bluuebunny/crossref_metadata_2025 huggingface dataset:
Contrasting Effects of Acute Versus Chronic Intermittent Hypoxia on Leptin Secretion in Differentiated Human Preadipocytes
Authors: Somers Kiran R , Becari Christiane , Polonis Katarzyna , Singh Prachi
Published: November 2023

BACKGROUND

Leptin is an adipokine with a central role in energy homeostasis and appetite regulation. Increases in leptin suppress appetite, while decreases in leptin increase appetite and may consequently cause weight gain. Patients with established obstructive sleep apnea (OSA) have been shown to have elevated leptin. Also, newly diagnosed OSA patients have a history of significant recent weight gain. Repetitive nocturnal intermittent hypoxia has been implicated in OSA pathophysiology and in increases in leptin. However, the factors contributing to weight gain in OSA are not completely understood. In contrast to the history of weight gain in OSA subjects, animal models of intermittent hypoxia (IH) are associated with weight loss along with increases in leptin. Furthermore, acute altitude dependent hypoxia in humans has also been associated with loss of appetite and increases in leptin. We postulated that the duration of IH may be important in defining the nature of effects on leptin. In this study we sought to examine the interactions between IH and leptin secretion, comparing acute versus chronic exposure to IH. We tested the hypothesis that although acute IH increases leptin secretion and likely suppresses appetite, repeated chronic exposure to IH will decrease leptin secretion, and thereby may increase appetite and predispose individuals such as patients with OSA to weight gain.

METHODS

We used an in‐vitro approach to examine the acute effects of IH (24 cycles of 30 min 0.1% O2 followed by 30 min exposure to 21% O2) in differentiated human white preadipocytes. Cells grown in normoxic conditions and continuous hypoxia were controls for these experiments. For chronic treatment, cells were exposed to 9 cycles of IH each day for 7 days. Leptin secretion was measured in 48 h conditioned media by ELISA.

RESULTS

Acute 24 hour exposure to IH or sustained hypoxia increased leptin secretion (p = 0.013). However, chronic 7 day exposure of differentiated human white preadipocytes caused decreases in leptin secretion (p = 0.02).

CONCLUSION

Acute intermittent hypoxia elicits increases in leptin secretion. Conversely, chronic IH decreases leptin secretion, suggesting a mechanism for development of obesity in the early stages of OSA. We speculate that decreased leptin, as a consequence of chronic IH, would result in increased appetite and hence weight gain. As obesity progresses, leptin levels likely rise secondary to the increase in body fat. Elevated leptin levels in patients with longstanding OSA may be indicative of increased fat mass and not a consequence of IH‐mediated effects on adipocytes.

Support or Funding Information

Christiane Becari was supported by a grant from CNPq Brazil (# 203802/2014‐4); Prachi Singh was supported by AHA scientist development grant (11SDG7260046).
Cardioprotective Intermittent Hypoxia Conditioning Induces Glyoxalase‐1 in Rat Left Ventricle
Authors: Ramani Azaan , Scott Gary F. , Williams Arthur G. , Ryou Myoung‐Gwi , Mallet Robert T.
Published: November 2023

Background

Intermittent, normobaric hypoxia (IH) conditioning increases myocardial resistance to subsequent ischemia‐reperfusion, resulting in near‐prevention of myocardial infarct and ventricular tachyarrhythmias after coronary artery occlusion and reperfusion. The cardioprotective mechanisms of IH are unknown. Myocardial ischemia‐reperfusion triggers overproduction of the powerful dicarbonyl glycating agent, methylglyoxal (MG), which injures cells by modifying arginyl and lysyl residues and, thus, inactivating enzymes and other proteins. The glyoxalase system detoxifies the modest amounts of MG normally generated by glycolysis, but this system may be insufficient to manage the excessive MG production induced by ischemia‐reperfusion. The enzyme components of this system are expressed and synthesized in response to reactive oxygen species, which are generated in myocardium by cyclic hypoxia‐reoxygenation.

Purpose

This study evaluated IH induction of glyoxalase‐1 (GLO‐1), the rate‐controlling enzyme in the MG‐detoxifying glyoxalase cycle.

Methods

Sprague‐Dawley rats (n=10) were conditioned by a 20 day IH program consisting of 5–8 daily, 5–10 min cycles of hypoxia (9.5–10% inspired O2) with intervening 4 min room air exposures, previously shown to produce robust cardioprotection [Exp Biol Med 2004;229:806–812; Basic Res Cardiol 2006;101:436–446]. Control rats (n=10) completed sham‐conditioning with 21% O2. 24 h after the last IH or sham session, left ventricles were harvested, flash‐frozen in liquid N2 and extracted for enzyme analyses.

Results

GLO‐1 activity (U/mg protein) was increased threefold in myocardium of IH (0.53±0.08) vs. sham (0.17±0.06) rats (P<0.01), while activity of the antioxidant enzyme glutathione reductase was unchanged (IH: 0.0154±0.0057; sham: 0.023274±0.0043).

Conclusion

IH augments the heart's anti‐glycation defenses, which may contribute to IH‐induced cardioprotection against ischemia‐reperfusion.

Support or Funding Information

Funding: NINDS NS076975; NCCAM AT003598
Physiology and Structure of Motion Sensitive Neurons in the Dragonfly Visual System
Authors: Shapiro Benjamin Goodman
Published: November 2023

Aeshnid dragonflies are among the largest North American insects and also among the fastest and most accurate predators. During prey pursuit, they quickly respond to deviations in their flying‐prey trajectory and alter their flight paths to intercept their quarry. Remarkably, a deviation in the prey's path results in a dragonfly turn in only 30 ms, much faster than the visual latencies in most animals. Visual neurons, called target‐selective descending neurons (TSDNs) are hypothesized to mediate the dragonfly's fast response to flying prey. Once stimulated, these neurons send signals down the nerve cord to the wing‐motor circuitry controlling flight, allowing for a flight path correction. In laboratory experiments with restrained dragonflies, TSDN activity is relatively weaker and slower than expected from the behavior. We are testing the idea that this neural “lethargy” is due to the lack of neuromodulators such as octopamine in the restrained dragonfly's brain. We are investigating this hypothesis by comparing TSDN visual responses before and after injection of the octopamine mimic, chlordimeform. Our results show dramatic increases in TSDN spike activity after chlordimeform injection, suggesting that TSDN activity is augmented in the behaving animal by the neuromodulator, octopamine.

