , Vadigepalli Rajanikanth
Published: June 2021

This study aims to elucidate the mechanisms by which microRNAs (miRNA) regulate autonomic control networks driving hypertension development. Using a high‐throughput assay for 419 miRNAs in the Spontaneously Hypertensive Rat (SHR) and Wistar‐Kyoto (WKY) control at three stages of hypertension development, significant differences in expression occurred in 9 miRNAs of the nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM). Alterations were stage‐ and region‐dependent, differing at hypertension onset in NTS vs prehypertension stage in RVLM. 144 gene targets corresponding to catecholaminergic processes and neuromodulation were predicted using miRWALK and RNA22 databases and tested with high‐throughput qPCR. Using correlational relationships between miRNAs and mRNAs, we observed a double‐negative regulatory motif consisting of a miRNA down‐regulating a negative regulator of a pro‐hypertensive signaling pathway like Angiotensin II signaling or leukotriene‐based inflammation. We observe during the development of hypertension cells in NTS and RVLM alter their patterns of miRNA and gene expression related to neural function. These include many genes related to Ang II and inflammatory processes affecting autonomic balance leading to an increase in blood pressure set point. We confirmed expression of key miRNAs in the brainstem using fluorescent in situ hybridization, and we examined the cell‐type specificity of each miRNA using 10 cell pools of neurons and astrocytes taken from the NTS and RVLM using laser capture microdissection. We demonstrated for the first time that the broad concordance of miRNA dynamics and target gene expression compose a regulatory network in the brainstem underlying hypertension.
Chronic Central Infusion of Hypertonic NaCl Increase Blood Pressure Variability and Exaggerates Sympathetic Reflexes
Authors: Stocker Sean , Simmonds Sarah , Lay Jennifer , Wenner Megan , Farquhar William
Published: June 2021

Recent studies indicate that dietary salt loading increases blood pressure variability (BPV) and exaggerates sympathetic reflexes in salt‐resistant animals. This effect was attributed to a central action of sodium as high salt diet increased plasma sodium concentration and lesion of the forebrain hypothalamus prevented these responses. Since dietary salt loading also affects neurohumoral systems, the present study tested whether central hypernatremia can increase BPV and exaggerate sympathetic reflexes. Sprague‐Dawley rats were implanted with telemetry units and infused with artificial cerebrospinal fluid (aCSF, n=6) or 1M NaCl (n=6, 6uL/h) for 10 days. Baseline blood pressure (BP) did not differ animals infused with 1M NaCl vs aCSF (99±3 vs 99±1 mmHg). Although mean BP did not change after 10 day infusion of 1M NaCl vs aCSF (3±1 vs ‐3±1 mmHg), the SD of 24‐h systolic BP was significantly greater in animals infused with 1M NaCl versus aCSF (9.8±1.2 vs 6.4±1.0, P<0.05). Under Inactin anesthesia, stimulation of sciatic afferents (1ms, 500µA, 1‐20Hz) produced frequency‐dependent increases in renal SNA, splanchnic SNA, and mean BP in both groups. However, animals infused with 1M NaCl vs aCSF displayed significantly larger increases in renal SNA (5Hz: 91±17% vs 43±15%, P<0.05), splanchnic SNA (5Hz: 111±25% vs 31±3%, P<0.05), and mean BP (5Hz: 25±3 vs 15±3mmHg, P<0.05). Plasma renin activity at rest was not different between groups (1M: 3.1±1.0 vs aCSF: 3.7±1.2 ng AngI/mL/min). Collectively, these findings suggest that central hypernatremia increases BPV and exaggerates sympathetic reflexes in salt‐resistant, normotensive rats.
How Does the Brain Talk to the Arteries and Heart?
Authors: Blaustein Mordecai , Chen Ling , Song Hong , Leenen Frans , Hamlyn John
Published: June 2021

In many hypertension (Htn) models, myogenic tone (MT) in isolated small arteries is increased. MT is regulated mainly by Ca2+ transporters. Arterial transporter expression is “reprogrammed” in many Htn models: e.g., Na/Ca exchanger (NCX) and SR Ca2+ pumps (SERCA2) are increased; this enhances constriction and MT. In heart failure (HF), cardiac Ca2+ transporter “reprogramming” impairs contraction: e.g., NCX1 is increased, and SERCA2 expression or function is reduced. Do these cardiovascular (CV) changes in Htn and HF have a common trigger? The brain RAAS is activated in both Htn and HF. Central Ang II infusion increases BP, circulating endogenous ouabain (EO), and arterial NCX and SERCA2 expression; brain RAAS blockade prevents all effects (Hamlyn et al., PloS one 9: e108916, 2014). Here we induced Htn in rats (mean BP = 124 vs Control = 99 mm Hg) and mice (139 vs C = 110 mm Hg) with sc low dose Ang II (150‐350 ng/kg/min) and a high (2‐6%) salt diet. Also, in mice, coronary artery ligation caused ~45% LV myocardial infarction (MI) and HF: a 38±4% fall in LV ejection fraction at 8 wks post‐MI. In both Htn and HF, plasma EO increased (1.31‐2.59 nM vs C = 0.07‐0.53 nM) as did expression of arterial NCX (1.7‐1.8xC) and SERCA2 (2.0‐2.3xC) and cardiac NCX (1.7‐1.9xC), but cardiac SERCA2 expression declined (0.58‐0.74xC). In vitro 48‐72 hr treatment with 50‐100 nM ouabain, but not digoxin, increased NCX and SERCA2 protein in primary cultured arterial myocytes (published), and NCX (1.3‐1.7xC) in cardiomyocytes.

