bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of Muscle Fiber Recruitment on Local Vasodilation During Work‐Matched Exercise in Humans: Role for KIR Channel Activation
Authors: Terwoord Janee D. , Hearon Christopher M. , Racine Matthew L. , Luckasen Gary J. , Dinenno Frank A. 
Published: November 2023

Under conditions of constant muscle contractile work, blood flow to active skeletal muscle is augmented with greater muscle fiber recruitment (MFR), but the mechanisms coordinating this response remain poorly understood. We tested the hypothesis that activation of inwardly‐rectifying potassium channels (KIR) underlies the augmented local vasodilation and hyperemia observed with increased MFR during work‐matched exercise in humans. We measured forearm blood flow (FBF; Doppler ultrasound) and calculated vascular conductance (FVC; quotient of FBF and mean arterial pressure) in 10 young adults (5 male, 5 female) during dynamic handgrip exercise protocols in which work was held constant but MFR was manipulated. Two bouts of rhythmic handgrip exercise (4 min each) were performed before and during local, intra‐arterial infusion of barium chloride (BaCl2) to inhibit KIR channels: 1) “High MFR,” in which participants used a pulley system to lift a load equivalent to 25% of maximal voluntary contraction (MVC) with a contraction‐to‐relaxation duty cycle of 1:7 seconds and 2) “Low MFR,” with contractions at 12.5% MVC and a 1:3 sec contraction‐to‐relaxation duty cycle. As expected, under control conditions, EMG activity of the flexor digitorum muscles was ~ 75% greater during the high vs. low MFR trial (P < 0.05). In control conditions, FBF (200 ± 28 vs. 166 ± 24 ml· min−1, P < 0.05) and FVC (207 ± 28 vs. 171 ± 24 ml· min−1· 100 mmHg−1, P < 0.05) were greater during the high vs. low MFR trials. Inhibition of KIR channels reduced steady‐state FBF and FVC during both high and low MFR trials, and abolished the differences between the two conditions (FBF: 143 ± 23 vs. 136 ± 21 ml· min−1, P = 0.36; FVC: 140 ± 21 vs. 134 ± 21 ml· min−1· 100 mmHg−1, P = 0.32) As such, the effect of KIR channel inhibition on FBF (−28 ± 7 vs. −17 ± 6%, P = 0.059) and FVC (−32 ± 6 vs. −21 ± 6%, P < 0.05) was greater in the high vs. low MFR condition. We conclude that augmenting MFR independent of contractile work elicits vasodilation via activation of KIR channels. We speculate that K+ released from skeletal muscle fibers upon repolarization may activate KIR channels and serve as a feed forward mechanism to increase muscle blood flow in proportion to the amount of muscle fibers recruited during exercise.Support or Funding InformationSupported by NIH HL119337
The Effect of Exogenous Adenosine Triphosphate on Blood Flow Kinetics During Dynamic Forearm Exercise
Authors: Shepherd John R. A. , Joyner Michael J. , Dillon Gabrielle A. , Dinenno Frank A. , Curry Timothy B. , Ranadive Sushant M. 
Published: November 2023

