bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Sex on Sympatho-inhibitors and Non-inhibitor Phenotypes during Acute Hyperoxia
Authors: Saboune Jinan , Usselman Charlotte , Davenport Margie , Steinback Craig
Published: May 2024

Acute hyperoxia (i.e., breathing air consisting of 100% oxygen, O2) reduces muscle sympathetic nerve activity (MSNA), positioning hyperoxia as a potential anti-hypertensive therapeutic. However, the link between hyperoxia and MSNA has not been established in females. We tested the hypothesis that males would exhibit greater reductions in MSNA during hyperoxia than females. We tested healthy females (n=18, 27±5yr, body mass index [BMI] 23±3kg/m2) and males (n=13, 27±5yr, 25±3kg/m2) of similar age (P=0.99) and BMI (P=0.08). Integrated MSNA, blood pressure, and end-tidal O2 (ETO2) and CO2 (ETCO2) were measured during normal room air breathing (BSL; 3-min) and hyperoxic breathing (100% O2; 3-min). Integrated MSNA was quantified as burst frequency (BF; bursts/min), amplitude (BA; a.u.), and total MSNA (a.u.); blood pressure was quantified as mean arterial pressure (MAP). Baseline MSNA BF was not different between females and males (24±7 vs 23±8 bursts/min, respectively, P=0.68); MAP was lower in females than males (85±7 vs 93±7 mmHg; p<0.01). Hyperoxia increased ETO2 (effect of cond: p<0.01) and reduced ETCO2 (effect of cond: p<0.01) in a manner similar between sexes for ETO2 (sex*cond: P=0.56) whereas ETCO2 decreased more in females than males (sex*cond: P=0.01). Overall, hyperoxia evoked reductions in MSNA BF (effect of cond: P=0.02) but not BA (effect of cond: P=0.80) or total MSNA (effect of cond: P=0.26). Nadir MSNA responses during hyperoxia unveiled sex differences insofar as total MSNA was reduced consistently only in males (sex*cond: P=0.04); within the females we observed the presence of sympatho-inhibitors and non-inhibitors. Whereas female and male inhibitors reduced total MSNA via substantial reductions in BF and non-significant reductions in BA, female non-inhibitors demonstrated limited reductions in BF (P=0.11 vs inhibitors) coupled with increases in BA (p<0.01 vs inhibitors), resulting in no net change in total MSNA (p<0.01 vs inhibitors). Overall, these findings indicate sex differences exist in the sympathetic response to hyperoxia, in marked variability in the female sympathetic response to acute hyperoxia.

The Women and Children's Health Research Institute.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Role of SIRT3 in Compensatory Flow-Induced Dilation Following High Pressure Stress in the Human Microcirculation
Authors: Jobe Alyssa , Schulz Mary , Hader Shelby , Beyer Andreas , Freed Julie K.
Published: May 2024

Reductions in flow-induced dilation (FID; vasodilation in response to increased blood flow from shear stress) is predictive of future adverse cardiac events. Vasodilatory capacity to flow is maintained in arterioles from healthy adults following exposure to high intraluminal pressure (150mmHg, 30min) by utilizing hydrogen peroxide (H2O2) to compensate for decreased bioavailability of nitric oxide (NO). Here, we tested the hypothesis that knockdown of NAD-dependent deacetylase sirtuin-3 (SIRT3), a mitochondrial protein activated during stress and known to stimulate cellular survival pathways, would prevent compensatory signaling during FID and reduce overall vasodilatory capacity following high intraluminal pressure. Adipose arterioles (100-200μm) from otherwise healthy adults (0-1 risk factor for cardiovascular disease) were treated intraluminally with siSIRT3 or negative control siRNA for 16-20hrs and cannulated for videomicroscopy prior to pre-constriction with endothelin-1. Changes in internal microvessel diameter in response to graded increases in flow were measured. Maximal dilation to flow was maintained both pre- and post-pressure in arterioles treated with negative control siRNA (93.3%±2.3 of maximal dilator capacity±SEM, n=3 versus 69.9%±11.5, n=3, respectively), however, vasodilatory capacity was significantly reduced post-pressure in arterioles treated with siSIRT3 (19.8%±5.7, n=3) compared to pre-pressure (76.0%±10.6, n=3, p<0.01, one-way ANOVA). These data suggest that SIRT3 plays a key mechanistic component in compensatory signaling during flow in human arterioles following stress. We conclude that SIRT3 may be a potential therapeutic target to increase vascular resilience and protect from stress in the human microcirculation thereby preventing microvascular dysfunction and future cardiovascular disease.

None.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Protective Effects of Growth Hormone-Releasing Hormone Antagonists in Interferon-γ-induced Endothelial Barrier Dysfunction
Authors: Barabutis Nektarios , Fakir Saikat
Published: May 2024

Growth Hormone - Releasing Hormone (GHRH) regulates the secretion of Growth Hormone from the anterior pituitary gland. An emerging body of evidence suggests that the activities of that neuropeptide are not limited to the GH /Insulin-like Growth Factor 1 axis, but expand towards the mediation of inflammatory processes. GHRH antagonists (GHRHAnt) were developed to oppose the activities of GHRH in malignancies, and have been associated with strong anti-inflammatory and anti-oxidative effects in a diverse variety of tissues, including the lungs. In the present study we report that GHRHAnt oppose interferon gamma (IFN-γ)-induced paracellular hyperpermeability and reactive oxygen species generation in bovine pulmonary endothelial cells. Moreover, those peptides suppress the activation of IFN-γ-triggered signal transducer and activator of transcription 3, cofilin and extracellular signal - regulated kinase 1/2. Our observations substantiate previous findings on the protective effects of GHRHAnt in endothelial inflammation, and suggest their potential application in disorders related to barrier dysfunction.