Conclusion

plasma EO is the signal from the brain that triggers Ca2+ transporter reprogramming in both Htn and HF. The novel slow brain RAAS‐plasma EO‐CV system modifies responses to the rapid RAAS‐activated sympathetic nerve pathway, and both modulate CV function in Htn and HF.
ROLE OF BARORECEPTORS IN HYPOTENSION AND RENAL SYMPHATHOINHIBITION INDUCED BY BLOCKADE OF THE MEDIAN PREOPTIC NUCLEUS
Authors: MOURÃO Aline , DA SILVA ELAINE , DOS SANTOS MOREIRA MARINA , PEDRINO GUSTAVO
Published: June 2021

The present study sought to evaluated the autonomic and cardiovascular effects of the MnPO inhibition following the sinoaortic denervation. Male Wistar (WT) rats and spontaneously hypertensive rats (SHR; 250‐300g) were anesthetized (ketamine 100mg.kg‐1, b.wt.; and xylazin 20mg.kg‐1, b.wt.), and submitted to sinoaortic denervation. Femoral artery and vein were catheterized and led subcutaneously to exit between the scapulae. In the following day, animals were anesthetized with urethane (1.2g.kg‐1, b.wt.) and instrumented for recording renal sympathetic nerve activity (RSNA) and for nanoinjections of saline (NaCl; 150 mM) and muscimol (GABAA agonist; 4 mM) into the MnPO. In WT group, the inhibition of the MnPO with muscimol reduced MAP in both sham (n=5) and denervated (17.5±0.8 vs. ‐28.0±6.5 mmHg, respectively; 3min; n=5). This response was maintained throughout the experimental period (‐15.9±2.3 vs. ‐22.5±4.3 mmHg; 30min). The sympathoinhibition induced by inhibition of MnPO were similar between sham (‐23.2±1.8%; 3min) and denervated WT rats (‐22.0±5.2%; 3min). In SHR groups, the blockade of the MnPO also promoted decrease in MAP, however this response was greater in denervated SHR (‐44.7 ± 7.1 mmHg; n=4) compared to the sham (‐21.0 ± 5.6 mmHg; n=5). We also observed similar decrease of RSNA induced by MnPO inhibition in SHR (‐34.9±8.2%; 3min) and denervated SHR (37.5±8.6%; 30min). The results demonstrated that aortic and carotids afferents participate in the modulation of autonomic and cardiovascular responses induced by the blockade of the MnPO.

Support

CNPq and FAPEG.
NMDA Receptors in the Raphe Pallidus Contribute to the Cardiovascular Response Induced by Acute Emotional Stress in Rats
Authors: Santos Machado Natalia , Coelho Tiago , Muller‐Ribeiro Flavia , Cordeiro Leticia , Fontes Marco
Published: June 2021

The projection between the dorsomedial hypothalamic region (DMH) and medullary raphe pallidus (RP) has been implicated in the reactive tachycardia evoked by acute emotional stress. We sought to determine the contribution of NMDA receptors in the RPa in mediating the cardiovascular response evoked by acute stress. The anatomical projection from DMH to RPa was also reevaluated. Wistar rats (300 ± 50g) were used in this study. Experiment 1: Under anesthesia (80 mg/kg ketamine and 11.5 mg/kg xylazine i.p.), a guide cannula was implanted into RPa. After 7 days of recovery, the femoral artery was cannulated to record mean arterial pressure (MAP) and heart rate (HR); 24 hs later, vehicle or the NMDA receptor antagonist (AP‐5) were injected into RPa (n=3‐5), the animal was placed in a restraining tube and exposed to an air jet (10 L/min). Experiment 2: Under tribromoethanol anesthesia (250 mg/kg i.p.), a nanoinjection of retrograde axonal tracing was made into RPa (n=6). The tachycardic and pressor responses evoked by air stress were largely attenuated by the preinjection of AP‐5 into the RPa (Δ HR: 131 ± 19 bpm after vehicle vs. 50 ± 5 bpm after AP‐5, P=0.002; Δ MAP: 15 ± 2 mmHg after vehicle vs 7 ± 2 mmHg after AP‐5, P=0.028). Anatomical experiments showed that many neurons located in the dorsal area and specifically in the caudal region of the DMH projects to RPa, supporting previous evidence of direct projections from DMH to RPa. The functional experiments suggest that NMDA receptors in the RPa are involved in mediating the tachycardic and pressor responses evoked by acute stress. Support: FAPEMIG, CNPq
N‐Methyl‐D‐Aspartate (NMDA) Receptors Contribute to the Excitatory Sympathetic and Hemodynamic Responses to Blood‐borne Pro‐inflammatory Cytokines in Rat
Authors: Wei Shun‐Guang , Yu Yang , Felder Robert
Published: June 2021

Pro‐inflammatory cytokines (PICs) have been implicated in the pathophysiology of hypertension (HTN) and heart failure (HF). The PICs tumor necrosis factor‐a (TNF‐a) and interleukin‐1b (IL‐1b) act within the brain to increase blood pressure (BP, mmHg), heart rate (HR, bpm) and renal sympathetic nerve activity (RSNA, %). However, the mechanisms by which PICs activate sympathetic drive to regulate cardiovascular function remain unclear. Evidence suggests that PICs can potentiate glutamate‐mediated neuronal excitation by increasing local glutamate concentrations and modulating NMDA and GABA receptor function in the CNS. In this study, we examined whether NMDA receptors contribute to the central excitatory effects of blood‐borne PICs. In urethane‐anesthetized SD rats,an intracarotid artery injection of TNF‐α (200 ng,n=5) or IL‐1β (200 ng, n=5), targeting the forebrain, significantly (* p<0.01, versus baseline) increased BP (21.8 ± 1.9* and 23.3 ± 2.1*), HR (61 ± 7* and 68 ± 7*) and integrated RSNA (85.6 ± 4.5* and 91.6 ± 4.7*, respectively). A concurrent continuous intracerebroventricular infusion of the NMDA antagonist AP5 (20 µg over 60 min) significantly (†p<0.01, versus PIC alone) attenuated TNF‐α or IL‐1β induced pressor responses on BP (9.1 ± 1.9†and 11.0 ± 2.1†), HR (18 ± 4†and 20 ± 5†) and RSNA (48.5 ± 3.1†and 46.6 ± 3.5†, respectively). These data suggest that increased activation of NMDA receptors plays an important role in mediating the central effects of circulating PICs on sympathetic drive and cardiovascular function in inflammatory conditions such as HTN and HF.
A Cross Sectional Study of Modifiable Cardiac Risk Factors in Young Adults of Different Personality Traits
Authors: Nepal Ojashwi , Bhattarai Supriya , Khanal Kishor , KC Rojan
Published: June 2021

