bluuebunny/crossref_metadata_2025 huggingface dataset:
A potential role for GPR160 and its ligand, CART, in the modulation of feeding behavior in Prader-Willi Syndrome
Authors: Bocke Colleen , Bocke Colleen , Yosten Gina , Samson Willis
Published: May 2023

Hyperphagia is a hallmark of Prader-Willi syndrome (PWS). Managing the extreme hunger and insatiability associated with PWS remains a considerable challenge to PWS patients and their caregivers. Appetite and feeding behavior are governed by numerous neural circuits, several of which are potentially disrupted when some or all of the Prader-Willi critical region on chromosome 15 is lost. Previous research has focused on well-established feeding circuits in an effort to uncover the physiology underlying PWS hyperphagic behavior; however, due to the complex interplay between these circuits, much is left to be explored. We have previously demonstrated that interactions between GPR160 and its ligand cocaine and amphetamine regulated transcript (CART) are important in the control of feeding behavior. Several groups have reported that CART exerts anorexigenic properties when injected into areas of the brain that are important to feeding behavior, including regions of the brainstem and hypothalamus. The prohormone convertase PSCK1, which is responsible for post-translational processing of the CART prohormone, appears to be reduced in PWS patients, suggesting that CART could play a role in the pathophysiology of PWS. Using a rat model of PWS supplied by the Foundation for Prader-Willi Research (Magel2- deficient), we seek to investigate this potential role of CART and GPR160 in PWS-associated hyperphagia. Through the use of continuous monitoring of food and water intake, we were able to define meal patterning differences between wild type and paternally Magel2-deficient rats. In addition to evaluating baseline meal patterning, we also administered CART centrally and recorded CART-induced changes in feeding behavior. Lastly, we determined physiologic changes in levels of GPR160, CART, and PSCK1 in the pituitary, hypothalamus, amygdala, and brainstem from WT and paternally-deficient Magel2 rats in the setting of metabolic stress (fasting). Although additional studies must be performed to better define the role of CART and GPR160 in the feeding behavior of PWS patients, we anticipate that this ligand-receptor pair has the potential to serve as a novel therapeutic target for the treatment of PWS-associated hyperphagia.

Foundation for Prader-Willi Research

This is the full abstract presented at the American Physiology Summit 2023 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.
Impact of intranasal insulin on muscle sympathetic nerve activity and peripheral vascular conductance in healthy young adults
Authors: McMillan Neil , Shariffi Brian , Jacob Dain , Harper Jennifer , Manrique-Acevedo Camilla , Padilla Jaume , Limberg Jacqueline
Published: May 2023

Objective: Systemic insulin increases muscle sympathetic nervous system activity (MSNA) via both central actions within the brainstem and peripheral activation of the arterial baroreflex. Augmented MSNA during hyperinsulinemia likely restrains peripheral vasodilation and contributes to the maintenance of blood pressure (BP). However, in the absence of insulin action within the peripheral vasculature, whether increased MSNA with insulin stimulation promotes vasoconstriction and increased BP remains unknown. Herein, using intranasal administration of insulin, we examined for the first time central actions of insulin on MSNA, as well as peripheral hemodynamic effects in healthy humans. We hypothesized intranasal insulin would increase MSNA and promote peripheral vasoconstriction and an increase in BP in healthy young adults. Methods: Twenty healthy young adults were randomized into time control [n=13 (5F/8M), 28±1 yrs] or 160 IU of intranasal insulin administered over 5 minutes [n=7 (0F/7M), 27±3 yrs]. MSNA (peroneal microneurography), BP (finger photoplethysmography), and leg blood flow (LBF, femoral Doppler ultrasound) data are reported from baseline and 15 minutes following insulin administration. Leg vascular conductance (LVC = LBF ÷ mean BP x 100) was calculated. Results: Following intranasal administration, MSNA (26±2 to 31±2 bursts/min, p=0.02; n=4) and mean BP (93±2 to 98±3 mmHg, p=0.02) increased while LVC tended to decrease (106±7 to 99±7 mL/min/100 mmHg, p=0.063). Venous systemic insulin and plasma glucose remained unchanged throughout the protocol (p>0.05). During time control experiments, MSNA (25±2 to 25±1 bursts/min, p=0.72; n=9), mean BP (92±2 to 93±2 mmHg, p=0.50), and LVC (80±8 to 81±9 mL/min/100 mmHg, p=0.58) did not differ from baseline. Conclusions: We provide the first evidence that intranasal insulin administration in healthy young adults acutely increases MSNA to promote peripheral vasoconstriction and an increase in BP. These preliminary results have important implications for our understanding of cardiovascular control mechanisms during hyperinsulinemia and provide the opportunity to extend these findings to disease states (e.g., insulin resistance, diabetes) in future studies.