Further, utilizing intracellular recording techniques, we aim to identify the individual neurons which mediate responses to specific types of stimuli, such as approaching objects. Once a cell is identified, we will inject a dye through the recording microelectrode, which will travel within the cell in question up into the brain. This will allow us to obtain a structural representation of the neuron, which can then be linked back to its specific function in the visual processing cascade.

Support or Funding Information

Funded in part by a Student Research Grant from Union College.

Special thanks to Prof. Robert Olberg, Biology Department, Union College
Species Differences in Gastrointestinal Tract Glucose Transporters between Rainbow Trout (Oncorhynchus mykiss) and Nile Tilapia (Oreochromis niloticus)
Authors: Subramaniam Marina , Weber Lynn P , Ching John C , Enns Cole B , Kilgour Alyssa B , Drew Murray D , Loewen Matthew E
Published: November 2023

Metabolic differences in omnivore and carnivore glucose homeostasis are well established. However, differences in the gastrointestinal glucose transporers have not been well characterized. Here we assess the differences in electrogenic transport of D‐glucose along different sections of the intestine between Rainbow trout (Oncorhynchus mykiss), a carnivorous fish and Nile tilapia (Oreochromis niloticus), an omnivorous fish in Ussing chambers. The kinetics of glucose transport in pyloric caeca and midgut of trout were similar to the sodium‐dependent glucose transporter isoform 1 (SGLT1) in mammals, and the kinetics in colon resembled mammalian SGLT2. In contrast to trout, the kinetics in all three intestinal sections in tilapia resembled mammalian SGLT2. In addition, SGLT1 and SGLT2 inhibitors further confirm the locations of glucose transporters. In conclusion, trout has two types of SGLTs, a high affinity, low capacity transporter in pyloric caeca and midgut, and a low affinity, high capacity transporter in the colon. Tilapia has only one type of SGLT throughout the gut, which is a low affinity, high capacity transporter

Support or Funding Information

NSERC ‐ CRDPJ: 446912‐13 to LPW, MEL & MDD
Aquatic hypercapnia and aerial excretion of CO2 in air‐breathing fishes
Authors: Jew Corey , Thomsen Mikkel , Bayley Mark , Hicks James W
Published: November 2023

The notion that bimodal breathers (animals that breathe both air and water) obtain O2 from the air and exhale CO‐2 into the water has been well established in the literature. However, while the majority of supporting experiments tested animals maintained in hypoxic water, freshwater systems that bimodal breather inhabit have been reported to be hypercapnic as well. Data from 3 air‐breathing fishes show that when in hypercapnic water, excretion of CO2 into the air does increase, but the majority of CO2 is still released into the water. To maintain a downward diffusion gradient for CO2 from the gills to the water, a high blood PCO2 must also be sustained. Our data suggest in aquatic hypercapnia, air‐breathing fish are unable regulate blood PCO2 below that of the water. This is likely due to low ventilation at the air‐breathing organ and high surface area contact with water at the gills.

Support or Funding Information

Society for Experimental Biology, American Physiological Society
Glycogen synthesis from lactate in skeletal muscle of the painted turtle in vitro.
Authors: Wang Dongying , Hill Craig A. , Grombka‐Murphy Caitlan E. , Fisher Jonathon S. , Warren Daniel E. , Nguyen Karena
Published: November 2023

Painted turtles (Chrysemys picta) can accumulate lactate loads approaching 200 mM while over wintering in ice‐covered ponds, a feat achieved, in part, because of large glycogen stores in the liver and skeletal muscle. Mammals cannot directly synthesize glycogen from lactate in muscle and rely on liver Cori cycling for this purpose. To investigate the potential for gluconeogenesis from lactate in skeletal muscle in this species, turtles were made anoxic for 24 hours at 20°C to deplete skeletal muscle glycogen. Bundles of iliofibularis muscle were isolated and incubated in HEPES or CO2/HCO3− buffered solutions for 8 hours to determine the dependence of glycogen repletion on the buffering system at 20°C. Bundles were also incubated for 4 hours in solutions containing L‐[14C(U)]‐lactate with varying concentrations of glucose and lactate, and then analyzed for the amount of 14C that was oxidized or incorporated into muscle glycogen. Muscle glycogen synthesis required the presence of CO2 and HCO3−. The rates of 14C‐lactate oxidation and 14C‐incorporation into glycogen were independent of extracellular glucose, but dependent on extracellular lactate concentrations. The involvement of PEPCK, a key enzyme in gluconeogenesis, was also assessed using the specific inhibitor, 3‐mercaptopicolinic acid (MPA). 100 μM MPA inhibited 40% of the 14C‐incorporation into muscle glycogen when added to lactate incubations. To confirm the specificity of MPA on turtle PEPCK, enzyme assays were carried out with liver tissue homogenate. 100 μM MPA inhibited 86% of cytosolic PEPCK activity and 61% of mitochondrial PEPCK activity. This work confirms that the skeletal muscle mass of the turtle is important in the direct metabolism of lactate and provides additional support for the hypothesis that in situ skeletal muscle gluconeogenesis is the norm among vertebrates, rather than the exception.