Even the young adults who are residing in the urban and suburban areas are unaware of many factors associated with increasing health risks. These factors are obesity, hypertension, physical inactivity, smoking habit and poor nutritional status. Those are directly associated with cardiovascular disease which is the leading cause of disability and premature death.

The study was to predict cardiac risk among young adults through modifiable cardiac risk factors of different personality traits.

A cross sectional study was conducted among 153 subjects at Kavre District, Nepal. The study of personality traits was based on the BFI questionnaire. The volunteers in this study were of 18 to 24 years in age. Each subject was asked to fill a set of standard questionnaires related to personality, physical activity and nutritional status after obtaining the consent from them. In addition, their Blood Pressure, Height and Weight were measured. Body Mass Index and Basal Metabolic Rate were calculated. The analysis was done using ANOVA and Independent T‐test.

Our study demonstrated that, the majority of the subjects exhibited two key personality viz: Agreeableness (41.83%) and Openness (48.36%). The numbers of physically active individuals were also high under these personality traits

Personality Types
Exercisers
Non‐exercisers

Agreeableness (41.83%)
36.70%
47.30%

Extraversion (3.26%)
5.10%
1.40%

Openness (48.36%)
49.40%
47.30%

Neuroticism (1.30%)
0%
2.70%

Conscientiousness (5.22%)
8.90%
1.40%

The nutritional count reveals that 112 (73.2%) subjects have good nutritional status

Nutritional status
Exercisers (No. of subjects)
Non‐exercisers (No. of subjects)

Good
60
52

Moderate risk
15
12

High risk
4
10

Utilizing the independent t‐test, nutritional status and personality traits of exercisers and non‐exercisers were found significantly different.

Exercisers and non‐exercisers have different personality traits and nutritional status. Greater percentage of young adults in the studied population do not fall under cardiac risks.

Exercise, Neuroticism, Blood‐pressure, Obesity, Risk‐factors
Bone Density and Strength Decreased in a Mouse Model of Diabetes, db/db Mice
Authors: Samadfam Rana , Rocheford Erik , Cornicelli Joe , Smith Susan
Published: June 2021

Diabetes is a disorder of glucose metabolism and uncontrolled or poorly controlled glycemia has the potential to impair all organs. Cardiovascular disease, renal impairment, neuropathy, inflammation, ocular changes and impaired wound healing are well recognized complications of this disease, sometimes even in the presence of reasonably well‐controlled blood glucose. Recently osteoporosis and increased fracture risk has also been added to this long list. To complicate matters, some therapies that provide good glycemic control have adverse effects on the skeletal system further compromising already fragile bones in diabetic patients.

Db/db mice are commonly used model for diabetes research. The goal of this work was to investigate the skeletal integrity in this model. Bones were collected from db/db mice and their wild type littermates. Femurs were scanned using pQCT and BMC, BMD and also bone geometry parameters were obtained at the metaphysis and also diaphysis site. The bone strength was obtained by the three point bending test. The results indicate that the db/db mice had smaller bones with lower bone density. The bone strength of these animals was also compromised. These results highlight the importance of the consideration to include bone assessment in safety studies to monitor for diabetic complications
Identification of cardio‐metabolic protective myokines from Akt1‐mediated hypertrophic glycolytic muscles
Authors: Wu Chia‐Ling , Walsh Kenneth
Published: June 2021

Glycolytic skeletal muscle fibers are preferentially lost during aging and many cachectic states such as diabetes or cancer. We have previously constructed a murine model, where a constitutively‐active Akt1 transgene can be conditionally activated specifically in glycolytic skeletal muscle fibers. Induction of Akt1 transgene in skeletal muscles induced significant muscle hypertrophy and transcriptional reprogramming that mimics the effects of resistance exercise training. Employing this murine system in diet induced‐obesity, we have previously shown improvements on insulin sensitivity, fat mass and liver transcription profile. We therefore hypothesized that skeletal muscle growth improves diet‐induced metabolic syndromes via secretion of small peptides or cytokines, referred to as myokines. To identify novel myokines with beneficial cardiovascular and metabolic effects, we employed polyA(+) RNA sequencing for gastrocnemius muscles with or without Akt1 transgene activation from mice on normal chow and 15weeks of high fat diet (HFD). In silico analysis identified gene expression changes and networks altered in muscles metabolically challenged by HFD. We also identified an array of putative myokines that was dysregulated in HFD but restored by Akt1‐transgene activation induced muscle growth. Our data provides an extensive characterization of muscle transcriptome during diet‐induced obesity and contributes to better understanding of muscle‐organ crosstalk mediated by myokines.
Prior Viral Infection Increases Heat Stroke Severity in Mice
Authors: Leon Lisa , Dineen Shauna
Published: June 2021