Funding: CAFNR Joy of Discovery (JKL, JP)

This is the full abstract presented at the American Physiology Summit 2023 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.
B1-adrenergic blockers provide cardiac protection through extracellular traps inhibition during widespread inflammation
Authors: Mansart Arnaud , Adam Lucille , Gasser Adeline , Bourcier Camille , Vinit Stephane , Annane Djillali
Published: May 2023

Sepsis is one of the leading causes of death worldwide, and no therapy is available other than intensive care treatments. Drug development attempts have mainly focused on controlling inflammation or treating dysfunction, without significant improvement in the last decades. Recently, interest has emerged in β1-adrenergic blockade, which has proved beneficial to both parameters. Unfortunately, the specific underlying mechanisms have not been addressed yet. Our study aimed to investigate on mice (adult Swiss male, 30-45g) lipopolyssacharide or cecal ligature and puncture models the effects of atenolol, a β1-adrenergic blocker, currently used in intensive care units for hypertension and arrhythmia. The results demonstrated a beneficial effect of treatment on survival and a preservation of cardiac function including left ventricular ejection fraction (33±2,8% in sepsis group versus 55±5,1% in sepsis-treated group, p<0,05) at a concentration reducing heart rate by approximately 10%.We wondered if beneficial results obtained with atenolol could be due to a modulation of extracellular traps. These components are essential in pathogen spreading control and are increased during sepsis. However, an excess of their production induces vascular occlusions and acute heart injuries.We demonstrated that neutrophils extracellular traps were increased in heart and blood during sepsis and decreased significantly following atenolol administration (blood: 1.1±0,3% in control group, 13,4±1.8% in sepsis group, 6.9±1.2% in sepsis-treated group). This beneficial effect of atenolol was not associated with other modulations of neutrophil function such as their ability to phagocyte (33,6±3,9% in sepsis group versus 25.6±3.6% in sepsis-treated group, p>0,05), to undergo apoptosis (Annexin V+/ L/D-: 13,2±2.1% in sepsis group versus 14.1±2.9% in sepsis-treated group, p>0,05) or to degranulate. Blood neutrophil phenotypes associated with their maturation state (expression of CD62L and CXCR2) or ability to migrate into tissue (expression of adhesion molecules PSGL1, LFA1, VLA4, PECAM1) was also similar between LPS and LPS-treated groups. Although, the modulation of extracellular traps production by atenolol was also observed in other immune cells population able to extrude chromatin fibers in extracellular space such as macrophages. These results suggest a specific beneficial effect of ß1-adrenergic blockers on extracellular traps formation associated with cardiac function preservation and ultimately survival without detrimental effect on heart rate during widespread inflammation.

This work was supported by funding from INSERM and Paris-Saclay University-UVSQ.

This is the full abstract presented at the American Physiology Summit 2023 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.
Cerebral Hemodynamics Comparison between Transcranial Doppler Ultrasound and 4D Flow MRI
Authors: Fico Brandon , Miller Kathleen , Rivera-Rivera Leonardo , Corkery Adam , Pearson Andrew , Loggie Nicole , Howery Anna , Rowley Howard , Johnson Kevin , Johnson Sterling , Weiben Oliver , Barnes Jill
Published: May 2023

Age-related changes in cerebral hemodynamics are controversial and discrepancies may be due to experimental techniques. As such, the purpose of this study was to compare cerebral hemodynamics measurements of the middle cerebral artery (MCA) between transcranial Doppler ultrasound (TCD) and four-dimensional flow MRI (4D flow MRI). Twenty young (25 ± 3 years) and 19 older (62 ± 6 years) participants underwent two randomized study visits to evaluate hemodynamics at baseline (normocapnia) and in response to stepped hypercapnia (4% CO2, and 6% CO2) using TCD and 4D flow MRI. Cerebral hemodynamics measures included MCA velocity, MCA flow, cerebral pulsatility index (PI) and cerebrovascular reactivity. Cerebrovascular reactivity was calculated as the linear relationship between cerebrovascular conductance (CVC using 4D flow MRI) or cerebrovascular conductance index (CVCi using TCD) and changes in ETCO2 at rest and during hypercapnia. MCA velocity between the methods was positively correlated across the conditions (r=0.262; p=0.004). Additionally, cerebral PI of the MCA was significantly correlated between TCD and 4D flow MRI across the conditions (r=0.236; p=0.010). However, there was no association between MCA velocity using TCD and MCA flow using 4D flow MRI across the conditions (r=0.079; p=0.397). When age-associated differences in cerebrovascular reactivity were compared using both methodologies, cerebrovascular reactivity was greater in young adults compared to older adults when using 4D flow MRI (2.11±1.68 ml/min/mmHg/mmHg vs. 0.78±1.68 ml/min/mmHg/mmHg; p=0.019), but not with TCD (0.88±1.01 cm/s/mmHg2 vs. 0.68±0.94 cm/s/mmHg2; p=0.513). In conclusion, our results demonstrated good agreement between the methods measuring MCA velocity at normocapnia and in response to hypercapnia, but MCA velocity with TCD and MCA flow with MRI were not related. In addition, measurements using 4D flow MRI revealed additional effects of aging on cerebral hemodynamics that were not apparent using TCD.

This study was funded by the NIH grants (HL118154, NS117746), the NIH, Ruth L. Kirschstein National Research Service Award T32's from the National Institute on Aging to the University of Wisconsin-Madison Biology of Aging & Age-Related Diseases (AG000213) and the National Heart Lung and Blood Institute to the University of Wisconsin-Madison Cardiovascular Research Center (HL007936) as well as the Wisconsin Alumni Research Foundation. This study was also supported by Alzheimer's Association Research Fellowship (AARF-22-924325).