IntroductionAdenosine triphosphate (ATP) is a vasodilating metabolite that plays a role in exercise hyperemia. In humans, exogenous infusion of ATP elevates skeletal muscle blood flow values to that observed during moderate‐intensity exercise. Recently ATP has been shown to evoke prolonged vasodilation over 150 minutes without tachyphylaxis. However, the steady‐state hyperemic responses to superimposed forearm exercise remain unaltered. The kinetics of blood flow during the initiation of exercise remains not well understood. Therefore we evaluated the effects of prolonged exogenous infusion of ATP on exercise hyperemia during the transition between rest and initiation of exercise.MethodsWhile supine, eight healthy young participants (4M/4F; 25±1 years) performed 5 minutes of rhythmic dynamic handgrip exercise bouts (20% of maximum), first during saline (control), then at minute 5 and minute 150 during a continuous ATP infusion into the brachial artery. Each duty cycle consisted of 1 second contraction and 2 second relaxation. Mean blood velocity (MBV; cm/s), forearm vascular conductance (FVC; ml/minutes/100 mmHg), and shear rate (8*MBV/diameter; seconds−1) were calculated. The kinetics at the onset of exercise was assessed by calculating the slope of the FVC responses for the first 20 duty cycles after the start of contractions. Data are presented as means ± SEM.ResultsDuring saline control FVC was 3.9±0.3 at rest and with exercise rose to 22.7±0.84 and 27.8±1.2 ml/minute/100mmHg at 30 seconds and 1 minute, respectively (P<0.05 for both). Infusion of ATP increased FVC (3.9±0.3 vs 43.1±2.0 ml/minutes/100 mmHg, P<0.05) at five minutes and to 61.0±1.1 ml/minutes/100 mmHg at 150 minutes (P<0.05) with no systemic hemodynamic changes. Prolonged infusion of ATP did not alter the kinetics at the onset of contractions over 20 duty cycles of exercise hyperemic responses compared to control (0.71±0.1 control vs 1.01±0.1 ml/minutes/100mmHg/cycle at 5 minutes and vs 0.65±0.1 at 150 minutes, P>0.05 for all). Shear rate significantly increased compared to control (92±5 vs 751±57 seconds−1, P<0.05) but was not different across exercise responses during ATP infusion (751±57 at 5 minutes vs 549±46 seconds−1 at 150 minutes, P>0.05).ConclusionsOur findings demonstrate that despite the ability of ATP to elevate blood flow to that observed during exercise, the blood flow kinetics for the initiation of dynamic exercise hyperemic response are unaffected and remain unaltered after 150 minutes of prolonged ATP infusion. Further investigation in needed to understand the role of ATP in regulating the blood flow kinetics during dynamic exercise in humans.Support or Funding InformationThis 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 study.
Effect of Normobaric Hypoxia Simulating 3,500 m on SpO2 and Workload in Women During Exercise at 65% VO2peak
Authors: Kambis Ken , Yasukawa Michio , Degarmo Anna , Quiroga Leonardo , Barbour Veronique , Muza Stephen , Looft‐Wilson Robin 
Published: November 2023

While prior work (Muza, J. Appl. Physiol. 91: 2001) suggests that women and men have similar responses to high altitude, no studies have compared women's sea level VO2peak workload (W) to subsequent exercise performance in a normobaric hypoxic environment simulating an altitude of 3,500 m. As part of a larger study examining individual variability upon acute exposure to normobaric hypoxia, SpO2, heart rate (HR), and VO2peak (cycle ergometer) were measured in 24 female subjects at sea level (SL). No sooner than two days later, subjects entered a normobaric hypoxia chamber at 13.55% FiO2 approximating O2 partial pressures equivalent to those found at 3,500 m (HYPO).METHODS24 informed volunteer female subjects (20.8±0.9 yr.; 165.7±6.4 cm; 61.2±7.7 kg;22.2±1.8 kg/m2; VO2peak 42.9±6.7 ml/kg/min; 185.7±9.5 bpm; 199±35W PeakPower) participated in this IRB approved study. All subjects were tested at SL then again 2+ days later after entering a normobaric hypoxia (FiO2=13.55%) chamber where SpO2 and HR were measured at rest and during exercise at a HR equivalent to that found at 65% SL VO2 peak.RESULTSBonferroni t‐tests revealed no difference in SpO2 between the rest and exercise conditions at SL (98±1% vs 98±1%). As expected, there was a difference (P<0.01) between the SpO2 SL and HYPO conditions at both rest and exercise (Rest: 98±1% vs 88±3%; Exercise: 98±1% vs 85±4%). As expected, a difference (p<0.01; Bonferroni) between SpO2 in the HYPO rest and exercise conditions was noted (88±3% vs 85±4%). The difference between workload (W) at SL 65% VO2peak and 65% SL VO2peak (via matching HR) in the HYPO conditions (120±28W vs 76±19W) reflected a 36.2±11.9% decrease in relative work capacity (p<0.01; paired t‐test).CONCLUSIONSWhile the HYPO workload at 65% SL VO2peak was calculated from SL HR at 65% VO2peak, the results do indicate a large (36.2±11.9%) decrease in workload at a similar HR when acutely exposed to a normobaric hypoxic environment simulating an altitude of 3,500 m along with the typical exercise induced desaturation seen at altitude. These data suggest that there is a decrease in work capacity in women similar to that found in men by Van Cutsem et al. (Eur. J. Appl. Physiol., 115: 2015) who studied 9 men at 3800 m and found a 38% reduction in work capacity at 75% Wmax.Support or Funding InformationThe Doug Morton/Marilyn Brown Endowment for Biomedical Research, The Foundation for Aging Studies and Exercise Science Research, and The Borgenicht Program
Hypoxic Preconditioning Improves Respiratory Muscle Function during Hypoxia by Regulating Mitochondria in COPD Mice
Authors: Zuo Li , Chuang Chia‐Chen , Zhou Tingyang 
Published: November 2023