Anecdotal evidence suggests that prior viral or bacterial infection increases heat stroke (HS) severity. We hypothesized that (1) Poly I:C (PIC; 100 mg, IP) or lipopolysaccharide (LPS; 50 mg/kg, IP) injection 48h or 72h prior to heat exposure (HE) would exacerbate core temperature (Tc; radiotelemetry; ±0.1°C) responses and HS severity of male C57BL/6J mice, and (2) these responses would occur in the absence of overt PIC or LPS sickness behaviors. PIC and LPS induced 2.0°C and 1.1°C fevers, respectively, and decreased activity (ACT) compared to saline (SAL; equivalent volume). PIC caused greater body weight (BW), food intake (FI) and water intake (WI) loss than LPS. Tc, ACT, BW, FI and WI of LPS mice were similar to SAL by 48h. FI and WI of PIC mice were similar to SAL by 72h; however, BW of PIC mice did not recover to pre‐injection levels by 72h. Heating time (190 min), thermal load (181°C·Min) and dehydration (9.6%) during HE were similar between PIC, LPS and SAL mice. PIC was associated with more severe HS recovery responses regardless of prior injection time. PIC injection 48h prior to HE decreased HS survival (60%) within ~4h of recovery and the PIC survivors showed a trend towards greater hypothermia depth (marker of HS severity; 30.4°C) compared to LPS (31.3°C) and SAL (31.5°C) mice. PIC injection 72h prior to HE had no effect on HS survival, but hypothermia depth was greater (29.2°C) compared to LPS (31.1°C) and SAL (31.2°C; ANOVA, P=0.022). Our data indicate that prior viral infection has no effect on Tc responses during HE, but exacerbates HS severity during recovery even after sickness behaviors are no longer evident. Future studies will delineate the inflammatory pathways mediating decreased HS survival during the early stages of HS recovery. Author views not official US Army or DOD policy
Cold Acclimation in Humans: Effects of Changes in Brown Fat on the Recruitment and Shivering Pattern of Superficial Muscles
Authors: Raytchev Sophia , Tingelstad Hans , Blondin Denis , Haman Francois
Published: June 2021

During cold exposure, humans rely primarily on shivering thermogenesis (ST) and to a lesser extent on nonshivering thermogenic (NST) processes in an attempt to counteract increases in heat loss. Recently, cold acclimation has been shown to increase the volume and activity of brown adipose tissue (BAT). The purpose of this study was to quantify changes in ST intensity, muscle recruitment and shivering pattern (i.e. continuous vs burst shivering) following 4 weeks of cold acclimation in young men. Nine participants were exposed to a cold condition for 180 min using a liquid‐conditioned suit (LCS) perfused with 4°C water before and after cold acclimation (2hr/day at 10°C using an LCS, 5 days/week, for 4 weeks). Changes in ST were monitored by surface electromyography (sEMG) in 12 superficial muscles of torso, arms and legs. For all these muscles, results showed that ST intensity, their relative contribution to total ST and shivering pattern (total number of bursts, burst rate and burst intensity) remained unchanged following this level of cold acclimation. In previously published work, we showed that these same subjects increased BAT volume by ~45% and metabolic activity increased ~120% following cold acclimation (Blondin et al., JCEM 2014). While this suggested an increase role of NST following acclimation, the present study shows that this increase in BAT activity does not alter shivering intensity and/or recruitment pattern of muscles specifically measured in this study. Additional work will be needed to determine whether the activity of deeper muscles is affected by changes in cold acclimation.
An Influence of Angiotensin II on Heat Loss Responses in Humans during Intermittent Exercise in the Heat: a Role for Oxidative Stress
Authors: Fujii Naoto , Meade Robert , Paull Gabrielle , McGinn Ryan , Foudil‐bey Imane , Akbari Pegah , Kenny Glen
Published: June 2021

Angiotensin II (Ang II) has been implicated in the pathophysiology of cardiovascular disease through several mechanisms, including evoking elevations in oxidative stress. We tested the hypothesis that increases in oxidative stress induced by Ang II impair the local heat loss responses of cutaneous vasodilation and sweating. Eleven young (24 ± 4 years) healthy adults (7 males, 4 females) performed two 30‐min cycling bouts at a fixed rate of metabolic heat production (400 W; equivalent to ~47 %VO2max) in the heat (35 ºC). Exercise was separated by 20 and 40 min of recovery, respectively.Sweat rate (ventilated capsule) and cutaneous vascular conductance (CVC, laser‐Doppler perfusion units/mean arterial pressure) were evaluated at four skin sites receiving either: 1) lactated Ringer (Control), 2) 10 μM Ang II, 3) 10 mM ascorbate (an antioxidant), or 4) a combination of 10 μM Ang II + 10 mM ascorbate via microdialysis. Compared to Control, Ang II reduced both CVC and sweating at baseline rest and during each recovery (all P < 0.05). When ascorbate was co‐infused with Ang II, the effect of Ang II on CVC at baseline rest and during each recovery remained intact (all P < 0.05), whereas its effect on sweating was abolished (all P > 0.05). No differences in CVC or sweating between the four treatment sites were observed during either exercise bouts (all P > 0.05). Thus, we show that at rest and during postexercise recovery in the heat, Ang II impairs cutaneous vasodilation independent of oxidative stress, while it impairs sweating through increases in oxidative stress. Support: Natural Sciences and Engineering Research Council of Canada (RGPIN‐06313‐2014).
Roles of Nitric Oxide Synthase Isoforms in Sweating in Young Adults during Intermittent Exercise in the Heat
Authors: Fujii Naoto , Meade Robert , Foudil‐bey Imane , Akbari Pegah , Louie Jeffrey , Kenny Glen
Published: June 2021