This is the full abstract presented at the American Physiology Summit 2023 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 Central Chemoreceptors on the Peripheral Chemoreflex Response to Hypoxia
Authors: Guluzade Nasimi , Huggard Joshua , Duffin James , Keir Daniel
Published: May 2023

In the absence of central chemoreceptor input, the slope of the hypoxic ventilatory response (HVR) to progressive oxyhemoglobin desaturation (L·min-1·mmHg-1·%SaO2-1) – a measure of peripheral chemoreflex sensitivity – increases linearly with carbon dioxide tension (PCO2). We assessed whether this relationship remains linear with increasing central PCO2 in humans. Over four days, 20 participants (10 females; mean±SD age: 24±4 years) completed three repetitions of modified rebreathing with end-tidal PO2 (PETO2) clamped at 150, 70, 60, and 45 mmHg. End-tidal PCO2 (PETCO2), PETO2, ventilation (V̇E), and SaO2 were measured breath-by-breath by dual gas analyser, pneumotach, and pulse oximetry. The V̇E vs PETCO2 relationship in the hyperoxic test gave the central chemoreflex response to PCO2 and the hypoxic tests provided a combined central-peripheral chemoreflex response. The V̇E vs PETCO2 relationship of repeated trials were linear-interpolated, combined, averaged into 1 mmHg bins, and fit with a linear function (V̇ES, L·min-1·mmHg-1) to provide hyperoxic and hypoxic profiles. HVR was computed at 1 mmHg intervals of PETCO2 as follows: the difference in V̇E between the three hypoxic profiles and the hyperoxic profile (ΔV̇E) was calculated; these three ΔV̇E values were plotted against their corresponding SaO2; and linear regression determined HVR (L·min-1·mmHg-1·%SaO2-1). Steps were repeated at each PETCO2 to produce the HVR vs PCO2 relationship. Each participant’s HVR vs PETCO2 relationship was fit with a linear and polynomial function and Akaike Information Criterion identified the best-fit model. One-way repeated measures analysis of variance assessed between-condition differences. V̇ES rose (p<0.001) with isoxic PO2 from 3.7±1.5 L·min-1·mmHg-1 at 150 mmHg to 4.4±1.8, 5.0±1.6, and 6.0±2.2 L·min-1·mmHg-1 at 70, 60, and 45 mmHg, respectively. Mean SaO2 fell progressively (99.3%, 93.7%, 90.4%, and 80.5% for 150, 70, 60, and 45 mmHg, respectively; p<0.001). In all individuals, HVR increased with PETCO2 and this relationship was best described by a linear model in 75% of participants. In most participants, the peripheral chemoreflex-mediated HVR maintained a linear relationship with PETCO2 despite increasing central chemoreflex activation. Data suggest that central chemoreceptors did not alter the peripheral chemoreflex response to low O2.

Natural Sciences and Engineering Research Council of Canada

This is the full abstract presented at the American Physiology Summit 2023 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.
Renal denervation mitigates renal dysfunction in a rat model of tacrolimus-induced nephrotoxicity
Authors: Dayton Alex , Lauar Mariana , Ross Jaryd , Evans Louise , Osborn John
Published: May 2023

Tacrolimus, a macrolide calcineurin inhibitor, is the most widely used immune suppressant medication after solid-organ transplant in humans, however, its use is complicated by nephrotoxicity and the development of chronic kidney disease. Interestingly, transplanted kidneys, which lack renal nerves, enjoy a relative protection from tacrolimus-induced nephrotoxicity. Consistent with this clinical observation, we explored the hypothesis that renal denervation would protect against the development of kidney disease in a rat model of tacrolimus-induced nephrotoxicity.To test this hypothesis, Sprague-Dawley rats underwent either total renal denervation (TRDN) or sham denervation and thereafter were injected with either vehicle (corn oil) or tacrolimus (2 mg/kg) for 14 days. At the end of this protocol plasma blood urea nitrogen (BUN), a marker of renal filtration function, was substantially lower in TRDN rats treated with tacrolimus than in their sham counterparts (24 vs 36 mg/dL, respectively). Similarly, TRDN rats treated with tacrolimus demonstrated substantially less renal fibrosis and glomerular damage than their sham counterparts as demonstrated by trichrome staining and PAS staining.Together our results demonstrate that total renal denervation is protective against the development of tacrolimus-induced nephrotoxicity. This finding suggests that renal denervation of the kidneys of solid-organ transplant recipients could substantially decrease the burden of chronic kidney disease in the transplant population.

R01 HL116476. T32HL144472.