Diaphragm weakness has been observed in patients with chronic obstructive pulmonary disease (COPD), which may be associated with the prolonged hypoxic conditions in the disease. We found that hypoxic preconditioning (HPC) can strengthen diaphragm under hypoxic conditions in COPD mice by treating the muscle with alternating low and high O2 concentrations. In this study, we tested the hypothesis that the protective effects offered by HPC are linked with the opening of mitochondrial ATP‐sensitive potassium channel (KATP) and the closing of the mitochondrial permeability transition pore (mPTP) in COPD mice. Adult C57BL6 mice were smoked for three months to develop COPD symptoms. Following the completion of smoking, diaphragms of the mice were isolated and mounted in a contractile chamber. Each muscle strip was treated (n = 6) or non‐treated with HPC (n = 6), or pre‐incubated with a combination of KATP channel inhibitor (glibenclamide; 100 μM) and mPTP opener (carboxyatractyloside; 50 μM; n = 6) for 30 min prior to HPC. Another two groups of muscles were treated either with KATP channel activator (diazoxide; 100 μM; n = 6) or mPTP inhibitor (cyclosporine A; 100 μM; n = 6) in the absence of HPC. The muscles were then consecutively stimulated for five minutes (0.5 Hz) during a 30‐min hypoxic period. Fatigue tolerance was determined as the ratio of residual force at the end of the five‐min contraction to the initial force. Data were expressed as means ± SE, and analyzed using multi‐way ANOVA. P < 0.05 was considered statistically different. Our results show that HPC significantly improved diaphragm function during hypoxia (29 ± 2.8% for HPC vs. 6 ± 1.3% for control, p < 0.05). However, such protective effects were eliminated via the simultaneous inhibition of KATP channel and the opening of mPTP (5 ± 2.1%, p < 0.05 vs. HPC). On the other hand, either the activation of KATP channel (27 ± 2.6%) or the inhibition of mPTP (24 ± 3.6%) significantly mitigates diaphragm fatigue (p < 0.05 vs. control) to an extent similar to that of HPC. These data collectively indicate that the mechanisms of HPC protection on diaphragm under hypoxia may involve the opening of mitochondrial KATP channel and inhibition of mPTP in COPD mice.Support or Funding InformationAmerican Physiological Society (APS) 2016 S&R Foundation Ryuji Ueno Award
Ventilatory and Carotid Body Chemosensory Responses In Rats Exposed To Short‐Term Sustained Hypoxia
Authors: Flor Karine C. , Silva Elaine F. , Menezes Miguel F. , Pedrino Gustavo R. , Colombari Eduardo , Zoccal Daniel B. 
Published: November 2023

Previous studies performed in in situ rat preparations reported that the exposure to short‐term (24 h) sustained hypoxia (SH) generates active expiration at rest, increases baseline sympathetic activity during expiration and enhances sympathetic responses to peripheral chemoreceptor stimulation. In the present study, we evaluated basal and hypoxic‐induced changes in ventilatory parameters of unanesthetized juvenile male Holtzman rats (80–90 g) previously exposed to SH (10% O2, 24 hs). In addition, we examined the chemosensory response of carotid body chemoreceptors of decerebrated, artificially‐perfused in situ preparations of juvenile rats (60–80 g) submitted to SH. At resting conditions, SH rats (n=12) exhibited augmented (P<0.05) respiratory frequency (109±2 vs 97±1 cpm), tidal volume (14±1 vs 10±1 ml/kg) and minute ventilation (1550±137 vs 979±114 ml/kg.min) compared to control rats (n=12). SH rats also showed greater tachypneic and hyperventilatory responses (P<0.05) to a new hypoxia episode (7% O2, 20 min) in comparison to control rats. The magnitude of increase in tidal volume was similar between groups. The in situ preparations of SH rats (n=8), but not controls (n=8), exhibited additional bursts in baseline abdominal motor activity, indicating the presence of active expiration at rest. Interestingly, basal afferent activity of carotid sinus nerve (CSN) was similar (0.67±0.18 vs 0.65±0.18 μV) between SH and control rats. Moreover, the CSN excitatory response to stimulation of peripheral chemoreceptors with potassium cyanide was not different between groups (ΔCSN: 1235±372 vs 922±278 %), although the in situ preparations of SH rats showed greater sympathoexcitatory reflex responses (P<0.05). Our findings indicate that augmented basal ventilation and enhanced ventilatory and sympathetic responses to hypoxia in rats exposed to SH are not dependent on increased basal and sensorial activity of carotid body chemoreceptors, but may rely on central mechanisms.Support or Funding InformationFAPESP (2013/17.251‐6) and CNPq
Zinc deficiency worsens and zinc supplement prevents the development of diabetic cardiomyopathy, respectively, in the db/db mice: A key role of Nrf2
Authors: Wang Bowei , Wang Shudong , Tong Jian , Wang Yuehui , Cai Lu 
Published: November 2023