Dr. Barabutis' research is supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P2O GM103424-21.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Sex differences in resting sympathetic activity and systemic inflammation in heart failure with preserved ejection fraction
Authors: Washio Takuro , Hissen Sarah , Akins John , Takeda Ryosuke , D'Souza Andrew , MacNamara James , Hearon Christopher
Published: May 2024

Background: The prevalence of heart failure with preserved ejection fraction (HFpEF) is higher in older women than in older men, with worse clinical outcomes for older women. The underlying mechanisms are unclear, but aberrant sympathetic neural control may in part contribute. Notably, >80% of patients with HFpEF, particularly women, are overweight or obese. This observation is important because obesity can augment chronic inflammation, which may lead to sympathetic overactivity. Therefore, we hypothesized that older women with HFpEF would have augmented sympathetic activity at rest compared to older men with HFpEF and similarly aged non-HFpEF controls, which would be associated with chronic inflammation. Methods: We studied 24 women with HFpEF [mean±SD; 70±7 yrs, body mass index (BMI) 39±7 kg/m2], 17 men with HFpEF (71±8 yrs, 35±6 kg/m2), 41 control women (70±7 yrs, 27±5 kg/m2), and 26 control men (71±6 yrs, 27±3 kg/m2). Mean arterial pressure (MAP), heart rate (HR), and muscle sympathetic nerve activity (MSNA, peroneal nerve microneurography) were measured during 10 minutes of supine rest. Blood samples were drawn for the measurement of C-reactive protein (CRP). Results: BMI was greater in patients with HFpEF compared with controls (p<0.001). There were no differences in resting MAP between groups and sexes (87±12 and 91±16 mmHg in men and women with HFpEF vs. 94±9 and 91±10 mmHg in control men and women, Pinteraction=0.130). Patients had higher HR compared to controls (p<0.001), but there were no differences between sexes (Pinteraction=0.108). Women with HFpEF had greater resting MSNA burst frequency (BF) compared to men with HFpEF (41±15 vs. 31±11 bursts/min, P=0.047) and control women (28±13 bursts/min, P=0.001); however, MSNA BF was not different between men with HFpEF and control men (31±13 bursts/min, P=0.940). All results were similar for MSNA burst incidence (Pinteraction=0.012). CRP was higher in patients than controls (P=0.002), but there were no differences between sexes (Pinteraction=0.148). However, a mediation analysis indicated that resting MSNA BF was associated with BMI rather than CRP in women. On the other hand, we did not observe any relationships between these variables in men. Conclusions: Women, but not men, with HFpEF have augmented sympathetic activity at rest, which seems to be linked to obesity rather than systemic inflammation. This sustained sympathetic overactivity may contribute to the poor clinical outcomes in women with HFpEF.

Supported by the National Institutes of Health (P01HL137630) and Harry S Moss Heart Trust, Bank of America, N.A., Trustee.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The effcacy of intranasal leptin for opioid induced respiratory depression depends on sex and obesity state
Authors: Singer Michele , Shin Mi Kyung , Kim Lenise , Freire Carla , Aung O , Pho Huy , Latremoliere Alban
Published: May 2024

Opioid-induced respiratory depression (OIRD) is the primary cause of death associated with opioids and individuals with obesity are particularly susceptible due to comorbid obstructive sleep apnea (OSA). Repeated exposure to opioids, as in the case of pain management, results in diminished therapeutic effect and/or the need for higher doses to maintain the same effect. With limited means to address the negative impact of repeated exposure it is critical to develop drugs that prevent deaths induced by opioids without reducing beneficial analgesia. We have previously shown that intranasal (IN) leptin can reverse apneas, hypoventilation, and upper airway obstruction while enhancing analgesia following acute morphine administration in obese males. Here we hypothesize that OIRD as a result of chronic opioid use can be attenuated by administration of IN leptin while also maintaining analgesia in both lean mice and mice with diet-induced obesity (DIO) of both sexes. To test this hypothesis, an opioid tolerance protocol was developed and a model of OIRD in mice chronically receiving morphine and tolerant to morphine analgesia was established. Subsequently, sleep and breathing were recorded by barometric plethysmography in four experimental groups: obese male, obese female, lean male, and lean female following acute administration of IN leptin. Operant behavioral assays were used to determine the impact of IN leptin on the analgesic effcacy of morphine. Acute administration of IN leptin significantly attenuated OIRD in DIO male mice decreasing the apnea index by 58.9% and apnea time by 60.1%. In lean mice leptin was ineffective. Morphine caused a complete loss of temperature aversion which was not reduced by intranasal leptin indicating IN leptin does not decrease morphine analgesia. We conclude that IN leptin is ineffective in lean mice but prevents OIRD in obesity by increasing hypercapnic sensitivity when leptin resistance at the blood brain barrier is present without reducing analgesia.

This work was supported by funding from the National Institutes of Health: R01NS112266 (AL), R01HL128970, R61HL156240, R41DA056239 (VYP), and T32HL110952 (MLS).