This is the full abstract presented at the American Physiology Summit 2023 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.
17 Beta-estradiol is associated with increased cardiovascular risk in the castrated male rat
Authors: Mallette Jordan , Oudomrath Speyrer Adrian , Crudup Breland , Rawls Adam , Cockrell Kathy , Willis Alex , Davenport Kacey , Yanes Cardozo Licy , Shawky Noha , Alexander Barbara
Published: May 2023

Gender affirming hormone therapy (GAHT) is used in individuals born one gender but identify as a different gender. For the male-to-female transition, GAHT includes 17β-estradiol (E2) plus either an anti-androgen (AA) or surgical intervention, castration (CTX). We hypothesize that GAHT will increase cardiovascular risk in the transfemale. Methods: Male Sprague Dawley rats were randomly assigned to the following groups: Control, E2 [5 mg/day, silastic capsule pellet s.c., replaced every 3 weeks], AA [Spironolactone, 10 ng/kg/day, diet], CTX, E2+AA, and E2+CTX. AA and E2 were initiated at 14 weeks of age; CTX were exposed to AA for 2 weeks prior to CTX at 16 weeks of age. Each group was subdivided into EchoMRI for measurement of lean and fat mass and serial E2 (ELISA) (N=6-8) up to 27 weeks of age, or implanted with radiotelemetry (N=4-5) inserted at 16 weeks for continuous measurement of blood pressure (BP) starting at 18 weeks to 27 weeks of age. Angiotensin (ANG) II (200 ng/kg/min, s.c. minipumps) was started at 24 weeks of age and continued for 3 weeks in the blood pressure group. Statistics: One-way ANOVA with multi-group comparisons, P<0.05 was considered significant. Results: Average testes weight was reduced in E2-treated male rats compared to Control, P<0.0001 (1.9±0.04, 0.3±0.02, 1.9±0.05, 0.3± 0.01 grams; Control, E2, AA, E2+AA, respectively). Body weight (374±5, 287±5, 390±2, 392±11, 303±8, 287±10 grams) and lean body mass (338±4, 254±5, 351±3, 350±10, 266±7, 262±6 grams) were decreased in E2-treated male rats compared to Control, P<0.005, Control, E2, AA, CTX, E2+AA, E2+CTX, respectively. E2 administration was associated with a significant increase in circulating E2 in E2-treated male rats versus Control, P<0.0001 (21±5, 367±37, 10±1, 19±5, 415±35, 359±41 pg/ml; Control, E2, AA, CTX, E2+AA, E2+CTX, respectively). The BP response to ANG II was elevated in Control, E2, AA, and E2+CTX, but not in CTX or E2+AA. These data indicate protection from ANG II hypertension was abolished with E2 in CTX male rats, but the BP response to ANG II was attenuated in CTX and E2+AA. Collectively, these studies indicate that E2 enhances cardiovascular risk in CTX male rats and highlights the importance of sex steroids on BP control.

HL143459, P20-GM-104357, P20-GM121334, T32-HL105324, LGBTQ Fund of MS

This is the full abstract presented at the American Physiology Summit 2023 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.
Effects of bioidentical hormone therapy on endothelial function and blood pressure
Authors: Schwab Allyson , Del Vecchio Angelica , Welti Laura , Johnson Ericka , Haigh Katherine , Wenner Megan
Published: May 2023

BACKGROUND: Traditional hormone therapy (HT) is effective for managing menopausal symptoms. Although controversial, HT may also have cardioprotective effects, such as improving endothelial function. However, HT usage plummeted following the Women’s Health Initiative. A popular therapeutic option that has emerged as an alternative is bioidentical hormone therapy (bioHT). Although popular for its claim of being a natural therapy, the effects of bioHT on the cardiovascular system, specifically endothelial function and blood pressure, are not well established in menopausal women. PURPOSE: To test the hypothesis that 5 weeks of bioHT will improve endothelial function and blood pressure in menopausal women. METHODS: Women were recruited from the local community and clinics offering bioHT. Women seeking bioHT completed baseline testing (pre) within seven days of pellet insertion, and again after 5 weeks of treatment (post). Control women were not using any form of hormones, and measured at their convenience 5 weeks apart. Endothelial function was measured using brachial artery flow mediated dilation (FMD). Resting brachial blood pressure was recorded in triplicate in the supine position using an automated sphygmomanometer (Dinamap Dash 2000). Comparisons were made using two-way repeated measures ANOVA. RESULTS: Eleven women completed the study: 4 bioHT (57 ± 5 yrs) and 7 Control (54+4 yrs). Women were well matched for body mass index (bioHT: 25+3 kg/m2; control: 24+3 kg/m2; p=0.75), total cholesterol (bioHT: 213+71mg/dL; control 206+46mg/dL, p=0.84), and fasting plasma glucose (bioHT: 89+6mg/dL; control 90+13mg/dL, p=0.83). After 5 weeks, FMD did not change in bioHT (pre: 4.89% ± .8; post: 5.76% ± 2.2) or control women (pre: 3.73% ± 1.3; post: 4.18% ± 1.7; p>0.10). Resting systolic blood pressure was also not different after 5 weeks in bioHT (pre: 132 ± 20mmHg, post: 126 ± 17mmHg) or control women (pre: 113 ± 5mmHg, post: 110 ± 9mmHg; p>0.05). However, resting diastolic blood pressure tended to decrease in bioHT (pre: 79 ± 12mmHg, post: 72 ± 11mmHg; p=0.08) but not control women (pre: 71 ± 5 mmHg, post: 70 ± 7mmHg; p=0.52). CONCLUSION: These preliminary findings suggest that 5 weeks of bioHT does not negatively impact endothelial function, and may lower resting blood pressure. Additional data are needed to further assess the implications of bioHT on the cardiovascular system.