Support or Funding Information

This study was funded by a National Institutes of Health R15 awarded to DEW.
Effects of High Intensity Interval Exercise on Peripheral Blood Flow and Muscle Tissue Oxygenation
Authors: Neeley Sarah K. , Luetkemeier Maurie J , Davis John
Published: November 2023

Intense physical exercise has profound effects on muscle metabolism. Previous studies have looked at muscle oxygenation changes with intense exercise. However, this study is unique in that its purpose is to look at the relationship between tissue oxygenation and blood flow delivery in response to a high intensity training protocol. Six subjects (Age = 20.5 ± 0.8 yrs, Weight = 68.6 ± 12.6 kgs) participated in four trials. During the first trial, a maximum cycle ergometer test was performed to determine the maximum power output for each participant. In the second trial, either condition one or condition two was performed in a random order. Condition one consisted of six bouts of high intensity exercise (HIE) followed by a one‐hour rest period. Each bout consisted of 30 seconds pedaling at the subject's maximum resistance followed by one minute pedaling without resistance (active recovery). Condition two consisted of two series of six HIE bouts separated by a 30 minute rest period followed by a one hour rest period. Near‐infrared spectroscopy (Portamon, Artinis Inc.) in the left gastrocnemius muscle was used to assess tissue saturation index (TSI). Slope of the TSI response was then calculated. Forearm blood flow was measured every ten minutes during the rest periods using venous occlusion plethysmography. Heart rate (HR) and beat‐to‐beat blood pressure were continuously recorded (CNAP 500, CNS Systems) throughout exercise and rest periods. In the third trial, baseline measurements of NIRS, forearm blood flow, and HR were taken. In the last trial, each subject completed whichever condition they did not complete on day two. TSI slope was consistently negative during the maximum resistance portions of exercise and was consistently positive during the active recovery portion of exercise. Slope of TSI % during the first bout of maximum resistance (Condition 1: −0.015 ± 0.007, Condition 2: −0.032 ± 0.046) declined at a greater rate than the following five bouts of exercise. Furthermore, slope of TSI % during the one‐hour rest in both conditions was highest one minute into the rest period (Condition 1: 0.0011 ± 0.0015, Condition 2: 0.0020 ± 0.0023) and then returned to baseline by 11 minutes into the rest period. Forearm blood flow during the one‐hour rest in both conditions was also highest one minute into the rest period (Condition 1: 11.4 ± 6.3 ml/100 ml/min, Condition 2: 10.3 ± 2.8 ml/100 ml/min) and then returned to baseline by 11 minutes into the rest period. In conclusion, muscle oxygenation declined at a high rate during HIE and was partially restored during active recovery. Most of the deoxygenation occurred during the first HIE bout, suggesting that increased blood flow in subsequent bouts facilitated an increase in oxygen delivery
Oxygen uptake efficiency slope in patients with metabolic syndrome and obstructive sleep apnea
Authors: Carvalho Jefferson Cabral , Cepeda Felipe Xerez , Rodrigues Sara , Dutra‐Marques Akothirene Cristhina Brisolla , Toschi‐Dias Edgar , Rondon Maria Urbana Pinto Brandão , Alves Maria‐Janieire Nazaré Nunes , Braga Ana Maria Fonseca Wanderley , Lorenzi‐Filho Geraldo , Trombetta Ivani Credidio
Published: November 2023

Patients with metabolic syndrome (MetS) and obstructive sleep apnea (OSA) have increased cardiovascular risk. Besides decreased peak oxygen consumption peak (VO2peak), the decreased on Oxygen uptake efficiency slope (OUES) during cardiopulmonary exercise testing (CPET) can be used as a marker submaximal of worst prognosis. Therefore, we tested the hypotheses that: 1) OUES is decreased in MetS patients and the association of MetS; 2) OSA causes further decreased on OUES; and 3) The MetS risk factors are associated with OUES. Seventy eight MetS sedentary patients (ATP‐III) without the use of drugs were divided into: MetS+OSA (n=39, 50±1 yrs) and MetS‐OSA (n=33, 45±1 yrs). A control group (C; n=21, 46±1 yrs) was also studied. OSA was determined by apnea/hypopnea index (AHI>15events/h‐polysomnography). The OUES was obtained through the CPET by linear regression analysis of the relation between relative oxygen uptake (ml/kg/min) and the logarithm of VE (l/min), from the 1st min up to maximum effort (OUES100%). Besides, we analyzed the OUES in relation to lean mass body (LMB) (OUES100% LMB). The LMB was obtained by bioimpedance. The MetS+OSA and MetS‐OSA were similar, and both presented lower levels than C regarding OUES100% (25.3± 0,8, 25.3±0,9 and 32.3± 1,7 ml/kg/min/log, respectively p<0.001). Similar results were found to OUES100% LMB (36.8± 1.0, 38.2± 1.1 and 44.2± 2.7 ml/kg/min/log, p=0.003) and to VO2peak (21.7±0.9 vs. 21.8± 0.7 vs. 28±1.4 ml/kg/min, p<0.001). MetS groups have similar MetS risk factors and in body mass index (BMI) and greater than C. Regarding LMB, no difference was observed among groups. Further analysis showed that there were no association between the MetS risk factors or apnea/hypopnea index with OUES. Only BMI was associated with OUES 100% (r=−0,31, p=0.002). MetS patients have impaired cardiorespiratory efficiency during exercise independently of the presence of OSA. The excess body fat seems to be the main cause of this impairment in MetS patients.