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Altered Glucose Kinetics Occurs With Aging
Authors: Curl Casey , Leija Robert , Arevalo Jose , Osmond Adam , Duong Justin , Huie Melvin , Masharani Umesh
Published: May 2024

Metabolic flexibility is the ability to respond or adapt to conditional changes in metabolic demand. The purpose of our study was to determine how age affects metabolic flexibility and underlying glucose kinetics in young and older healthy adults. We hypothesized that in response to a glucose challenge: 1) young participants would exhibit greater glucose clearance than older participants, and 2) young participants would have decreased endogenous glucose production via gluconeogenesis. Glucose and lactate tracers, along with gas exchange data were used to measure glucose kinetics and respiratory exchange ratios (RER=VCO2/VO2) to determine metabolic flexibility during a 2-hour 75-gram oral glucose tolerance test (OGTT). After a 12-hour overnight fast, 28 participants, 15 young (21-35 yr; 7 men and 8 women) and 13 older (60-80 yr; 7 men and 6 women) individuals received venous primed continuous infusions of [6,6-2H]glucose, and [3-13C]lactate with a H13CO3− bolus. Following a 90-minute metabolic stabilization and tracer equilibration period, volunteers underwent an OGTT. In all study participants arterialized glucose concentrations ([glucose]) rose 15 minutes post-glucose consumption, peaked at 60 minutes, and remained elevated. Older individuals had sustained increases in [glucose] compared to the young. As assessed by rates of appearance (Ra), disposal (Rd) and metabolic clearance (MCR) glucose kinetics were suppressed in older compared to young individuals. As well, unlike in young individuals, fractional gluconeogenesis (fGNG) remained elevated in the older population during the OGTT. Lastly, there were no differences in RER between young and older volunteers, making RER an incomplete measure of metabolic flexibility in volunteers studied. Our study revealed that glucose kinetics are significantly altered in an aged population following a glucose challenge. Further, these physiological deficits are not detected from changes in RER during an OGTT.

Supported by NIH grant R01 AG059715 to GAB.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Untargeted lipidomics to identify characteristic signatures and mechanisms of mitochondrial diseases according to genetic origin
Authors: Ichkhan Gabriel , Deschênes Sonia , Daneault Caroline , Robillard Frayne Isabelle , Bouchard Bertrand , Des Rosiers Christine , Ruiz Matthieu
Published: May 2024

Background: The major challenge in mitochondrial diseases relies in their great heterogeneity, in terms of genetic origin (i.e. nuclear or mitochondrial), mutation diversity and clinical manifestations. The underlying mechanisms are still unclear and often considered common to most mitochondrial diseases. Hypothesis: According to the genetic origin, the different lipidomic profiles will reveal common as well as mutation-dependent signatures. Aims: i) Establish the characteristic signatures of human fibroblasts from mitochondrial diseases of distinct genetic origins: either nuclear: LRPPRC and MTFMT, or mitochondrial: NDUFS4, UQCRC2 and ECHS1 compared with healthy fibroblasts and, based on the established signatures, ii) identify the underlying mechanisms. Methods: We used a mass spectrometry-based untargeted lipidomics approach to scan for thousands lipid signals. Based on the identified signatures, selected players were evaluated by quantitative PCR. Results: Principal component analysis shows that each cell line differs from the others. Our lipidomics analyses show that few lipids were modulated in a similar way irrespective of the genetic origin, and especially the increase in cholesterol esters. In contrast, ganglioside metabolism was differentially changed according to the genetic origin. More specifically, while GM3 forms were mostly and significantly increased for MTFMT, UQCRC2 and ECHS1 and moderately increased for NDUFS4, GM3 were decreased for LRPPRC. In addition, the GA1 and GM2 forms produced from GM3 were reduced in all cell lines except for LRPPRC and NDUFS4 where their signals remained unchanged. Since the formation of GA1 and GM2 involves the B4GALNT1 enzyme, we measured its mRNA expression and observed a drastic decrease up to 90% for MTFMT, while it remained unchanged for LRPPRC. Conclusion: The use of untargeted lipidomics is a relevant and powerful approach for the identification of specific signatures and underlying mechanisms of mitochondrial disorders, illustrated here by differentially affected ganglioside metabolism according to genetic origin, providing a starting point that will ultimately guide towards nutritional and therapeutic alternatives.

Montreal Heart Institute Fundation, Lactic Acidosis Association and FRQS.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Elevation of miR-150-5p in Brain Microvascular Endothelial Cells as a Result of Prenatal Alcohol Exposure Is Mediated by Transcriptional Mechanisms
Authors: Westenskow Marissa , Gardiner Amy
Published: May 2024