Supported by NIH R01 HL 146558 and P20 GM113125

This is the full abstract presented at the American Physiology Summit 2023 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.
Impaired Endothelial Vasomotor Function with Borderline-High Triglycerides
Authors: Garcia Vinicius , Dow Caitlin , Greiner Jared , Diehl Kyle , Stauffer Brian , DeSouza Christopher
Published: May 2023

Approximately 1 in 3 adults in the United States have a triglyceride (TG) concentration above 150 mg/dL and 1 in 5 adults have TG levels 200 mg/dL or higher. Moreover, the prevalence of suboptimal TGs (>150 mg/dL) has increased 5-fold in middle-aged and older adults over the last 3 decades. While much attention has focused on the cardiovascular effects of high and very high TG levels, where other lipid and metabolic abnormalities are often present, there are currently little data on the influence of borderline-high TG concentrations on vascular health. This represents a critical void in our understanding of the pathogenesis of cardiovascular disease (CVD) with TGs. Impaired endothelial vasomotor function is a central etiologic feature in the development of CVD and associated thrombotic events. We tested the hypothesis that endothelium-dependent vasomotor function is impaired in adults with borderline-high TG concentrations. Thirty-two sedentary, adults were studied: 15 (7M/8F, age: 56±1 yr; BMI: 26.8±0.6 kg/m2) with normal TG (35-140 mg/dL) and 17 (9M/8F, age: 57±1 yr; BMI: 28.7±0.8 kg/m2) with borderline-high TG (150-199 mg/dL) levels. Forearm blood flow (FBF; plethysmography) was determined in response to the intra-arterial infusion: acetylcholine (ACh) (4.0, 8.0, and 16.0 mg/100 mL tissue/min), sodium nitroprusside (1.0, 2.0, and 4.0 mg/100 mL tissue/min) and selective ETa receptor blocker (BQ-123, 100 nmol/min for 60 min). FBF response to ACh was significantly lower (~20%) in the borderline-high TG (from 4.7±0.3 to 11.6+0.6 mL/100 mL tissue/min) vs normal TG (from 4.3±0.3 to 14.6±0.5 mL/100 mL tissue/min) group. There were no significant group differences in the FBF responses to sodium nitroprusside. BQ-123 elicited a significant vasodilator response (~20%) in the borderline-high TG adults but did not alter FBF in the normal TG adults. Co-infusion of BQ-123 did not affect FBF responses to ACh in normal TG group but resulted in an ~30% increase in Ach-induced vasodilation (from 4.3±0.4 to 15.1±0.7 mL/100 mL tissue/min; P<0.05) in borderline-high TG group. Triglyceride levels were significantly and inversely associated with total FBF response to ACh (r=-0.63) and positively associated with the peak FBF response to BQ-123 (r=0.53; P<0.05). These results indicate that borderline-high TG concentrations are associated with diminished endothelium-dependent vasodilation and enhanced ET-1-mediated vasoconstrictor tone. Impaired endothelial vasomotor function may underlie the increased risk of CVD in adults with borderline-high TG levels.

Nothing to disclose

This is the full abstract presented at the American Physiology Summit 2023 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.
Neonatal colon exhibits enhanced post-ischemic repair relative to the neonatal jejunum
Authors: Rose Elizabeth , Ziegler Amanda , Blikslager Anthony
Published: May 2023

Intestinal ischemia is the most common cause of gastrointestinal-related morbidity and mortality within the neonatal intensive care unit. Ischemia-induced loss of the intestinal epithelial barrier predisposes patients to life-threatening sepsis unless that barrier is rapidly restored. Early barrier restoration relies on epithelial restitution to achieve wound closure, followed by rearrangement of tight junction proteins to re-establish barrier resistance. To inform putative therapeutics that promote rapid barrier repair in neonates, we have developed a highly-translational model of intestinal ischemia in the neonatal pig. Previous studies have demonstrated a significant defect in post-ischemic repair of the neonatal pig (2-weeks-old) jejunum relative to the juvenile (6-weeks-old) pig. Therefore, we hypothesized that the neonatal colon will demonstrate a similar defect in epithelial barrier repair. Segments of distal jejunum and spiral colon were subjected to surgically-induced ischemia followed by ex vivo recovery on Ussing chambers. Barrier repair was calculated by percent mucosal epithelialization, a measure of restitution, as well as transepithelial electrical resistance, a measure of barrier resistance. Unexpectedly, the ischemically-injured, ex vivo-recovered neonatal colon demonstrated significantly increased epithelial wound healing by restitution (p<0.005) as well as barrier resistance (p<0.05) relative to the neonatal jejunum. Furthermore, scanning electron microscopy revealed that colonocytes demonstrate a restitution phenotype defined by loss of their columnar morphology, marked flattening of their cellular profile and frequent formation of lamellipodia-like processes. Under identical experimental conditions, enterocytes do not demonstrate this phenotypic change. These findings suggest the presence of a colon-specific mechanism of intestinal epithelial barrier repair that is not present in the jejunum. Ongoing experiments aim to better elucidate the inter- and intracellular pathways that define this colon-specific mechanism of repair. Defining these pathways may inform the formulation of future pharmaceuticals that directly upregulate these pathways along the entire length of the intestine and therefore mitigate the effects of ischemic injury in neonates.

