bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sphingosine-1-Phosphate Promotes Resiliency to External Stress in the Human Microvasculature
Authors: Cohen Katie E. , Bordas-Murphy Henry , Durand Matthew J. , Freed Julie K. 
Published: May 2024

Exposure to external stress (e.g. high pressure, high glucose) promotes human microvascular endothelial dysfunction and reduces the overall magnitude of flow-induced dilation (FID). We have previously shown that treatment with sphingosine-1-phosphate (S1P), a sphingolipid known to activate pro-survival pathways in endothelial cells, restores nitric oxide (NO) as the primary mediator of flow-induced dilation (FID) in arterioles from patients with coronary artery disease. Whether pre-treatment with S1P can prevent stress-induced microvascular endothelial dysfunction remains unknown. Our hypothesis is that pre-conditioning with S1P will promote resiliency to external stress (high intraluminal pressure) and prevent stress-induced reduction of FID. Human resistance arterioles (100-250μm) from otherwise healthy adults (one risk factor or less for coronary artery disease) were dissected from discarded surgical adipose tissue and treated with S1P (1μM) or vehicle control for 16-20 hr prior to the flow experiment. Vessels were cannulated for videomicroscopy and stressed with elevated intraluminal pressure (150mmHg, 30 min) then pre-constricted with endothelin-1 prior to initiating flow to elicit dilation. Arterioles treated with vehicle and exposed to high intraluminal pressure exhibited an overall reduction in vasodilatory capacity to flow (37.3%±8.6) compared to non-stressed, vehicle treated microvessels (66.1%±5.5). However, the ability to dilate to flow was preserved in microvessels pre-treated with S1P and exposed to high pressure (74.8%±6.7) compared to vehicle and high pressure (37.3%±8.6). These data suggest that S1P-activated pathways may foster resilience by reversing stress-induced microvascular endothelial function. Targeting S1P signaling may offer a novel therapeutic strategy to prevent microvascular dysfunction and the myriad diseases it causes, such as large vessel atherosclerosis, and heart failure with preserved ejection fraction. 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.
Spontaneous Sympathetic Baroreflex Sensitivity Is Impaired in Patients with Chronic Kidney Disease
Authors: Sabino-Carvalho Jeann , Zanuzzi Matias , Li Sabrina , Park Jeanie 
Published: May 2024

Patients with chronic kidney disease (CKD) have chronic overactivation of the sympathetic nervous system that contributes to hypertension and increased cardiovascular risk. The sympathetic baroreflex is a major regulator of sympathetic activity in response to changes in blood pressure; however, limited information is available regarding sympathetic baroreflex control in non-dialysis patients with CKD. In the present study we tested the hypothesis that baroreflex control of muscle sympathetic nerve activity (MSNA) is attenuated in non-dialysis patients with CKD. In 17 sedentary patients with CKD stages III-IV (76% hypertensive and 29% with diabetes) [12 male/5 female, age: 57 ± 13 yr, 13 Black/4 White, systolic/diastolic BP: 122 ± 17/75 ± 7 mmHg, BMI: 31 ± 5 kg/m2, eGFR: 40 ± 14 mL/min/1.73m2] and 9 controls (CON) (89% hypertensive and 22% with diabetes) [7 male/2 female, age: 51 ± 13 yr, 8 Black/1 White, systolic/diastolic BP: 123 ± 6/79 ± 6 mmHg, BMI: 30 ± 6 kg/m2, eGFR: 95 ± 12 mL/min/1.73m2], resting beat-to-beat blood pressure (finger photoplethysmography), heart rate (electrocardiography) and muscle sympathetic nerve activity (MSNA, microneurography) were continuously recorded during 10 min of semi-recumbent rest. Weighted linear regression analysis between MSNA burst incidence and diastolic blood pressure was used to determine the spontaneous sympathetic baroreflex sensitivity (sBRS). Resting MSNA burst incidence was higher in patients with CKD [CKD: 70 ± 19 bursts (100 heart beats)−1. mmHg−1 versus CON: 47 ± 9 bursts (100 heart beats)−1. mmHg−1; p<0.001], and a higher MSNA burst frequency was observed in CKD (CKD: 43 ± 11 bursts. min−1 versus CON: 32 ± 10 bursts. min−1; P=0.021], whereas resting mean arterial blood pressure (91 ± 9 mmHg versus 94 ± 5 mmHg; P=0.317) and heart rate were similar between groups. Patients with CKD had reduced sBRS compared to controls [CKD: -1.37 ± 0.59 bursts (100 heart beats)−1 mmHg−1 versus CON: -2.79 ± 1.33 bursts (100 heart beats)−1 mmHg−1; P=0.013]. The MSNA burst incidence (r = -0.63, p<0.001) and the sBRS (r = -0.57, P=0.002) were significantly associated with the estimated glomerular filtration rate (eGFR). Overall, these preliminary findings suggest an attenuated sympathetic baroreflex sensitivity in patients with CKD compared with age and-comorbidities matched controls, with greater impairment in those with more severe kidney dysfunction. This work was supported by National Institutes of Health Grants R01HL135183 and R61AT010457 (J.P). 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 type of fatty acid dictates their impact on gut permeability and nutrient absorption
Authors: Evangelista-Silva Paulo Henrique , Prates Rodrigo Pereira , de Faria Rodrigo Lucas , Bargi-Souza Paula , Miyamoto Sayuri , Anhe Fernando Forato , Goulart-Silva Francemilson 
Published: May 2024

We showed that short- and long-term (3 to 12 weeks) high-fat diet (HFD) feeding reduced protein expression of nutrient transporters in the proximal jejunum of mice. The most abundant fatty acids (FA) in HFD were oleic (OA), palmitic (PA) and stearic (EA) acid. Because PA and EA are generally regarded as pro-inflammatory, we hypothesize that dietary PA and EA alter gut permeability and absorption via inflammatory activation. To test this hypothesis, we orally administered HFD-matched doses of OA, PA, and EA to male C57BL/6 mice, fed on purified diet control (LFD), for 3 weeks. Food intake and body weight were monitored, and composition were also evaluated. We next qPCR-assessed the mRNA expression of cytokines ( TNF-α, IL-6, IL-1β, IFN-γ, IL-10) and inflammatory signaling transducers ( MD-2 and Myd88) as well as the protein content of nutrient transporters (Glut2, Pept1, Fat/cd36 and Npc1l1) and cell-cell adhesion proteins (Occludin) in the gut. Small intestinal permeability was assessed ex vivo and gut morphology was histologically determined. In addition, Caco-2 enterocytes were used to assess the impact of specific cytokines on nutrient transport and gut barrier integrity. All dietary FA reduced food intake without affecting lean or fat mass. In the jejunum, OA increased TNF-α gene expression whereas PA upregulated IFN-γ and MD-2 gene expression. Furthermore, OA reduced the nutrient transporters Glut2, Pept1, and Fat/cd36 without affecting Npc1l1, whereas PA and EA reduced Occludin protein content. PA, but not OA and EA, increased jejunum paracellular permeability ex vivo and increased villus length. In Caco-2 cells, while Tnf-α did not affect Glut2, Pept1 and Fat/cd36 or Npc1l1 content, Ifn-γ downregulated Occludin protein content. We conclude that OA and, more potently, PA exert inflammatory effects which contribute to damage gut barrier integrity and downregulate nutrient absorption. Our data point to IFN-γ as a main player coupling dietary stress from PA to altered gut homeostasis. Funding: FAPESP (grants number: 2014/12871-9, 2019/05086-7, 2020/12201-4, and 2022/14545). 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.
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.