Fetal Alcohol Spectrum Disorders (FASD) encompass a variety of conditions impacting development in children exposed to alcohol in utero. Vascular alterations such as defective angiogenesis, blood brain barrier permeability, vessel reactivity, and blood flow have been found in various animal models of prenatal alcohol exposure (PAE). The underlying mechanisms of these vascular defects are not fully understood. Our lab previously showed that miR-150-5p was upregulated in brain microvascular endothelial cells (BMVECs) isolated from embryonic mouse cortices following moderate PAE. We identified downstream vascular targets of miR-150-5p in BMVECs and demonstrated that miR-150-5p inhibition could counter alcohol-mediated effects on BMVECS and the cortical microvasculature in vitro and in vivo, respectively. Here, we investigate upstream mechanisms that contribute to miR-150-5p elevation in BMVECs following PAE. We hypothesized that multiple mechanisms, including pathways at the transcriptional level, contribute to increased miR-150-5p abundance in BMVECs following ethanol (EtOH) exposure. Overall transcriptional activity at the miR-150 promoter was increased in BMVECs with EtOH treatment, and pri-miR-150, the primary transcript for miR-150-5p, was elevated in EtOH-treated BMVECs. Additionally, miR-150 promoter methylation was decreased in PAE cortices compared to saccharine-exposed controls (SAC). Current work aims to confirm the role of DNA methylation in transcriptional regulation of the miR-150 promoter in BMVECs and characterize DNA methyltransferase activity in BMVECs during PAE. We also assessed transcription factor binding at the miR-150 promoter and found that miR-150 promoter activation by several transcription factors was blunted with EtOH treatment. Current work involves the investigation of global transcription factor activation in BMVECs in PAE versus SAC. In summary, our research sheds light on multiple mechanisms of miR-150-5p regulation that may contribute to brain microvascular defects as a result of PAE.

American Physiological Society Porter Physiology Development Fellowship University of New Mexico Health School of Medicine Department of Cell Biology and Physiology.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Neurophysiological Mechanisms of Exertional Dyspnea in Patient’s Post-Pulmonary Embolism: The Effect of Inhaled Nitric Oxide
Authors: Phillips Devin , James Matthew , Vincent Sandra , Smyth Reginald , Chau Bridgett , Milne Kathryn , D'Arsigny Christine
Published: May 2024

Following pulmonary embolism (PE), up to a third of patients develop persistent activity-related dyspnea, even in those without chronic thromboembolic pulmonary hypertension (CTEPH). It has been shown that heightened exertional dyspnea in patients post-PE (without CTEPH) is linked to greater inspiratory neural drive (IND) during exercise. The heightened IND, in turn, is secondary to increased physiological dead space (VD/VT) and greater ventilatory requirements for CO2 (VE/VCO2). The reasons for the increased VD/VT and VE/VCO2 are unclear, although pulmonary microvascular dysfunction and the corresponding capillary hypoperfusion is a potential mechanism. Thus, the current study tested the hypothesis that inhaled nitric oxide (iNO), a selective pulmonary vasodilator, would lower exertional IND and dyspnea, and improve exercise endurance in patients post-PE. In turn, the reduced IND and dyspnea would be linked to reductions in VD/VT and VE/VCO2. In this randomized, double-blind, placebo-controlled crossover study, 14 clinically stable patients with chronic activity related dyspnea post-PE (without evidence of PH) completed symptom-limited constant work rate cycle exercise tests while breathing iNO (40 ppm) or placebo (21% O2), on separate days. IND (assessed by diaphragm electromyography), VD/VT and VE/VCO2 (expired and arterialized blood gas), and dyspnea intensity (modified Borg 0-10 scale) were compared throughout exercise. At rest, right-ventricular systolic pressure (RVSP) with placebo or iNO was estimated by echocardiography. At the highest individual standardized exercise time (5.8±2.0 min), iNO decreased VD/VT (0.22±0.09 vs 0.27±0.07, p=0.02), VE/VCO2 (33.0±3.5 vs 34.5±3.8 units, p=0.04), IND (48.8±10.3 vs 57.6±11.8 %, p=0.02) and dyspnea intensity (3.0±1.0 vs 4.0±1.4 Borg units, p<0.01), compared with placebo. Throughout exercise, estimated alveolar ventilation, O2 saturation, O2 pulse and operating lung volumes were unaffected by iNO (all p>0.05). iNO increased exercise endurance time (8.1±3.5 vs 6.5±2.3 min, p<0.001), compared with placebo. iNO reduced resting RVSP by 2.5±2.0 mmHg. iNO decreased exertional IND and dyspnea, and improved exercise endurance in patients with post-PE. The reduced IND, in turn, may be linked to decreased VD/VT and VE/VCO2, reflecting improved ventilation/perfusion. These data provide preliminary evidence of a partially reversible pulmonary vasculopathy, that contributes to dyspnea and exercise limitation in symptomatic patients post-PE.

Queen’s University Spear Endowment Grant.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The effect of acute estrogen suppression on cutaneous endothelium-dependent vasodilation in women with endometriosis
Authors: Colburn Abigail , Leone Cheryl , Alexander Lacy , Stachenfeld Nina
Published: May 2024