Recent studies demonstrate that nitric oxide synthase (NOS) is involved in sweating during intermittent exercise in the heat in young adults (Stapleton, Exp Physiol 99:921, 2014; Fujii, J Physiol 2014, in press). However, it remains unknown which NOS isoform mediates NOS‐dependent sweating. We tested the hypothesis that endothelial NOS (eNOS), but not inducible NOS (iNOS) or neuronal NOS (nNOS), contributes to NOS‐dependent sweating during intermittent exercise in the heat. Seven young (24 ± 4 years), healthy adults (4 males, 3 females) peformed two 30‐min bouts of cycling at a fixed rate of metabolic heat production (400 W; equivalent to ~50 %VO2max) in the heat (35 ºC). Exercise was separated by a 20‐ and 40‐min recovery respectively. Forearm sweat rate (ventilated capsule) was evaluated at four skin sites instrumented with intradermal microdialysis fibres that were continuously perfused with: 1) lactated Ringer (Control), 2) 5mM Nω‐amino‐L‐arginine (LNAA, eNOS inhibitor), 3) 0.1mM N‐3‐aminomethyl‐benzyl‐acetamidine (1400W, iNOS inhibitor), or 4) 5mM Nω‐propyl‐L‐arginine (NPLA, nNOS inhibitor). Forearm sweat rate (mg min‐1 cm‐2) during the last 5 min of the first exercise was reduced with 1400W (0.72 ± 0.04, P = 0.035) but not LNAA (0.83 ± 0.05, P = 0.550) or NPLA (0.84 ± 0.05, P = 0.878) in comparison to Control (0.90 ± 0.08). A similar pattern of response was observed throughout the second exercise bout. We show that iNOS, but not nNOS or eNOS, mediates NOS‐dependent sweating during moderate intensity intermittent exercise in the heat in young adults. Support: Natural Sciences and Engineering Research Council of Canada (RGPIN‐06313‐2014).
Physiological Differences Between Torpor and Forced Hypothermia in Mice
Authors: Vicent Allende Maria , Swoap Steven
Published: June 2021

Clinical advantages of forced hypothermia (FH) are mitigated by homeostatic mechanisms invoked to prevent core cooling. Torpor, a physiological state used by mice as a survival strategy, lowers body temperature (Tb) without eliciting such mechanisms. It was hypothesized that torpor is different from FH at multiple levels, including autonomic balance, aerobic/anaerobic metabolism, and hypoxia related gene expression in heart and liver. To test this hypothesis, female C57Bl/6 mice were implanted with ECG/ Tb telemeters and subjected to both conditions‐ FH and naturally induced torpor‐ in a random crossover design. During cooling and at a Tb of 30°C, mice showed a heart rate (HR) of 185 ± 18 bpm during torpor, and a HR of 484 ± 20 bpm during forced hypothermia. Analysis of hysteresis curves of Tb vs HR showed parasympathetic influence during entrance and maintenance of torpor, which shifted to sympathetic influence during recovery. Mice undergoing FH showed consistent and maximal sympathetic activity. ECG tracings showed evidence of substantial shivering during rewarming from both states, but showed vigorous shivering during cooling only in FH. Circulating lactate levels were significantly elevated in FH relative to torpor, (3.9 ± 0.9 vs 0.6 ± 0.2 mM, respectively), suggesting an increased reliance on anaerobic metabolism during forced hypothermia. Steady state mRNA levels in the heart and liver from torpid mice, as assessed by qRTPCR arrays (80 different genes), showed a unique pattern of expression compared to euthermic and forced hypothermic mice. In conclusion, data in this study support the hypothesis that forced and natural hypothermia only have low Tb in common, and have vastly different sympathetic, shivering, anaerobic, and hepatic/cardiac gene expression profiles.
The Effect of N‐acetylcysteine on Peripheral Hemodynamics and Fatigue during Exercise
Authors: Smith Joshua , Broxterman Ryan , Ade Carl , Barstow Thomas , Harms Craig
Published: June 2021

We hypothesized that oral N‐acetylcysteine (NAC) would lead to higher exercising arm blood flow and a delayed onset of peripheral fatigue. Thus far, three healthy men have completed constant power handgrip exercise tests at 80% peak power to exhaustion. Subjects orally consumed either placebo (PLA) or NAC (70mg/kg) 60 min before exercise. Brachial artery blood flow (BABF) was measured via Doppler ultrasound and flexor digitorum superficialis oxygenation characteristics were measured via near infrared spectroscopy. Peripheral and central fatigue were assessed via potentiated doublet twitch force (Qtw), MVC, and voluntary activation (%VA). The mean time to exhaustion was similar (p=0.83) with NAC (368.8±37.5s) and PLA (353.9±90.9s). Mean resting BABF was similar (p=0.68) with NAC (92.7±12.0mL/min) and PLA (112.3±37.2mL/min). Mean peak exercising BABF was similar (p=0.77) between NAC (550.5±73.1mL/min) and PLA (527.5±94.3mL/min). Mean deoxy‐[Hb+Mb] was not different between NAC and PLA from rest to exercise (p=0.63). Mean total‐[Hb+Mb] was similar (p=0.08) between NAC and PLA at rest (NAC: 101.6±2.2 µM; PLA: 90.8±1.8 µM) and during exercise. % change in MVC from pre to post exercise was not different (p=0.18) between NAC (‐43.9±16.6%) and PLA (‐32.5±13.2%). % change from pre to post exercise in Qtw was similar (p=0.29) with NAC (‐34.6±20.4%) and with PLA (24.8±18.6%). Change (%) from pre to post exercise in %VA was less (p=0.019) with NAC (‐8.0±8.9%) than PLA (‐13.8±9.0%). These preliminary data suggest NAC does not affect exercising BA blood flow, but may increase microvascular hematocrit at rest and during exercise. Also, NAC may reduce central fatigue during exercise.
Prolonged Sitting Impairs Forearm and Lower Leg Microvascular Reactivity
Authors: Restaino Robert , Credeur Daniel , Holwerda Seth , Padilla Jaume , Fadel Paul
Published: June 2021