Diabetic cardiomyopathy (DCM) is highly prevalent in the type 2 diabetic (T2DM) patients. Zinc is one of the important essential trace metals, and its deficiency associates with various chronic pathogenesis, including vascular diseases. We used B6.BKS(D)‐Leprdb/J (db/db) mice as a T2DM mouse models and provided mice, for six months, with normal diet containing three levels of zinc: deficient, adequate, and supplemented, to explore the role of zinc in the development or progression of DCM. Cardiac function, reflected by the EF%, was significantly decreased along with increases in left ventricle mass and the ratio of heart weight to tibial length, in the db/db mice. As molecular cardiac hypertrophy marker, ANP protein was also significantly increased in db/db mice. The cardiac dysfunction and hypertrophy were also accompanied with significant increases in fibrotic responses (accumulated collagens and increased TGF‐β and CTGF expression) and inflammatory responses and signalings (increased expression of TNF‐α, IL‐1β, CARD9, and BCL10 and activated p38 MAPK) in the heart of db/db mice. All these diabetic effects were exacerbated and ameliorated by zinc deficiency and zinc supplement, respectively. Mechanistically the oxidative stress and damage, mirrored by 3‐NT and 4‐HNE, was significantly increased along with significant decrease in the expression of Nrf2 and its down‐stream antioxidants (NQO‐1 and catalase), which was exacerbated and ameliorated by zinc deficiency and zinc supplement, respectively, in the heart of the db/db mice. These results suggest that zinc deficiency worsens the pathological progression of cardiac disorders in type 2 diabetic db/db mice, which can be significantly prevented by zinc supplement, all which may be related to the role of Nrf2 in the prevention of DCM development and progression.Support or Funding InformationThis work was supported in part by the Scholarship of China Scholarship Council(No.201506175180)
Telomerase deficiency predisposes to heart failure and ischemia‐reperfusion Injury
Authors: Ait‐Aissa Karima , Heisner James S , Strande Jennifer L , Harmann Leanne , Camara Amadou K.S. , Beyer Andreas M 
Published: November 2023

IntroductionCoronary heart disease remains one of the main cause of death worldwide. With lack of successful treatment, new therapeutic targets and effective treatments are yet to be discovered.HypothesisOur preliminary results suggest a strong correlation between telomerase impairment and impaired mitochondrial respiration in hearts from human subjects with coronary artery disease. Additionally, it has been shown that acute overexpression of the catalytic subunit of telomerase, TERT, increases survival rate and decreases infarct size in left anterior descending artery ligation mice model. In the present study, we examined the role of TERT on cardiac structure and function under baseline conditions and following ischemic stress.MethodsTransthoracic echocardiogram was performed on wild‐type (WT) and TERT knockout rats (TERT−/−) to assess cardiac structure and function. To evaluate heart function further, Langendorf model was used to evaluate the effects of acute global ischemia reperfusion (I/R) on cardiac function and infarction.Coronary Flow (CF) and left ventricular pressure (LVP) were measured continuously online before, during and after 30 min no flow global ischemia. Functional data were assessed at 60 min reperfusion while infarct sizes were determined at the end of the 120 min reperfusion using TTC staining.ResultsEchocardiographic analysis revealed early singes of diastolic heart failure in TERT−/− rats. No change in CF or LVP was found during pre‐ischemia, however, at 60 min reperfusion); infarct size was reduced in TERT−/− rats (TERT−/−: 36±2%*; WT: 42±1%; n=7–8; *p<0.05). Functionally TERT−/− had decreased recovery as Isovolumic relaxation time was decreased (TERT−/−: 11.36±0.74ms*; WT: 13.9±0.59ms; n=12; *p<0.05) while E velocity was elevated more in TERT−/− (TERT−/−:1.15±0.03ms*; WT: 1.02±0.04ms; n=12; *p<0.05) suggesting a component of diastolic dysfunction in the setting of increased intracardiac pressures.ConclusionTERT deficiency causes additional cardiac dysfunction unrelated to the degree of myocardial necrosis suggesting underlying metabolic defects in TERT−/− rats. These results suggest a therapeutic role of telomerase to prevent heart failure after myocardial infarction.
Spinal Dorsal Column and Vagus Nerve Stimulation Modulate Vagal Afferent Transduction of Myocardial Ischemia
Authors: Salavatian Siamak , Beaumont Eric , Armour John Andrew , Ardell Jeffrey L. 
Published: November 2023