Support or Funding Information

This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP# 2011/17533‐6 ) and, in part, by Fundação Zerbini. Jefferson C Carvalho was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Felipe X Cepeda was supported by FAPESP# 2015/03274‐0,Sara Rodrigues was supported by FAPESP# 2013/15323‐0, Akothirene CB Dutra‐Marques was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Edgar Toschi‐Dias was supported by FAPESP# 2013/07651‐7.
Persistent augmentation of the blood pressure and heart rate responses to dynamic exercise in rats with chronic bilateral femoral artery occlusion
Authors: Kuczmarski James M. , Unrath Kellee , Thomas Gail D.
Published: November 2023

The blood pressure (BP) response to treadmill walking or low‐intensity leg exercise is exaggerated in patients with atherosclerotic peripheral artery disease (PAD), but the contribution of muscle hypoperfusion to the heightened pressor response independent of other disease mechanisms is unclear. In healthy humans and animals, the pressor response to exercise is augmented when blood flow is acutely restricted to the active muscles. Whether BP is similarly exacerbated by chronic hypoperfusion of exercising muscle is uncertain, because BP during exercise is reported to be both increased and unchanged in cross‐sectional studies of rats with occluded versus freely perfused hindlimbs. To address this question, we performed a longitudinal study of the pressor response to exercise before and after bilateral femoral artery ligation in Sprague Dawley rats (n = 8; 5M, 3F). BP and heart rate (HR) were measured using radiotelemetry before, during, and after treadmill exercise (15 m/min; 5° incline) at repeated intervals pre‐and post‐ligation. Before ligation, exercise evoked reproducible increases in mean BP (115 ± 1 vs 123 ± 2 mmHg, P<0.05) and HR (402 ± 13 vs 496 ± 11 bpm, P<0.05), both of which returned to pre‐exercise levels within 10 min of recovery (108 ± 2 mmHg and 405 ± 12 bpm, P>0.05 vs pre‐exercise). Beginning as early as day 3 post‐ligation, the exercise‐induced increases in mean BP (+15 ± 2 mmHg) and HR (+150 ± 9 bpm) were augmented compared to the pre‐ligation responses (BP, +8 ± 2 mmHg; HR, +94 ± 11 bpm; both P<0.05 vs day 3). BP responses remained enhanced by 1.6–2.2 fold and HR by 1.2–1.4 fold from day 6 until the final measurement at day 28 post‐ligation (BP, +16 ± 2 mmHg; HR, +138 ± 11 bpm; p<0.05 vs pre‐ligation). These findings indicate that non‐atherosclerotic femoral artery occlusion elicits exaggerated, sustained BP and HR responses to dynamic exercise in rats that resemble those of PAD patients, suggesting that functional muscle ischemia is an independent factor underlying abnormal cardiovascular responses to exercise. Long‐term telemetric recording of blood pressure coupled with treadmill exercise offers a sensitive method to evaluate cardiovascular mechanisms and potential therapeutic interventions in rodent models of demand ischemia.
A novel model of weightlifting in mice: Signaling and gene transcription responses in skeletal muscle
Authors: Cui Di , Lewellen Bevan , Wilson Rebecca , Zhang Mei , Yan Zhen
Published: November 2023

Resistance exercise promotes skeletal muscle hypertrophy, prevents muscle atrophy and improves muscle function. However, despite the significant biological and clinical relevance we still have a poor understanding of the molecular and cellular mechanisms. A critical barrier is the lack of an appropriate animal model of resistance training. We have developed a novel weightlifting cage for mice to perform squat like movements against weight and subjected adult wild type mice (C57BL/6) to an acute bout of weightlifting (WL; n = 4) using sedentary mice as control (CON; n = 3). Following 3 days of acclimatization in the cage, mice in the WL group were allowed to perform weightlifting against 150% of their body weight overnight during the dark cycle (12 hrs). Immediately following the dark cycle, all the mice were sacrificed, and skeletal muscle, liver and heart tissues were harvested for RNA and protein analyses. Mice in the WL group pushed 419±83 times overnight. Semi‐quantitative RT‐PCR showed 3‐fold increase of tumor necrosis factor receptor superfamily, member 12 (Tnfrsf12a or Fn14) mRNA and 2‐fold increase of down syndrome critical region gene 1 (Dscr1) mRNA with no change in TNF‐related weak inducer of apoptosis (Tweak) mRNA in gastrocnemius muscle. Western blot analysis no significant changes in 5′ AMP‐activated protein kinase (AMPK), phospho‐AMPK (p‐AMPKThr172), protein kinase B (Akt), p‐AKTSer473 and cleaved Notch1 proteins. Therefore, we have developed a novel model of resistance exercise and confirmed that weightlifting results in increased Fn14 and Dscr1 mRNA in recruited skeletal muscle. This novel weightlifting cage may be used as a model of resistant exercise for future research.

Support or Funding Information

China Scholarship Council Fund (201506140108)
Power Reserve at the Limit of Ramp‐incremental Exercise is Affected by Incrementation Rate
Authors: Davies Matthew J , Benson Alan P , Birch Karen M , Rossiter Harry B , Ferguson Carrie
Published: November 2023

The mechanisms that bring about task failure during exercise in which VO2max is attained remain poorly understood. A fundamental question is whether maximum voluntary power declines to the point at which it no longer exceeds the requirements of the exercise task (i.e. no power reserve). We recently demonstrated that there was no power reserve at the limit of tolerance (LoT) of ramp‐incremental (RI) cycle ergometry, but that the central and peripheral contributions to performance fatigue (PF; i.e. the decline in maximal voluntary power) were widely heterogeneous amongst individuals. As the kinetics of central and peripheral limitations to power generation are likely to be influenced by the kinetics of the task, we aimed to determine the influence of ramp‐incrementation rate on the power reserve at the LoT.

Using an instantaneous switch from cadence‐independent to isokinetic cycling, peak isokinetic power (PISO, measured at 80 rpm for 6 s) was measured at baseline, and at the LoT of 3 maximal RI exercise tests (LoT PISO). Ramp‐incrementation rates of 10, 25 and 50 W·min−1 (RI‐10, RI‐25 and RI‐50, respectively) were performed in seven healthy participants (mean ± SD; 27 ± 6 yr; 174 ± 9 cm; 72 ± 10 kg; 5 m, 2 f). Breath‐by‐breath pulmonary gas exchange was measured throughout all protocols.