Previous studies examining the effects of sitting on vascular function have focused on flow‐mediated dilation of conduit arteries. However, whether prolonged sitting affects the reactivity of the microvasculature is largely unknown. Likewise, previous studies have focused on leg vascular responses; whether sitting alters vascular reactivity in the arms also remains unknown. In 8 young healthy men, lower‐leg (popliteal artery) and forearm (brachial artery) reactive hyperemia responses to 5‐min of limb occlusion were assessed at baseline and following 6 hours of uninterrupted sitting. Popliteal artery blood flow (BF) area under the curve (AUC) during reactive hyperemia was markedly reduced after 6 hours of sitting (BF, Baseline: 74650.85 A.U.; Post Sitting: 29745.67 A.U.; p<0.05). Interestingly, reactive hyperemia was also reduced in the forearm post sitting (BF, Baseline: 69523.06 A.U.; Post Sitting: 38996.12 A.U.; p<0.05). Next, since previous studies have demonstrated that physical activity can favorably impact microvascular function, we examined whether 10 minutes of walking (~1,000 steps) could improve microvascular reactivity following sitting. Reactive hyperemia in the lower leg (BF, Post Walking: 79630.49 A.U.; p>0.05 vs. Baseline) but not the forearm (BF, Post Walking: 44478.05 A.U.; p<0.05 vs. Baseline) was restored after walking. Collectively, these data suggest that prolonged sitting markedly reduces forearm and lower leg microvascular reactivity but only leg vascular responsiveness can be restored with a short bout of walking.
No Effect of N‐acetylcysteine on Histamine‐receptor Mediated Sustained Post‐Exercise Vasodilation in Humans
Authors: Romero Steven , Ely Matthew , Sieck Dylan , Luttrell Meredith , Buck Tahisha , Kono Jordan , Halliwill John
Published: June 2021

An acute bout of aerobic exercise elicits a sustained post‐exercise vasodilation which is histamine‐receptor mediated. This histaminergic vasodilation appears to be blunted by systemically infused high dose ascorbate, a potent antioxidant. However, ascorbate may catalyze the degradation of histamine in vivo. Therefore, we tested the hypothesis that systemically infusing high dose N‐acetylcysteine, an antioxidant with no known histaminergic interaction, would blunt sustained post‐exercise vasodilation. Eight healthy subjects performed 1 hr of unilateral dynamic knee extension at 60% of peak power on 2 separate days: 1) control, intravenous saline infusion and 2) intravenous N‐acetylcysteine infusion (primer dose, 125 mg kg⁻1 hr⁻1, maintenance dose, 25 mg kg⁻1 hr⁻1). Femoral artery blood flow (Doppler ultrasound) was measured before exercise and for 2h post‐exercise. Femoral vascular conductance was calculated as flow/pressure. Pre‐exercise femoral vascular conductance was similar for both conditions (P = 0.9). Compared with pre‐exercise, femoral vascular conductance was elevated throughout the recovery from exercise for both control (4.0 ± 0.1 ml min‐1 mmHg‐1) and N‐acetylcysteine conditions (4.0 ± 0.1 ml min‐1 mmHg‐1; P < 0.05). Femoral vascular conductance was similar between conditions throughout the recovery from exercise (P = 0.8). Taken together, these results suggest that the inhibition of sustained post‐exercise vasodilation by ascorbate was due to a direct degradative effect on histamine and not to the blunting of exercise‐induced oxidative stress.
Exercise Training Activations PI3K/Akt/eNOS Signalling Improves Insulin Resistance in Post‐Myocardial Infarction Rats
Authors: Wang Youhua , Tian zhenjun , Li Youyou , Chen shengfeng
Published: June 2021

Myocardial infarction (MI) has been shown to induce cardiac dysfunction and insulin resistance. This study was designed to examine the effects of MI‐related insulin resistance on vaso relaxation function and its underlying mechanisms, with specific focus on the role of exercise in reversing vasorelaxation response. Adult male Sprague‐Dawley rats were divided into three groups: Sham, MI, and MI+Exercise. MI+Exercise rats were subjected to 8 weeks of treadmill training (50 min/day, 5 days/week). Myocardial infarction caused significant impairments in endothelial structure and vasodilation (P < 0.05‐0.01), which was evidenced by decreased arterial vasorelaxation to ACh and insulin. Myocardial infarction attenuated myocardial contractile response to insulin, decreased PI3K/Akt/eNOS expression and its phosphorylation by insulin, and increased IL‐1β, IL‐6, and TNF‐α (P < 0.05‐0.01). Exercise improved insulin sensitivity, facilitated arterial vasorelaxation to ACh and insulin, and increased arterial PI3K/Akt/eNOS activation in post‐MI rats. Inhibition of PI3K with LY294002, and eNOS with L‐NAME significantly blocked exercise‐facilitated arterial vasorelaxation and PI3K/Akt/eNOS activation response to insulin. In conclusion, these results demonstrate that endothelial dysfunction in response to insulin plays an important role in the development of myocardial infarction‐related insulin resistance. The reversal of insulin resistance by exercise is most likely associated with normalizes inflammatory cytokines, and PI3K/Akt/eNOS‐dependent improvement in insulin sensitivity.
Alterations in Metabolic Relations and Adiposity during and after Cigarette Smoke Exposition, in Young Female and Male Mice
Authors: Gaspar‐Reis Rejane , S Silva Cynthia , Santos Aline , Rangel Ninive , Albuquerque Karine , Abreu‐Villaça Yael , Souza Erica , Nascimento‐Saba Celly Cristina
Published: June 2021

Cigarette smoking is worrisome in adults and also in adolescents. This study aim evaluates the influence of smoking in puberty and the consequences of withdrawal, body composition of female and male mice.