BackgroundAutonomic regulation therapy (ART), including vagus nerve stimulation (VNS) and spinal cord stimulation (SCS), is an emerging therapy in managing heart diseases, doing so by modulating multiple elements of the cardiac neuronal hierarchy.ObjectiveTo determine if ART impacts primary cardiac sensory afferent transduction of myocardial ischemia (MI).MethodsUsing extracellular recordings in 19 anesthetized canines, 36 cardiac‐related nodose ganglia neurons were identified by their response to epicardial touch, great vessel occlusion (inferior vena cava occlusion and descending aorta), left anterior descending (LAD) coronary artery occlusion(CAO) and chemical activation of sensory neurites with epicardial veratridine. Neural responses to 1 min LAD CAO were then evaluated prior to and following either SCS [T1–T3 spinal level; 50Hz, 90% motor threshold] or cervical VNS [15–20 Hz; 1.2× threshold]. Cardiac nodose neural activity was also assessed at progressive levels of VNS [2 Hz; 1–8 mA].Results66% of cardiac‐related nodose neurons responded to LAD CAO, with activity increasing ~140% (0.33±0.08 to 0.79±0.19 Hz, p=0.001). The neural response to LAD CAO was suppressed by SCS (0.85±0.3 to 0.11±0.4 Hz, p=0.03) or VNS (0.74±0.26 to 0.11±0.05 Hz, p=0.03). Nodose neural activity increased progressively with VNS current from 1 to 5 mA (0.2±0.1 to 0.69±0.1 Hz, p=0.005) but decreased when VNS current exceeded 5 mA (0.69±0.1 to 0.12±0.08 Hz, p=0.004).ConclusionsLAD CAO activates multi‐modal and nociceptive afferent inputs to the central nervous system. VNS and SCS have the capability to obtund this afferent response, likely doing so by modifying the myocyte/nerve interface. Cardiac nodose neurons did not show linear response to progressive VNS, indicating they are not simple relay stations, and these processing capabilities of the nodose include a damping function in response to excessive neural input.Support or Funding Informationnone.
Calcium Inhibition of Oxidative Phosphorylation
Authors: Bazil Jason N , Zhang Yizhu 
Published: November 2023

Calcium induced mitochondrial dysfunction is an important event that occurs during ischemia/reperfusion injury. But the details and precise mechanism of inhibition are obscure. Here we show that ADP stimulated respiration (state 3) is inhibited by calcium in a titratable manner. Isolated cardiac mitochondria from guinea pigs were exposed to varying levels of calcium while respiration was monitored using an Oroboros O2k oxygraph. The levels of calcium used are below the mitochondrial permeability transition threshold and reveal an additional component of calcium induced mitochondrial dysfunction that occurs during ischemia. Calpain I, II, and III inhibitors, as well as, calpeptin had little to no effect suggesting a mechanism other than calcium‐activated proteases leading to the decrease in state 3 respiration. In addition, unloading of mitochondrial calcium did not ameliorate the calcium‐induced state 3 dysfunction. The presence of extra‐mitochondrial ATP did protect against calcium; however, this was primarily due to calcium chelation. Higher levels of calcium to compensate for ATP complexation depressed state 3 respiration; however, a protective effect of ATP was still observed. The physiological implications for this phenomenon is significant for the ischemia/reperfusion paradigm.Support or Funding InformationThis work was supported by NIH grant R00‐HL121160.