Baseline PISO was not different amongst the three RI protocols (732 ± 140, 739 ± 143, and 737 ± 144 W for RI‐10, RI‐25 and RI‐50, respectively; p > 0.05). VO2max at LoT was within the normal day‐to‐day variation (< 7 %) across the three RI protocols (mean: 3.69 ± 0.74 L·min−1); however, flywheel power requirement at LoT increased with ramp rate (RI‐10: 270 ± 38; RI‐25: 318 ± 43; RI‐50: 354 ± 52 W; p < 0.05). PF was 313 ± 135, 346 ± 129, 380 ± 139 W for RI‐10, RI‐25 and RI‐50, respectively (p > 0.05), with LoT PISO decreasing to 54 ± 12 % of baseline PISO. Thus at LoT, PISO was greater than flywheel power in RI‐10 (p < 0.05), but was not different from flywheel power in RI‐25 and RI‐50 (p > 0.05).

At the limit of ramp‐incremental exercise in which VO2max is attained, the absence of a power reserve in RI‐25 and RI‐50 is consistent with the notion that exercise intolerance occurs when maximal evocable power equals the power required by the task. However, our data indicate that, while there was considerable fatigue during RI‐10, the decline in PISO was insufficient to limit the exercise, thus other mechanisms were contributory to the exercise limitation in this slow ramp condition. This suggests that the mechanisms that precipitate task failure at VO2max are plastic in young healthy subjects, and dependent on the kinetics of the task.
X‐irradiation and Simulated Microgravity affects Rat Weight, Food Intake, Insulin and Paw Pressure Pain Threshold
Authors: Chowdhury Parimal , Akel Nisreen , Parsian Azmat‐Jamshidi , Griffin Robert , Yadlapalli Jai , Dobretsov Maxim
Published: November 2023

The aim of this study is to examine various physiological measurements in response to range of space‐like radiation doses in a NASA‐validated rodent model of simulated microgravity.

Methods

Four groups of rats (6 rats per group), control (CON), irradiated (IR), irradiated plus hindlimb suspended (IR+HLS) and suspended (HLS), were used in the study and maintained for two consecutive weeks. IR and IR+HLS groups were exposed to five sessions of X‐ray irradiation (0.5 Gy each, at 3–4 days intervals; cumulative dose 1.2 Gy). Body weights, food and water intakes, pressure pain thresholds and random blood plasma insulin levels were measured.

Results

Compared to CON, weight gain was slowed by about 25% in IR animals and by 50% in HLS and IR+HLS groups. IR acutely decreased food consumption by 20%‐50% when compared to pre‐exposure levels. Effect of HLS on food consumption (15% decrease) was evident during first day of post‐suspension. HLS but not IR resulted in deep tissue hyperalgesia (45% decreases in PPT) and a 40%–60% decrease in plasma insulin levels.

Summary and Conclusions

These observations suggest that exposure to IR may contribute to space flight‐associated anorexia and weight loss. However exposure to microgravity and lower limb disuse appear to be associated with complications. These include insulinopenia, deep tissue hyperalgesia and the muscle atrophy in addition to weight loss and, from our previous studies, bone degenerative effects.

Support or Funding Information

Supported by a grant from Arkansas Space Grant Consortium
Are Inert Gases Inert? Hyperbaric Nitrogen and Hyperoxia Stimulate Singlet O2 Production in Solitary Complex Neurons of the Dorsocaudal Medulla in Rat Brain Slices
Authors: Roberts Teryn , Dean Jay B.
Published: November 2023

InertGas Narcosis (IGN, or N2 Narcosis) at hyperbaric pressure is alimiting factor in US Naval diving operations; however, little is known aboutthe mechanisms underlying this CNS disorder. It has been hypothesized that inertgases such as N2 interact with O2 at hyperbaric pressureto form collision complexes that generate singlet oxygen (1O2). If true then 1O2 maycontribute, in part, to onset of IGN. Accordingly, we predict that hyperbaric nitrogen (HBN2) willinteract with O2‐sensitive neurons in the caudal solitary complex(cSC) to generate 1O2. The goals of this study were to 1)develop an in vitro system for measuring 1O2 productionin real time in the mammalian CNS; 2) determine the effect of hyperoxia (0.4→0.95 atmospheres absolute, ATA) on 1O2production at normobaric pressure; and 3) determine the effect of HBN2(up to 6.6ATA N2) on 1O2 production duringhyperoxia (0.95ATA O2). The fluorescent probe Singlet Oxygen SensorGreen (SOSG) was used to detect 1O2 production in thebrain slices of rat medulla oblongata (P16‐40, male/female, 400μm, 30–36°C). Fluorescence intensity of cSC neurons was measured at 1–2.5min intervalsand correlated with 1O2 production using one of two NikonTE2000 inverted microscopes; one microscope was automated for use inside asealed hyperbaric chamber (MWP=85psig). Confocalimaging indicated that SOSG reaction product during excitation was confined tothe soma, proximal processes and fibers. Results show that increasing pO2 from 0.4 to 0.95 ATA increased the rate of 1O2 production. Ascorbate (1–4mM),an inhibitor of 1O2, decreased the rate of 1O2production in control O2 and hyperoxia in a dose‐dependent manner. Exposure to HBN2 (0.25ATA/min) at maximum depth (10 min) followed by decompression (0.5ATA/min) back to sea level caused a post‐dive transientincrease in 1O2 that lasted at least 10min. These findings demonstrate 1O2 can be measured in CNS neurons in brain slices using SOSG and that 1O2production is stimulated by normobaric hyperoxia. Additionally, exposure to HBN2 increases 1O2 production but not untilde compression. This suggests that 1O2production is activated by compression to at least 6.6ATA N2, decompression or both. Thus, we postulate that 1O2 generated subsequent to exposure to HBN2 may contribute to IGN and decompression sickness.