Cardiovascular disease risk is elevated in women with endometriosis and may be exacerbated by treatments that suppress estrogen. The purpose of this study was to determine the effects of acute estrogen suppression on endothelial function in women with endometriosis. We hypothesized that estrogen suppression would attenuate cutaneous endothelium-dependent vasodilation in endometriosis patients (ENDO; n = 2, 30 (1) y, 21.4 (0.2) kg·m2) but not in healthy controls (CON; n = 6, 28 (5) y, 24.9 (5.2) kg·m2). Trials were conducted with (POST) and without (PRE) 4 days of estrogen suppression (400 mg/day gonadotropin-releasing hormone antagonist, Elagolix®) during the first week of separate menstrual cycles. The cutaneous circulation was utilized as a model of microvascular vasodilatory function. Laser Doppler flowmetry was continuously measured during graded perfusions of acetylcholine through intradermal microdialysis (ACh, 1x10−10 – 1x10−1 M). Maximal vasodilation was elicited via 28 mM sodium nitroprusside perfusion and local heating (42°C). Cutaneous vascular conductance was calculated as LDF/mean arterial pressure (MAP). Dose response curves were generated with nonlinear modeling of normalized data with constraints and compared via median effective ACh dose (ED50) and HillSlope. Data are presented as mean (SD) and significance was set at α = 0.05. Baseline MAP was similar between trials for CON (PRE, 80.70 (6.32) mmHg; POST, 82.30 (5.37) mmHg; t[5] = -0.74, P = 0.49) and ENDO (PRE, 72.22 (0.31) mmHg; POST, 79.17 (7.31) mmHg; t[1] = -1.29, P = 0.42). ED50 was not impacted by estrogen suppression in CON (PRE, -3.61 (2.19) logM; POST, -2.80 (1.13) logM; t[5] = -1.04, P = 0.35) or ENDO (PRE, -3.08 (1.74); POST, -2.85 (0.68); t[1] = -0.13, P = 0.91). Similarly, HillSlope was not altered in CON (PRE, 1.00 (0.96); POST, 0.99 (1.14); t[5] = 0.01, P = 0.99) or ENDO (PRE, 0.81 (0.72); POST, 1.16 (1.15); t[1] = -0.26, P = 0.84). Acute estrogen suppression did not impact cutaneous endothelium-dependent vasodilation in healthy controls or women with endometriosis. A greater sample size will further evaluate this relationship.

National Institutes of Health Grant 1R01HL161000.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Long-duration bed rest augments sympathetic neurovascular responses to simulated orthostatic stress among females
Authors: Iannarelli Nathaniel , Greaves Danielle , Arbeille Philippe , Hughson Richard , Klassen Stephen , Shoemaker Kevin
Published: May 2024

Our understanding of the impact of long-duration head-down bed rest (HDBR) on sympathetic neurovascular regulation during orthostatic stress remains incomplete. Through retrospective analysis of the WISE-2005 long-duration bed rest trial, this study aimed to investigate the impact of 60 days of -6° HDBR on the transduction of integrated muscle sympathetic nerve activity (MSNA; peroneal microneurography) into total peripheral resistance (TPR; Finometer Modelflow) responses during rest and graded lower body negative pressure (LBNP; -20, -30, and -45 mmHg). Signal averaging quantified sympathetic transduction for 12 cardiac cycles (ECG) following integrated MSNA bursts in healthy females ( n = 12; 25-40 years). Mixed-effects modeling and post-hoct-tests assessed the impact of HDBR on sympathetic transduction during rest (5-min) and graded LBNP (3-min per level). Data are presented as mean ± SD. Long-duration HDBR did not affect resting total MSNA (pre-HDBR: 909 ± 368 AU/min, post-HDBR: 910 ± 254 AU/min; p = 0.999). HDBR did not affect total MSNA responses to -20 mmHg LBNP (pre-HDBR: 1430 ± 599 AU/min, post-HDBR: 1823 ± 433 AU/min), -30 mmHg LBNP (pre-HDBR: 1574 ± 549 AU/min, post-HDBR: 1924 ± 587 AU/min), or -45 mmHg LBNP (pre-HDBR: 1950 ± 819 AU/min, post-HDBR: 2328 ± 880 AU/min; p = 0.191). HDBR did not affect resting sympathetic transduction to TPR (pre-HDBR: 0.002 ± 0.16 mmHg/L/min, post-HDBR: -0.091 ± 0.12 mmHg/L/min; p = 0.296). However, HDBR augmented TPR transduction responses to graded LBNP (HDBR-by-LBNP interaction: p = 0.050). Pre-HDBR, TPR transduction responses were unchanged with graded LBNP (all p > 0.05). In contrast, post-HDBR, TPR transduction responses increased progressively with graded LBNP (rest: -0.09 ± 0.12 mmHg/L/min, -20 mmHg: 0.22 ± 0.31 mmHg/L/min, -30 mmHg: 0.30 ± 0.34 mmHg/L/min, -45 mmHg: 0.44 ± 0.12 mmHg/L/min; all p < 0.005). The same effect of HDBR was observed when sympathetic transduction of mean arterial pressure was analyzed (data not shown). These data suggest that long-duration HDBR augments sympathetic neurovascular responses to integrated MSNA bursts during orthostatic stress among females.

This work was supported by the Canadian Space Agency, the French “Centre National d’Etudes Spatiales”, the European Space Agency, and the National Aeronautics and Space Administration of the USA.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The Effects of Puberty Blocking Treatment (Gonadotropin Releasing Hormone Agonist) on Reproductive Function in Young Female Rats
Authors: Jones Brandon , Hydock David
Published: May 2024