NIH K01 OD 028207, NIH-NICHD R01 HD095876, U01 TR002953, T32OD011130

This is the full abstract presented at the American Physiology Summit 2023 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.
Glutamine metabolism improves cardiac function after myocardial infarction independent of macrophage polarization
Authors: Mouton Alan , Aitken Nikaela , Stanford Joshua , Brown Jordan , Schrimpe-Rutledge Alexandra , Codreanu Simona , Sherrod Stacy , McLean John , da Silva Alexandre , Do Carmo Jussara , Omoto Ana , Wang Zhen , Hall John
Published: May 2023

During myocardial infarction (MI), macrophages (MØ) infiltrate the ischemic left ventricle (LV) and mediate cardiac remodeling and healing. Metabolic shifts in the LV and infiltrating MØs is a hallmark of the response to injury. Glutamine is a major metabolic fuel for cardiac muscle and MØs. However, the role of GLN metabolism in the remodeling heart after MI is not well understood. We used a model of permanent coronary artery ligation in adult male C57BL/6J mice to assess GLN metabolism in extracted cardiac MØs at post-MI days (D) 1, 3, and 7. Using untargeted metabolomics, we found time-dependent changes in metabolites related to GLN and glutamate (GLU) metabolism in cardiac MØs (p=6E-4). GLN levels were significantly increased at day 3, while GLU was decreased at day 7, and the GLN/GLU ratio was higher at both D3 and 7 compared to D1 post-MI. Using Seahorse extracellular flux analysis, GLN consumption in MØs was increased on D1 and 3. In the remote area of the heart (RA), genes for GLN-metabolizing enzymes (Glud1, Got1, Gpt1) were decreased at D3 and 7, indicating a loss of GLN metabolism. We then administered GLN (1 g/kg body weight, i.p.) daily post-MI for up to D3 or 7. Compared to vehicle, GLN administration increased ejection fraction at D3 (1.2-fold increase) and 7 post-MI (1.6-fold increase), and attenuated anterior and posterior wall thinning at D7 by 1.6-fold and 1.3-fold, respectively. GLN also restored expression of genes associated with GLN metabolism (Gls1, Glul, Got1, Gpt1, Glud1) in the RA, as well as glucose oxidation (Pdha1). GLN also restored Myh6 expression and attenuated Myh7 expression, indicating favorable expression of myosin heavy chains. However, GLN did not affect cardiac MØ phenotype, as assessed by flow cytometry and cytokine mRNA levels (Il1b, Tnf, Il6, Ccl2, Il18, and Il10). We then blocked GLN metabolism by administering BPTES (12.5 mg/kg daily i.p. in corn oil) to mice for 3 days post-MI. BPTES exacerbated anterior wall thinning (1.4-fold decrease) and further decreased EF (1.4-fold) after MI, and also increased expression of Myh7 in the RA. However, BPTES did not affect MØ phenotypes. In conclusion, dysregulation of GLN metabolism is a hallmark of post-MI cardiac remodeling, and enhancing GLN metabolism may improve cardiac function, but may not be effective for reducing MØ-mediated inflammation post-MI.

Funding: NIDDK 1R01121411, P20GM104357, U54GM115428, AHA856365

This is the full abstract presented at the American Physiology Summit 2023 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.
Piezo1 activation stimulates Na, K-ATPase-mediated ion transport in mouse lens
Authors: Delamere Nicholas , Lopez Rosales Joaquin , Mathias Richard , Gao Junyuan , Shahidullah Mohammad
Published: May 2023

Purpose: Lens ion homeostasis is dependent on Na, K-ATPase and NKCC1. TRPV4 and TRPV1 channels, which are mechanosensitive, are known to regulate the activity of both these transporters. Here, we examined another mechanosensitive channel, piezo1, which also is expressed in the lens. Methods: Rubidium (Rb) uptake rate was measured as an index of inward potassium transport. Cytoplasmic calcium was measured using Fura-2. Hydrostatic pressure in cells at the lens surface was determined using a manometer-coupled microelectrode approach. Results: Rb uptake was increased in intact lenses (CTRL 2.0±0.3 vs Yoda1 3.3±0.5 nmoles/Kg lens dry wt., n=5, p<0.05) and cultured lens epithelium (CTRL 0.23±0.006 vs Yoda1 0.44±0.01 μmoles/mg protein/10 min, n=6, p<0.001) exposed to Yoda1, a piezo1 agonist. While most Rb uptake is Na, K-ATPase-dependent, there also is an NKCC-dependent component. In the presence of the Na, K-ATPase inhibitor ouabain, Yoda1 did not increase Rb uptake. However, Yoda1 increased Rb uptake similarly in the presence or absence of the NKCC inhibitor bumetanide. The Rb uptake response to Yoda1 was inhibited by a piezo1 antagonist GsMTx4 (5 μM) and also by nonselective stretch-activated channel antagonists, ruthenium red (50 μM) and gadolinium (50 μM). In intact lenses Yoda1 was observed to cause a pronounced but transient decrease of surface intracellular hydrostatic pressure. Yoda1 increased cytoplasmic calcium in isolated cultured lens epithelium (peak concentration: CTRL 181±53 vs Yoda1 683±194 nM, n=10, p<0.001). The calcium and Rb uptake responses to Yoda1 were absent in calcium-free bathing solution, consistent with calcium entry when piezo1 is activated. Conclusion: The findings point to stimulation of Na, K-ATPase, but not NKCC, when piezo1 is activated. Na, K-ATPase is the principal mechanism responsible for ion and water homeostasis in the lens. The functional role of lens piezo1 is a topic of further study.