Support or Funding Information

ONR Undersea Medicine
Prolonged Adenosine Triphosphate Infusion & Exercise Hyperemia
Authors: Shepherd John Roger Alden , Joyner Michael J. , Dinenno Frank A , Curry Timothy B , Ranadive Sushant M
Published: November 2023

Adenosine triphosphate (ATP) is postulated to be a major exercise related vasodilating metabolite. In humans, ATP infusion mimics exercise hyperemia. However, it remains unknown whether ATP can evoke the prolonged vasodilation seen during exercise. Therefore we tested two hypotheses during a three‐hour intra‐arterial infusion of a high dose of ATP (20 μgrams ·100 mL forearm vol−1·min−1): (1) skeletal muscle blood flow would wane over time (tachyphalaxis); (2) exercise hyperemic responses during ATP administration would be blunted compared to baseline. Nine healthy young participants (25 ± 1 years) performed seven rhythmic handgrip exercise bouts (20% of maximum), two during saline (control) and five during 180 minutes of continuous ATP infusion. Forearm vascular conductance (FVC; ml min−1 (100 mmHg) −1) and percent (%) change from control were calculated. Five minutes of ATP infusion resulted in a 710% increase in FVC (4.8±0.3 vs 35.0±1.9 ml min−1 *100 mmHg −1, P<0.05). FVC did not wane over time with values of 35.0±1.9 and 36±2.6 ml min−1 (100 mmHg) −1 (P>0.05) seen prior to the exercise bouts at 5 vs 150 minutes respectively. With superimposed exercise FVC increased from 35.0±1.9 to 49.6±2.2 ml min−1 *100 mmHg −1 at five minutes and 36.0±2.6 to 54.5±1.1 at 150 min (P<0.05). Our findings demonstrate (1) ATP vasodilation is sustained over time without tachyphalaxis; (2) vasodilator responses to exercise during high dose ATP infusion remain intact. This latter finding questions the extent to which ATP is obligatory for exercise hyperemia.

Support or Funding Information

This research was supported by National Institutes of Health Research Grants HL‐119337 and by CTSA UL1 TR000135. The Caywood Professorship via the Mayo Foundation also supported this research.
Effect of High‐intensity Interval Training on Endothelial Function in Older Postmenopausal Women: a Randomized Controlled Trial
Authors: Yoo Jeung‐Ki , Hwang Moon‐Hyon , Kim Han‐Kyul , Hwang Ehueh‐Lung , Handberg Eileen Mary , Christou Demetra
Published: November 2023

Vascular endothelial function is impaired with aging and is an independent predictor of cardiovascular disease. Moderate‐intensity continuous training (MICT) is associated with enhanced vascular endothelial function in older men. However, in older postmenopausal women the data are inconsistent. A higher exercise intensity might be needed for improvements in vascular endothelial function in postmenopausal women, but this has not been investigated. We hypothesized that vascular endothelial function will improve following high‐intensity interval training (HIIT), but not MICT in older postmenopausal women. To test this hypothesis, twenty four sedentary older postmenopausal women (age 56 to 76 yrs, 65±1yrs; mean±SE), free of overt cardiovascular disease, were randomized to HIIT (n=9), MICT (n=7), or non‐exercise control group (CONT; n=8). Equal volumes of HIIT and MICT were performed on Airdyne bicycles, 4 days/week for 8 weeks under supervision. HIIT consisted of cycling at alternating intensities of 90 and 70% of maximal heart rate for 40 min, while MICT consisted of 47 min of cycling at 70% of maximal heart rate. Vascular endothelial function was evaluated before and after the intervention using brachial artery flow‐mediated dilation (FMD) in response to post‐occlusion reactive hyperemia via ultrasonography. HIIT and MICT did not improve % FMD (HIIT: 4.39±1.15 vs. 4.41±1.05 %, MICT: 5.12±1.13 vs. 4.97±0.58 %, CONT: 4.18±0.87 vs. 4.24±0.95 %, pre‐ vs. post‐intervention; P>0.05) or absolute change in FMD (HIIT: 0.14±0.03 vs. 0.16±0.04 mm, MICT: 0.16±0.03 vs. 0.16±0.03 mm, CONT: 0.13±0.03 vs. 0.14±0.03 mm; P>0.05). Baseline brachial artery diameter did not change in any of the groups (HIIT: 3.32±0.14 vs. 3.43±0.16 mm; MICT: 3.23±0.08 vs. 3.16±0.07 mm; CONT: 3.21±0.16 vs. 3.28±0.16 mm; P>0.05). Systolic blood pressure remained unchanged in all groups (HIIT: 122±6 vs. 119±6; MICT: 117±4 vs. 118±5; CONT:119±4 vs. 120±5, P>0.05). Diastolic blood pressure decreased with HIIT (70±2 vs. 67±2 mmHg, P<0.05), but not with MICT (66±4 vs. 66±3 mmHg; P>0.05) or CONT (67±2 vs. 70±2 mmHg; P>0.05). In conclusion, neither HIIT or MICT lead to restored vascular endothelial function in older postmenopausal women, although HIIT improves diastolic blood pressure.
Tempol Augments the Blunted Cutaneous Microvascular Thermal Reactivity in Healthy Young African Americans
Authors: Hurr Chansol , Patik Jordan C , Christmas Kevin M. , Brothers R. Matthew
Published: November 2023