The number of adolescents identifying as transgender has been increasing with many transgender youth receiving treatment with a gonadotropin releasing hormone agonist (GnRHa) that suppresses sex hormone production (i.e., puberty blocker). Transgender individuals taking a GnRHa to block puberty have reported improved mental wellbeing, but the physiological impact on reproductive function needs to be examined. Objective: To investigate the effects of puberty blocking treatment using GnRHa on reproductive morphology and function in young female rats. It was hypothesized that puberty blocking treatment would decrease fertility. Methods: Four-week old female Sprague Dawley rats were given daily subcutaneous injections of the GnRHa triptorelin or saline as control. After four weeks of treatment a group of rats were euthanized and the uterus and ovaries were removed for H&E staining to assess morphology. An additional group was taken off GnRHa treatment for 4-weeks to examine recovery of reproductive organ morphology. The final group was taken off GnRHa treatment and housed with fertile males to determine reproductive performance. Results: GnRHa treatment led to a reduction in the mass of uteri and ovaries which recovered after 4-weeks of drug withdrawal. The myometrial and endometrial thickness of the uterus was reduced in GnRHa treated animals. The ovaries of puberty blocked animals exhibited a disruption in follicle development and corpora lutea health. The morphology of the uterus and ovaries recuperated after 4-weeks of drug withdrawal. No significant difference in pregnancy rate was detected; however, both the number of days until pregnancy detection and number of days until giving birth were considerably longer in GnRHa rats following withdrawal. The number of pups per litter was also significantly reduced by puberty blocking treatment but no abnormalities were observed in the pups. Conclusion: Young female rats treated with a GnRHa had significantly delayed development of the reproductive organs. After 4 weeks of GnRHa withdrawal reproductive organ mass and morphology recovered. A minor disruption in reproductive function was detected immediately following GnRHa withdrawal. These physiological effects on reproductive health should be considered when administering a GnRHa to block puberty.

No external funding was used to support this research.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Mitochondrial AKAP1 Is Necessary for Obesity- and Angiotensin II-induced Hypertension
Authors: Zhao Yuying , Guo Dengfu , Strack Stefen , Rahmouni Kamal
Published: May 2024

Best known as the powerhouse of the cell, mitochondria play a crucial role in obesity and associated cardiovascular diseases. A-kinase anchoring protein 1 (AKAP1) is a mitochondrial scaffold protein that regulates mitochondria function by promoting protein kinase A (PKA)-mediated phosphorylation of Dynamin-related protein 1 at Ser637 through recruitment of PKA to the outer mitochondrial membrane. However, the role of mitochondrial AKAP1 in the regulation of blood pressure and the development of hypertension is not known. Here, we used mice harboring the Akap1 gene deletion to investigate the importance of AKAP1 in obesity- and angiotensin II (Ang II)-induced hypertension. AKAP1−/− mice and wild type (WT) littermates were maintained on a high fat high sucrose diet (HFHSD) for 12 weeks starting from 4 weeks of age. Interestingly, AKAP1−/− mice fed HFHSD displayed significantly attenuated weight gain compared to control mice fed HFHSD (male: 39.5 ± 1.7 vs 47.3 ± 2.3 g, and female: 29.7 ± 1.3 vs 32.5 ± 1.5 g, p<0.05 for both). This was associated with decreased fat mass in AKAP1−/− mice-fed HFHSD (male:16.2 ± 0.9 g and female: 8.7 ± 1.1 g) compared to controls (male: 21.2 ± 1.7 g and female: 13.9 ± 1.6 g, p<0.05 for both). Transmission electron microscope analysis of neuronal mitochondrial in the accurate nucleus of the hypothalamus showed that AKAP1−/− mice fed HFHSD have remarkably reduced mitochondria size (0.14 ± 0.05 vs 0.20 ± 0.07 μm2, p<0.05) and mitochondria length (0.57 ± 0.10 vs 0.50 ± 0.10 μm, p<0.05) relative to controls. Next, using the radio-telemetry system, we found that blood pressure was lower in AKAP1−/− male mice fed HFHSD compared to WT mice fed HFHSD (systolic: 118.2 ± 3.2 mmHg vs 126.7 ± 4.3 mmHg, p = 0.05, n= 5WT and 6 AKAP1−/−). Furthermore, infusion of Ang II (600ng/kg/min for 14 days) via osmotic minipumps in normal chow-fed male mice tended to evoke less increase in mean blood pressure in AKAP1−/− mice compared to WT controls (35.2 ± 3.5 vs 45.7 ± 10.1 mmHg, n=3). Taken together, our findings point to the importance of mitochondrial AKAP1 for the development of hypertension induced by obesity and Ang II.

Veterans Affairs NIH.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Pioglitazone does not affect exogenous glucose oxidation or metabolic clearance rate during steady-state aerobic exercise at high altitude
Authors: Margolis Lee , Wilson Marques , Drummer Devin , Carrigan Christopher , Murphy Nancy , Allen Jillian , Dawson M. Alan
Published: May 2024

Background: Hypoxia-induced insulin insensitivity decreases exogenous glucose oxidation and metabolic clearance rate (MCR, proxy for peripheral glucose uptake) in native lowlanders exercising during the initial hours of high-altitude (HA) exposure compared sea level. These data suggest that administering an insulin sensitizing drug before HA exposure may increase exogenous glucose oxidation rate by stimulating peripheral glucose uptake. Objective: To compare the effects of pioglitazone (PIO) and placebo (PLA) on exogenous glucose oxidation and MCR during steady-state aerobic exercise at HA. We hypothesized that exogenous glucose oxidation and MCR would be higher with PIO than PLA. Methods: Using a randomized, crossover design, native lowlanders (n = 7 males, mean ± SD, age: 23 ± 6 y, body mass: 84 ± 11 kg) consumed 145 g (1.8 g/min) of glucose while performing 80-min of metabolically-matched (1.43 ± 0.16 VȮ2 L/min) treadmill exercise at HA (460 mmHg) after being administered PIO (15 mg) or PLA (microcrystalline cellulose pill) daily for five days. Substrate oxidation and glucose turnover were determined using indirect calorimetry, oral 13C-glucose and [6,6-2H2]-glucose primed, continuous infusions. Results: Exogenous glucose oxidation rate was not different between PIO (0.31 ± 0.03 g/min) and PLA (0.32 ± 0.09 g/min). Total carbohydrate oxidation with PIO (1.65 ± 0.22 g/min) was the same as PLA (1.68 ± 0.32 g/min). There were no treatment effects on glucose rate of appearance (PIO: 2.46 ± 0.27, PLA: 2.43 ± 0.27 mg/kg/min) disappearance (PIO: 2.19 ± 0.17, PLA: 2.20 ± 0.22 mg/kg/min), and MCR (PIO: 1.63 ± 0.37, PLA: 1.73 ± 0.40 mL/kg/min). Conclusion: These data do not support our hypothesis that exogenous glucose oxidation during exercise at HA can be restored through the short-term administration of PIO. Findings from this study may suggest that hypoxia-induced insulin resistance may be a symptom and not the primary etiology of dysregulated glucose metabolism during acute HA exposure.