At 35d mice were exposed to 3R4F cigarette smoke, 8 h/day for 15d (S, n =24).Then, half of animals were evaluated and the other half was maintained and evaluated thirty days after stop exposure (30d AS). An unexposed group accompanied the events (NS, n = 24). Body mass, body composition, food intake, blood, ipGTT and adipose tissue were evaluated. During exposure food intake was similar all groups, however, S groups showed low body mass gain. 30dAS, S groups increased body mass and food intake in females. In regard blood, males didi not alter insulin or ip GTT during exposure whilst females had high insulin levels and glycemia at 30min. Withdrawal induced in males, high insulin and low glycemia the ipGTT and in females normal insulin and low glycemia.

The set of results indicates different response cigarette smoke in young that seem to start in females and lead malefic metabolic alterations in adulthood.
Increased Levels of Heme‐Oxygenase‐1 Rescues Fructose‐Mediated Adipocyte Dysfunction
Authors: Stevens Sarah , Ansinelli Hayden , Bellner Lars , Khitan Zeid , Abraham Nader
Published: June 2021

Obesity is an epidemic that is becoming increasingly more prevalent, particularly in Western societies, and is associated with an increase in oxidative stress. Unregulated fructose metabolism contributes to obesity by increasing reactive oxygen species (ROS). The aim of this study was to examine whether fructose and uric acid modulate adipogenesis in murine preadipocytes. We also hypothesize that an increase in HO‐1 will decrease ROS and adipocyte hypertrophy. Fructose (5 μM ‐ 1000 μM) and uric acid (10 mg/mL, ‐ 100 mg/mL) or apocynin (50‐500 mM) or allopurinol (550‐100 mM) were added to preadipocytes both in the presence and absence of cobalt protoporphyrin (CoPP), a known HO‐1 inducer. Fructose and uric acid decreased HO‐1 and Wnt10b expression and increased the expression of the adipogenic markers PPARγ, PEG‐1/Mest, and lipid accumulation. An increase in HO‐1 gene expression and HO activity decreased fructose and uric acid mediated lipid deposition and inflammatory cytokine levels, (IL‐1, IL‐6) and the expression of genes of the canonical Wnt signaling cascade (p<0.05). Preadipocytes treated with allopurinol and apocynin had a decreased number of large lipid droplets and ROS. These novel findings demonstrate that increased levels of HO‐1 appear crucial in modulating the phenotype of adipocytes exposed to both fructose and uric acid, in expressing canonical downstream signaling proteins, and in suppressing Peg‐1/Mest proteins, markers of adipocyte hyperplasia and inflammation. Furthermore, this data offers new insights into potential therapies by which targeting the production and/or downstream signaling of uric acid can curtail adipogenesis. Support NIH, HL‐55601, HL34300, BrickStreet Foundation (N.G.A.)
MicroRNA‐150 Knockout (miR150‐KO) Prevents Age‐Related Glucose Intolerance and Extends Life‐Span
Authors: Wang Shieley , Liu Xiaocan , Sun Zhongjie
Published: June 2021

Background and Hypotheses

Ageing is associated with metabolic syndrome. The purpose of this study is to assess if miR150 regulates glucose tolerance, insulin sensitivity, and lifespan in male mice.

Methods and Results

Thirteen wild‐type (WT) and 32 Mir150‐KO male mice were used. Mir150‐KO decreased insulin sensitivity and improved aging‐related glucose intolerance. Mir150‐KO extended lifespan in male mice compared with the age‐matched WT mice. The longest lifespan was 37 months in Mir150‐KO mice and 30 months for WT controls (p<0.05 Kaplan Meier Analysis). The survival percentage was 28.1% in the Mir150‐KO group and 7.7% in the wild type group at the age of 30 months. IHC data showed that the pancreatic insulin content was increased by Mir150‐KO. Western blot analysis indicated that Mir150‐KO decreased insulin/IGF‐1 receptor and Akt activity in the kidneys but increased ACCs and p‐ACCs in the liver of aged mice.

Conclusion

Mir150‐KO extended lifespan by suppressing the renal insulin/IGF‐1/Akt activity and upregulating the hepatic ACC activity.
Effects of Chronic Stress on Pancreatic Beta Cell Density in Obese and Lean Zucker Rats
Authors: Clegg Aric , Brooks Steven , Frisbee Jefferson , Leon Camille , Olfert Mark , Alway Stephen , Bryner Randall
Published: June 2021

Chronic stress has been implicated as a possible contributing factor to the onset of Type 2 Diabetes Mellitus through its negative effects on the insulin producing β cells of the pancreas. The objective of this study was to evaluate a model of chronic stress and the metabolic syndrome on beta cell density in rats. Obese (OZR) and lean Zucker rats (LZR) were randomly divided into stress (OZR‐S, n=6; LZR‐S, n=6) and non‐stress (OZR‐NS, n=3; LZR‐NS, n=3). Stress included bath, damp bedding, no bedding, cage tilt, altered light cycles, and cage‐switching for 7 hours/day, 5 days/week for 8 weeks after which animals were euthanized. Pancreases were harvested and mounted on cork using OTC freezing medium. Pancreas sections of 7µm thickness were cut and collected on slides then stained using Alexa‐Fluor 546 targeting primary insulin antibodies and DAPI. Slides were then imaged using the Zeiss LSM 510 Confocal microscope and Zeiss computer software. The insulin positive area of the stained islets was measured using the Image J program.The images of stained cells and islets were merged and the number of beta cells per islet recorded. A two‐way ANOVA was used to compare the beta cell density (beta cell/µm2 insulin positive area) among groups with significance set at p<.05. There was a significant main effect of stress with stressed animals having a lower beta cell density compared with non‐stressed (Stressed: 0.00566±.001; Non‐Stressed: 0.00861±.001µm2). No differences were observed between OZR and LZR. These results indicate that 8 weeks of chronic stress caused beta cell density to be reduced in both OZR and LZR and this was not affected further by the metabolic condition of the animals.
Identification of a Candidate Adropin Receptor
Authors: Stein Lauren , Samson Willis , Yosten Gina
Published: June 2021