African Americans (AA) have a higher risk for a variety of cardiovascular and metabolic diseases including hypertension, stroke, peripheral artery disease, and type 2 diabetes mellitus when compared with Caucasian Americans (CA). While this elevated risk is multifactorial impaired vascular endothelial function is a contributing factor. In this study, we hypothesized that cutaneous hyperemic response to a standard local heating protocol is reduced in young AA when compared with CA. We further hypothesized that tempol (a superoxide dismutase mimetic) would increase this cutaneous vasodilatory response to local heating in AA. Microdialysis fibers were randomly assigned to receive 1) lactated Ringer's solution (Control), 2) 10 mM ascorbic acid, or 3) 10 μM 4‐hydroxy‐2,2,6,6‐tetramethylpiperidine‐1‐oxyl (Tempol) at a rate of 2.0 μl/min. Cutaneous vascular conductance (CVC) was calculated as red blood cell flux divided by mean arterial pressure. All CVC data were presented as a percentage of maximal CVC (%CVCmax) that was determined by maximal cutaneous vasodilation induced by 44 °C plus sodium nitroprusside administration. Twenty‐four (12 AA, 12 CA) young (23 ± 4 years of age) and healthy (body mass index (24.3 ± 2.8 kg/m2) subjects participated in the study. At the Control site, there were no differences between groups for baseline %CVCmax during resting without heat (P = 0.275). During 33 °C, there were still no differences in %CVCmax between groups (P = 0.107); however, %CVCmax at 39 °C was lower in AA when compared with CA (P < 0.001). At the ascorbic acid site, there were no differences between groups for both baseline %CVCmax during resting without heat (P = 0.549) and %CVCmax during 33 °C (P = 0.120); however, %CVCmax at 39 °C was attenuated in AA relative to CA (P < 0.001). At tempol site, there were no differences between groups for all phases including baseline CVC during resting without heat (P = 0.791), %CVCmax during 33 °C (P = 0.550), and %CVCmax at 39 °C (P = 0.948). These data suggest that 1) cutaneous vasodilation in response to local heating is blunted in AA relative to CA. 2) in AA, elevated O2− generation attenuates cutaneous vasodilation when heat is directly applied to the skin.

Support or Funding Information

Institutional start‐up funds from The University of Texas at Austin
Long Term Endurance Exercise Training Ameliorates Conduit Artery Retrograde and Oscillatory Shear in Older Adults
Authors: Schneider Aaron C. , Ueda Kenichi , Casey Darren P.
Published: November 2023

With aging, there tends to be an increase in retrograde and oscillatory shear in peripheral conduit arteries of humans. Whether the increase in shear rate is due to the aging process or an effect of a less than active lifestyle that often accompanies aging is unknown. Therefore, in a cross‐sectional study we evaluated whether chronic endurance exercise training attenuates retrograde and oscillatory shear in older adults. Brachial and common femoral artery mean blood velocities and diameter were determined via Doppler ultrasound under resting conditions in 13 young (Y = 24 ± 1 years), 17 older untrained (OU = 66 ± 1 years), and 16 older endurance exercise trained adults (OT = 66 ± 2 years). Mean shear rate (s−1) was defined as 4·Vm/D, where Vm is mean blood velocity (cm · s−1) and D is arterial diameter (cm). For calculations of antegrade and retrograde shear rate, antegrade and retrograde mean blood velocities were used, respectively. Oscillatory shear index is an indicator of the magnitude of oscillation between antegrade and retrograde shear. Vascular resistance in the forearm and leg were also calculated (mean arterial pressure/blood flow) using each respective limb blood flow and mean arterial pressure derived from beat‐to‐beat finger plethysmography measurements. Brachial artery retrograde (−9.1 ± 1.7 vs. −12.6 ± 2.3 s−1; P = 0.35) and oscillatory (0.14 ± 0.02 vs. 0.14 ± 0.02 arbitrary units; P = 0.99) shear were similar between the OT and OU groups, whereas brachial retrograde and oscillatory shear were greater in OU compared to Y adults (−5.0 ± 0.9 s−1, 0.08 ± 0.01 arbitrary units, both P < 0.05; respectively). There was no difference between the Y and OT brachial artery retrograde (P = 0.29) and oscillatory (P = 0.07) shear. Common femoral artery retrograde (−6.3 ± 0.7 s−1) and oscillatory (0.21 ± 0.02 arbitrary units) shear was reduced in OT compared to the OU group (−10.4 ± 1.0 s−1 and 0.30 ± 0.02 arbitrary units, both P < 0.05; respectively), yet similar to Y adults (−7.1 ± 1.0 s−1 and 0.19 ± 0.02 arbitrary units, P = 0.81 and 0.87; respectively). Vascular resistance did not differ between groups in the arm (P = 0.56) or the leg (P = 0.32). However, vascular resistance was inversely related to retrograde shear in the brachial and common femoral artery (r = −0.33 and −0.37, both P < 0.05; respectively) and positively related to oscillatory shear in the brachial and common femoral artery (r = 0.46 and 0.54, both P < 0.05; respectively) when all subjects were pooled together. Our results suggest that chronic endurance exercise training in older adults ameliorates retrograde and oscillatory shear rate patterns, particularly in the common femoral artery.

Support or Funding Information

Research was supported by NIH HL‐105467 (DPC)
Elevated Extracellular Potassium Prior to Muscle Contraction Reduces Exercise Hyperemia in Humans
Authors: Terwoord Janee D. , Hearon Christopher M. , Luckasen Gary J. , Larson Dennis G. , Joyner Michael J. , Dinenno Frank A.
Published: November 2023