Supported by MOMRP; authors’ views not offcial US Army or DoD policy.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Inhibition and potentiation of the mechanoreflex following pharmacological modulation of TRPC6 in male rats
Authors: Ducrocq Guillaume , Anselmi Laura , Stella Salvatore , Copp Steven , Kaufman Marc
Published: May 2024

We determined the role played by the transient receptor potential canonical 6 (TRPC6) in evoking the mechanical component of the exercise pressor reflex in male decerebrated Sprague-Dawley rats. Quadruple-labelled immunohistochemistry were used in dorsal root ganglion cells to identify the cells that innervate the triceps surae muscles (DiI), the cells that express TRPC6 and the cells that are (Nf200) or are not myelinated (peripherin) (n=4). In addition, static contraction of triceps surae muscles was evoked by electrically stimulating the left tibial nerve before and after injecting into the superficial epigastric artery the TRPC6 antagonists, BI-749327 (n = 11; 12μg.kg−1) or SAR7334 (n = 11; 7μg.kg−1), or the TRPC6 positive modulator, C20 (n = 11; 18μg.kg−1). Similar experiments were conducted while the triceps surae muscles were passively stretched (n = 8 to 12), a maneuver that isolates the mechanical component of the reflex. Blood pressure, tension, renal sympathetic nerve activity (RSNA) and blood flow were recorded throughout the experiments. The neurons innervating the triceps-surae muscles were positive to TRPC6 antigen and co-expressed the neurofilament 200kDa. These cells were not positive for peripherin. While the TRPC6 blockers decreased the pressor response to static contraction (-32 to -42%; P < 0.05) and passive stretch (-35 to 52%; P < 0.05), the positive modulator increased both of these responses (55 to 65%; P < 0.05). In addition, BI-749327 decreased the peak and integrated RSNA responses to both static contraction (-39 to -43%; P < 0.05) and passive stretch (-56 to -62%; P < 0.05) whereas C20 increased these responses to stretch only (55 to 235%; P < 0.05). All of these results were not replicated when the drugs were injected intravenously or when the vehicle of the drug was injected into the superficial epigastric artery. Collectively, our results showed that TRPC6 play a key role in evoking the mechanical component of the exercise pressor reflex in male rats.

Supported by NIH grants HL 161160, HL 156594 and HL 156513.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Brief Repetitive Pressure Overload Elicits a Fibrosis-Independent Reduction in Left Ventricular Diastolic Compliance in Swine
Authors: Hudson Emily , Tajlil Arezou , Rolland Tyler , Palka Beth , Young Rebeccah , Canty John , Weil Brian
Published: May 2024

Objective: We have previously shown that swine subjected to repetitive pressure overload (RPO) via daily 2-hr infusions of phenylephrine (PE) develop a reduction in left ventricular (LV) diastolic compliance that coincides with increased interstitial myocardial fibrosis. The objective of the present study was to determine if brief episodes of RPO produce a similar cardiac phenotype. Methods: Swine (n=6) were subjected to a single 30-min PE infusion (300 μg/min) to determine if brief pressure overload causes myocardial injury (circulating cardiac troponin I; cTnI), inflammation (IL-6), and cardiac dysfunction (echocardiography). A separate group of swine (n=5) were subsequently instrumented with an indwelling venous catheter to enable daily 30-min PE infusions for 2 weeks (“Brief RPO”). LV diastolic compliance (ΔLVEDV/ΔLVEDP during PE) and interstitial fibrosis (picrosirius red staining) were compared to values derived from swine subjected to prolonged RPO (2-hr PE/day; n=8) and age-matched controls (n=8). Results: A single episode of brief pressure overload led to an increase in circulating cTnI (from 22±6 ng/L at baseline to 365±12 ng/L 3-hours post-PE) and IL-6 (from 10±2 to 34±4 pg/mL), along with a transient reduction in LV ejection fraction (from 65±2 to 45±5 %, all p<0.05). Brief RPO led to a significant reduction in LV diastolic compliance (ΔLVEDV/ΔLVEDP: 0.59±0.13 mL/mmHg vs. 1.87±0.12 mL/mmHg in controls; p<0.01) that was nearly identical to that observed after prolonged RPO (0.58±0.17 mL/mmHg, p=0.95). Surprisingly, in contrast to prolonged RPO (10.0±1.4% collagen) the brief RPO-induced reduction in LV compliance was not accompanied by an increase in interstitial fibrosis (5.0±0.3 % collagen vs. 5.0±0.3 % collagen in controls, p=0.95). Conclusion: Brief pressure overload initially causes myocardial injury and inflammation, with repetitive exposure leading to a reduction in LV compliance that is similar to that observed following prolonged RPO. However, the brief RPO-induced reduction in LV compliance occurs in the absence of fibrosis, suggesting that mechanisms of repetitive stretch-induced myocardial stiffening may depend on the duration of episodic pressure overload.