Adropin, a peptide secreted by the liver, has been reported to be a novel mediator of energy metabolism. Clinical studies have shown an association between adropin levels and pathological markers of metabolic disease. Our lab has found that intra‐arterial administration of adropin enhances glucose disposal despite decreases in plasma insulin levels in healthy male rats. These data support a role for adropin in the regulation of glucose homeostasis; however, the mechanism has yet to be elucidated, partly due to the elusiveness of the adropin receptor. In endothelial cell cultures adropin stimulated downstream signaling pathways typically associated with G protein coupled receptor (GPCR) activation (Lovren 2010). Therefore, we hypothesized that adropin signals via a GPCR and in particular one of the known ~135 orphan GPCRs. To test this hypothesis, we first identified three adropin responsive cell lines [human gastric carcinoma (KATOIII), human coronary artery endothelial cells (HCAEC) and mouse fibroblasts (3T3‐L1)] using cfos mRNA expression as a reporter of cellular activation. We then applied the “Deductive Ligand‐Receptor Matching Strategy” developed in our lab (Yosten 2012) to generate an orphan GPCR expression profile of each cell line and identified five adropin receptor candidates; GPR151, TAAR9, GPR160, GPR19, and GPR63. In preliminary experiments, knockdown of one of these orphan receptors using siRNA abrogated adropin‐induced cfos mRNA expression in KATOIII cells, identifying this orphan receptor to be our top candidate adropin receptor. Identification of the cognate adropin receptor will facilitate our current attempts to identify the sites and mechanisms of action of this potent, liver‐derived hormone.
Chronic Ethanol Feeding Promotes Azoxymethane (AOM) and Dextran Sodium Sulfate (DSS)‐Induced Colonic Tumorigenesis by Enhancing Mucosal Inflammation
Authors: Shukla P. , Chaudhry K. , Mir H. , Gangwar R. , Yadav N. , Manda B , Rao R.
Published: June 2021

Alcohol consumption is a major risk factor for colorectal cancer, but the mechanism involved in this is unknown. We evaluated the effect of ethanol (EtOH) on AOM‐DSS‐induced colonic tumorigenesis in mice. Adult female mice were treated with AOM (10 mg/kg BW) and colitis was induced after 5 days (d) by 3% DSS in drinking water for 5 d. DSS colitis was repeated twice with 15‐d intervals. Tumorigenesis was observed at 30 d after the 3rd DSS cycle. During the 15‐d intervals and 30 d after 3rd DSS cycle animals were fed Lieber‐DeCarli liquid diet with or without 4% EtOH; non‐EtOH group were pair fed with isocaloric diet. Colon was examined for tumors, cryosections stained for p‐Smad, VEGF and HIF1α. At a precancerous stage, colon was analyzed by microarray analysis and RT‐PCR. Cryosections of colon were examined for inflammatory markers, myeloperoxidase (MPO), GR1 (neutrophil) and CD68 (macrophage) by confocal microscopy. EtOH feeding dramatically elevated colonic tumors; both the number and size of tumors were greater. AOM+DSS‐induced elevation of p‐Smad, VEGF and HIF1α in the colon was greater in EtOH‐fed mice. At the precancerous stage, EtOH feeding significantly reduced (46‐94% decline) the AOM+DSS‐induced expression of defensin genes (Defcr1,3,5,6,20,21,26); colons in untreated and EtOH alone controls showed no defensin expression. EtOH feeding increased the expression of proinflammatory cytokines/chemokines (IL‐6 & CCL5) and the elevation of inflammatory markers MPO, GR1 & CD68 in AOM+DSS treated mice. This study suggests that chronic EtOH feeding promotes colonic tumorigenesis by delaying the post colitis recovery by suppressing defensins leading to sustained inflammation.
Human Papillomavirus and sexually transmitted infections in women with and without abnormalities in cervical cytology
Authors: Abreu Andre , Souza Raquel , Bonini Marcelo , Gimenes Fabricia , Consolaro Marcia
Published: June 2021

This report evaluated the molecular prevalence of HPV and sexually transmitted infections (STI) agentsas C. trachomatis, Herpes simplex virus (HSV)1/2, N. gonorrhoeae, M. hominis, T. vaginalis and T. pallidumto contribute to the elucidation of STI infections in cervical carcinogenesis. Were recruited 828 Brazilian women between 15 to83 years old, 614 with normal and 224 with abnormal cytology (05 AGC/ atypical glandular cells; 65ASC‐US/atypical squamous cells of undetermined significance; 27ASC‐H – can't exclude high‐grade squamous intraepithelial cervical lesion; 77 LSIL/low‐grade SIL and 50 HSIL/high‐grade). The HPV was detected by polymerase chain reaction (PCR) and further genotyped by PCR‐RFLP (based restriction fragment length polymorphism analysis). STIs were detected by multiplex‐PCR. The HPV prevalence was 33.8%, n=284, showing correlation with abnormal (81.7% p = 0.0001) compared to normal cytology, 16.4%. The most frequent genotype was HPV‐16 (28.4%) in normal and abnormal cytology, followed by HPV‐31 ‐58 and ‐72 (7.9%, 6.9%, 6.0% respectively). HPV co‐infections were found in 26.7% and associated with abnormal cytology (p = 0.01). STI were detected in 30.4% (n= 255), 18.4% (n= 47) showed multiple agents: T. vaginalis 11.6% (n= 97), C. trachomatis 10.3% (n= 86), N. gonorrhoeae 4.7% (n= 39), HSV‐2 3.9% (n= 33), M. hominis 3.5% (n= 29), T. pallidum 1.7% (n=14), and HSV‐1 1.1% (n= 9). C. trachomatis was correlated with HPV especially with high‐risk regardless of cytology. This significant association suggests they may have synergistic pathological effects on cervical carcinogenesis, so it's important screening both microorganisms simultaneously than individually