NIH (NEI) grant, R01EY029171

This is the full abstract presented at the American Physiology Summit 2023 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.
Are observed sex differences in forearm exercise vasodilation mediated through differences in cytochrome P450 2C9 signaling?
Authors: Song Jiwon , Buelow Alexander , Matney Jacob , Skillett Sarah , Ashley John , Mixon Chris , Bemben Debra , Larson Daniel , Kellawan J
Published: May 2023

Previous research has identified that women have greater vasodilation during exercise at the same relative intensity when compared to men and these differences are not due to nitric oxide or cyclooxygenase mechanisms. Therefore, we tested the hypothesis that sex differences in exercising vasodilation were due to differences in cytochrome P450 2C9 signaling. Methods: 18 healthy young adults (11 females, F, 10 males, M, 22.0±3yrs, 23.9±4yrs, respectively) completed two 5 minute of bouts dynamic forearm exercise at 20% effort, supine with arms at heart level, separated by ≥ 72hrs. 120 min prior exercise participants ingested 150mg of fluconazole (FLZ) to inhibit cytochrome P450 2C9 or a placebo (microcrystalline cellulose, PLA) in randomized, single-blind, counter balanced fashion. All female participants were regularly menstruating and examined during days 1-5 of their cycle (early follicular phase). Forearm blood flow (FBF; Echo and Doppler ultrasound; ml/min), forearm lean mass (FLM; DXA, g), mean arterial pressure (MAP, finger photoplethysmography, mmHg) were measured to calculate relative forearm vascular conductance (rFVC) = FBF/100mmHg/100g FLM. Results: Expressed as mean ± SD. There were no differences or interaction observed in rFVC at rest (PLA, M: 3.5±2 vs F: 3.4±2, FLZ, M: 3.9±2 vs F:4.3±1, p=0.51, η2=0.02). Interestingly, while no significant interaction between sexes and treatments were found, a large effect size (η2) was observed (PLA, M: 23.9±10 vs F:26.2±7, FLZ, M:22.8±7 vs F:32.5±9, p=0.07, η2 =0.16). Expressing the data as the change in rFVC from rest to exercise yields the same interpretations. Conclusion: In contrast to our hypothesis, both sexes showed similar rFVC responses to dynamic forearm handgrip exercise with no effect of cytochrome P450 2C9 inhibition. However, the large observed effect size indicates this investigation is likely underpowered to observe an effect of sex and cytochrome P450 2C9 inhibition. Therefore, these data advocate for further data collection in this investigation and provide justification for additional research into mechanistic differences of skeletal muscle vascular control between men and women.

This is the full abstract presented at the American Physiology Summit 2023 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.
An animal physiology Pressbook (OER) creation process, a synergistic collaboration with undergraduates and faculty
Authors: Joo Eddie , Hannah Rachael
Published: May 2023

OERs or Open Educational Resources have shown to reduce financial barriers in undergraduates by providing low cost or no cost textbooks. However, the potential OER textbooks available for a three-hundred level Biological Sciences and Natural Sciences majors Animal Physiology course (BIOLA310) at UAA do not align with the foundation of this course’s structure of homeostasis and core concepts in physiology. Thus an OER Pressbook was created by a former BIOLA310 undergraduate student for future students that mapped the course outline, utilizing the essential core concepts of Homeostasis, Systems Integration, and Scientific reasoning. This study explores current attitudes regarding OER usage of undergraduates enrolled in BIOLA310 as compared to undergraduates that were enrolled in Fall 2021 BIOLA310, when there was not an official OER textbook. Anonymous demographic data, including first generation student and pell grant status will be collected for all participants to explore any potential differences in OER impression based on student resources. Data will also be collected regarding the informational component of the OER pressbook that students engage with the most. Hypothesis: Students connected more directly with the material of the undergraduate created Pressbook OER’s, as compared to a previous version of instructor curated OER materials in Fall 2021, due to low cost, the information presented from a near peer, and how the textbook was designed for the course. Data will be collected by an anonymous qualtrics survey to protect the identity of the volunteers. Pressbooks, the web host of the Animal Physiology OER gathers Key Performance Indicators (KPIs) and tracks relevant metrics, to compare student perception of use to actual use of the materials. Data will be analyzed to assess usage evaluated by financial barriers and perceived inclination due to the OER being designed by a fellow student. Supporting student learning from diverse perspectives, OER’s created with content expert faculty and undergraduate student interpretation might increase OER availability. By lowering the barrier of OER creation, then potentially more curated resources are created that resonate with near peer learning that will increase the diversity of learning viewpoints to support undergraduate students.