Supported by funding from the U.S. Department of Veterans Affairs and National Institutes of Health.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
FK506-Binding Protein 51 (FKBP51) Suppresses PPARα Activity and Shifts the Insulin Receptor Alternative Splicing Driving Hepatic Insulin Resistance
Authors: Lee Wang-Hsin , Bates Evelyn , Maharramov Agil , Martinez Genesee , Kipp Zachary , Xu Mei , Hinds Terry
Published: May 2024

FK506-binding protein-51 (FKBP51) is a molecular chaperone protein that has great potential to serve as a treatment target for non-alcoholic fatty liver disease (NAFLD) and type II diabetes (T2DM). FKBP51 has been known to regulate nuclear receptors such as glucocorticoid receptor (GR) and peroxisome proliferator-activated receptor γ (PPARγ). However, the connections between FKBP51 and other PPAR family members, such as peroxisome proliferator-activated receptor α (PPARα), are yet to be identified. FKBP51 can also inhibit protein kinase B (AKT) activation, which may impact the insulin receptor signaling pathway. It has been reported that FKBP51 knockout mice presented less adiposity, reduced liver steatosis, and increased insulin sensitivity and insulin clearance, indicating that FKBP51 plays a role in insulin resistance and fatty liver development. However, how FKBP51 regulates insulin resistance, especially in the liver, still needs to be unveiled. It has been shown that insulin receptor (IR) alternative splicing is associated with insulin sensitivity and that PPARα activation is critical in reducing insulin resistance. Thus, we hypothesize that FKBP51 can regulate hepatic insulin resistance through insulin receptor alternative splicing and PPARα suppression. To test this hypothesis, we developed an FKBP51 knockout mouse hepatocyte cell line, 51KO AML12, and treated the cells with insulin for 1hr. We measured RNA and protein expressions in the cells through RT-PCR and western blotting and found that 51KO AML12 had increased phospho-AKT Ser473 (pAKT S473) and IR isoform B (IR-B), indicating increased insulin signaling activity. We also found increased IR isoform A (IR-A) and IR-B expression in 51KO AML12. In addition, we found an increased ratio of IR-B: IR-A in 51KO AML12 treated with insulin. These data indicate a great potential for FKBP51 to be a novel treatment target for hepatic insulin resistance and T2DM.

This research is supported by the National Institute of Health R01DK121797 (T.D.H.), R01DA058933 (T.D.H.), and Start-Up funds from the University of Kentucky (T.D.H.).

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
The Role of GLP-1 Affects Fate of Astrocytes Following Ischemic Stroke in Mice
Authors: Lu Hsuan-Yu , Li Su-Ying , Yang Jenq-Lin
Published: May 2024

Stroke is one of the leading causes of physical and intellectual disability and mortality in adults of most of the developed countries. The most of studies in ischemic stroke focus on neuronal pathological mechanisms and neuronal death trying to rescue neurons via stopping the detrimental pathological processes or enhancing neuronal viability. Although astrocytes are the most abundant cells and in mammal central nervous system (CNS), they were ignored for period of time but are return to spotlight in recent years. Astrocyte play multiple roles in maintain normal function of central nervous system and respond to all kinds of CNS injury and disease. Responses of astrocytes to CNS damage lead to both detrimental and beneficial consequences. Previous studies have reported that astrocyte inflammatory responses to ischemic stroke may devastate the ischemic lesion, but other astrocytic responses lead to anti-excitotoxicity, secreting neurotrophic factors, neurogenesis, synaptogenesis, axonal remodeling, and angiogenesis promoting neuroprotective effects. Glucagon-like peptide-1 (GLP-1) have been intensively studied on beneficial effects of neurons, but not many studies work on effects of GLP-1 to astrocytes. Our early study has found that activation of GLP-1 receptors prevented ischemia-induced brain cell death and observed newly neuronal progenitor cells were from astrocyte-lineage in penumbral area of 3-day post-ischemic mouse brains by immunohistochemistry (IHC). RT-PCR, immunoblotting, and immunofluorescent results also clearly indicated the astrocytes expressed GLP-1 receptors. Furthermore, Western blotting results showed administration of GLP-1 analogue, exendin-4 (EX-4), suppressed expression of pro-inflammatory proteins in oxygen-glucose deprivation (OGD) treated mouse primary astrocytes. Interestingly, we also observed that infarct site obtained sever DNA damage and less GFAP positive astrocytes, on contrary, the penumbral area had more GFAP positive astrocytes and less DNA damage in IHC images of stroke brains. The results implied that A1 and A2 astrocytes play certain roles in ischemic brains and recovery. The goal of this study is to determine the mechanisms of GLP-1 involving in astrocytic fate decision and approach on minimizing detrimental effects and amplifying the beneficial effects, which possibly develop innovative therapies for ischemic stroke.

The study is supported by 108-2320-B-182A-005-MY3 and 112-2320-B-182A-003- from Taiwan National Science and Technology Council.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.