During muscle contractions, an increase in interstitial potassium (K+) and subsequent activation of inwardly‐rectifying K+ (KIR) channels is thought to be a functional vasodilatory signal contributing to exercise hyperemia. Indeed, our laboratory has recently demonstrated that inhibition of KIR channels blunts exercise hyperemia ~30% in humans. In theory, the vasodilatory response to changes in interstitial K+ during muscle contraction could be minimized by artificially elevating the concentration of K+ perfusing the vasculature prior to the onset of muscle contractions, thus limiting further recruitment of this pathway and blunting the dilatory response to exercise. We tested the hypothesis that infusion of potassium chloride (KCl) to elevate extracellular potassium concentrations and induce hyperpolarization prior to the onset of muscle contractions would reduce the contribution of this mechanism to the dilatory response to exercise. In young adults (n = 10), we measured forearm blood flow (FBF; Doppler ultrasound) and calculated changes in vascular conductance (FVC; FBF/intra‐arterial blood pressure) during 4 minutes of rhythmic handgrip exercise at 10% of maximal voluntary contraction during 1) control conditions (CTRL), 2) local, intra‐arterial infusion of KCl to elevate the concentration of K+ prior to the initiation of exercise, and 3) intra‐arterial infusion of sodium nitroprusside (SNP) as a high flow control to match the K+‐induced vasodilation observed at rest. As intended, infusion of KCl or SNP elevated resting FVC similarly prior to the onset of exercise (CTRL: 40 ± 7 vs. KCl: 84 ± 13 and SNP: 85 ± 14 ml·min−1·100 mmHg−1; both P < 0.01 vs. CTRL). Infusion of KCl diminished the subsequent vasodilatory response to handgrip exercise by ~31% when compared to control conditions (ΔFVC: KCl: 92 ± 14 vs. CTRL: 133 ± 16 ml·min−1·100 mmHg−1; P < 0.01), whereas elevation of resting FVC with SNP prior to contractions did not change the vasodilatory response to exercise (ΔFVC, SNP: 117 ± 15 vs. CTRL: 133 ± 16 ml·min−1·100 mmHg−1; P = NS). These findings indicate that K+‐mediated hyperpolarization prior to the onset of muscle contractions blunts the normal vasodilatory response to exercise, which supports a role for elevated K+ signaling in the hyperemic response to exercise in humans.

Support or Funding Information

HL119337, HL095573
Hypercapnic Cerebral Vasodilation: Contribution of Cyclooxygenase and Reactive Oxygen Species in Healthy and Metabolic Syndrome Adults
Authors: Harrell John , Peltonen Garret , LaPlante Kaylie , Ernst Brady , Schrage William
Published: November 2023

Excess reactive oxygen species (ROS) limit cerebral vasodilation in animal models of metabolic syndrome (MetSyn). Cyclooxygenase (COX) may be a source of ROS, but data are lacking in humans. We hypothesized ROS limit hypercapnic cerebral vasodilation in human MetSyn, but COX is not the source. We measured middle cerebral artery velocity (MCAv) with transcranial Doppler ultrasound in 12 MetSyn adults (34±2 yr) and 12 healthy adults (28±1 yr) during baseline and hypercapnia (end‐tidal CO‐2 +10 mmHg). Hypercapnia was performed under three conditions: 1) control, 2) ROS inhibition (intravenous ascorbic acid infusion), and 3) combined ROS and COX inhibition (oral indomethacin). MCAv was normalized for MABP and expressed as cerebrovascular conductance index [CVCi = (MCAv ÷ MABP) * 100]. The change in CVCi from baseline (ΔCVCi) indicated hypercapnic cerebral vasodilation. Hypercapnia increased CVCi in both groups across all conditions (p<0.05). ΔCVCi was similar between groups in control trials and was unaffected by ROS inhibition. Combined ROS‐COX inhibition greatly decreased hypercapnic ΔCVCi (p<0.05) similarly in both groups (healthy: 70±7% vs. MetSyn 84±8%). The decrease in hypercapnic cerebral vasodilation with combined ROS‐COX inhibition was quantitatively greater than previous published results with COX inhibition alone (~50% in both groups). In summary, MetSyn does not decrease hypercapnic cerebral vasodilation. ROS alone are not obligatory or inhibitory for hypercapnic cerebral vasodilation. Rather, ROS interact with COX to account for the vast majority (>70%) of hypercapnic cerebral vasodilation in healthy and MetSyn adults.

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AHA PRE7390038
Aerobic Exercise Dampens Acute Hypertension‐Induced Vascular Oxidative Stress
Authors: Robinson Austin T , Fancher Ibra Seaphus , Bian Jing‐Tan , Ali Mohamed M , Sudhahar Varadarajan , Ushio‐Fukai Masuko , Fukai Tohru , Levitan Irena , Phillips Shane A
Published: November 2023

Regular exercise prevents endothelium dysfunction (ED) following acute strenuous physical exertion. Acute strenuous exertion induces ED via exposing the vascular endothelium to transient hypertension (HTN). The purpose of this study was to determine the mechanisms through which regular exercise may protect the endothelium against HTN‐induced ED. Twenty‐eight 14–18 week mice were assigned to voluntary wheel running for two weeks (EX; mean: 7 miles/day) or control (CON). Hind limb subcutaneous adipose resistance arteries (RAs) were dissected and cannulated for measures of flow induced dilation (FID) with and without exposure to high intraluminal pressure (HILP; 110mmHg) and pharmacological agents including the nitric oxide synthase (NOS) inhibitor L‐NAME (100 μM), hydrogen peroxide (H2O2) scavenger PEG‐Cat (500 U/ml, and the angiotensin receptor blocker losartan (10 μM). Fluorescence microscopy was used to determine O2− and H2O2 production and western blot was used to determine NOX2 and SOD content. Following exposure to acute HILP, FID was preserved in EX and reduced in CON but rescued with losartan, NADPH oxidase inhibition (VAS2870; 2 μM) and the anti‐oxidant Apocynin (50 μM). Furthermore, preserved FID in EX was significantly reduced in the presence of PEG‐Cat compared to L‐NAME. CON expressed more NOX2 and produced greater amounts of O2− following transient HTN while EX expressed more SOD and produced more H2O2. These findings suggest regular exercise prevents HTN‐induced reductions in FID and the mechanism involves attenuating RAAS activation of NOX2 generation and dismutation of O2− to H2O2.

Support or Funding Information

NHLBI K23HL85614, RO1HL095701, and HL095701‐01A2S