Research reported in this publication was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103395.

This is the full abstract presented at the American Physiology Summit 2023 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 bodyweight support and incline running on electromyographic activity of triceps surae
Authors: Paizis Christos , Timbert Tom , Amiez Nicolas , Cometti Carole , Babault Nicolas
Published: May 2023

During rehabilitation, body weight support (BWS) system is often used. It can be useful for optimizing time to return to practice by unloading joints and muscles. The present study aimed to explore the effects of Body Weight Support (BWS) and Incline Running (IR) on electromyographic activity (EMG) of triceps surae. We hypothesized that running with a slope of 7% and 30% of BWS could result in EMG comparable to level running. Eighteen healthy individuals participated in four randomized experimental sessions of ten minutes run at 10 km/h: 1) level running and 0% of BWS (LR), 2) incline running at 7% and 0% of BWS, 3) incline running at 7% and 15% of BWS, 4) incline running at 7% and 30% of BWS. EMG activity of Vastus Lateralis (VL), Gastrocnemius Lateralis (GL), Gastrocnemius Medialis (GM), and Soleus (SOL) was recorded during each 10 minutes running conditions and before two times during 30 seconds level running to normalize EMG activity (baseline). In addition, gait spatiotemporal parameters were taken at 1’, 5’ and 9 minutes and Rating of Perceived Exertion RPE was asked at 5’, 7’, and 10 minutes. Tests were conducted before and two minutes after running conditions. They included Counter Movement Jump (CMJ), and quadriceps low-frequency fatigue test.The results of the present study revealed a significant decrease in electromyographic activity of SOL at IR at 30% of BWS condition compared to IR without BWS (P < 0.002). Moreover, a significant decrease in electromyographic activity was observed of VL at IR at 30% of BWS condition compared to level running and IR conditions without BWS (P < 0.002 and P < 0.001). No changes were found in jump test (P = 0.246) and gait spatiotemporal parameters (P > 0.05) except in flight time (decrease with IR, increase with BWS, P < 0.006). Rate of Perceived Exertion was decreased with 30% of BWS (P < 0.002) and was no different to level running (P = 0.079). 15% of BWS (vs. uphill without BWS) did not significantly decrease the difficulty perception (P = 0.570). Also, low-frequency fatigue of the quadriceps was induced without BWS (P = 0.011) but not with 15% and 30% BWS (P > 0.05)Our results show that EMG activity of the triceps surae can be similar between running on a flat surface and running on a slope and 30% BWS. Furthermore, muscle fatigue, perceived exertion rate and spatio-temporal running parameters were similar between running on a flat surface and 30% BWS at 7% IR. Therefore, it can be useful to optimize the return time to practice and it is recommending for monitoring loads in Achilles Tendon and triceps surae.

This is the full abstract presented at the American Physiology Summit 2023 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.
Perinatal ethanol exposure alters respiratory chemoreflex responses in anesthetized rats
Authors: Wollman Lila , Fregosi Ralph
Published: May 2023

In the USA 10-15% of pregnant women drink alcohol (ethanol) leading to a variable compilation of developmental abnormalities, including deficits in critical homeostatic functions such as poor coordination of suckling, breathing, and swallowing. Here, we test the hypothesis that perinatal ethanol exposure alters respiratory chemoreflex responses in neonatal rats. Pregnant rats were exposed to 5% ethanol through their drinking water starting on embryonic day 5, which exposes the fetuses to ethanol during gestation and then after birth through the breast milk. Pups of both sexes were studied in the first week of life (postnatal days (P) 1-5). First, in awake pups, we used head-out plethysmography to assess the effects of ethanol exposure on the respiratory response to a brief, 5- minute episode of hypoxic hypercapnia (12% O2/5% CO2, balance N2, delivered through a nose cone). We found no significant differences in the frequency (P = 0.6667), tidal volume (P = 0.3627), or minute ventilation (P = 0.1582) responses to the challenge between control and ethanol exposed pups (2-way ANOVA, n = 6 control and 6 ethanol pups). In a second experiment, we used electromyography in anesthetized pups to study the diaphragm and tongue muscle responses to nasal occlusion, which results in strong muscle efforts but an absence of lung inflation, as well as hypoxia, hypercapnia, and acidosis. Here, we found that both diaphragm and tongue muscle EMG responses were significantly blunted in ethanol exposed animals compared to control. This included a decrease in the peak amplitude responses of both muscles (2-way ANOVA: diaphragm, P = 0.0175; tongue, P= 0.0317, n = 8 control and 8 ethanol pups), as well as a delay in the onset of the tongue muscle activation (Student’s unpaired T-test, P = 0.0219, n = 8 control and 8 ethanol pups). Together, these data indicate that perinatal ethanol exposure causes impairments in respiratory chemoreflex control, which appear to be highly dependent on level of arousal.

NIH 5R01HD071302-08

This is the full abstract presented at the American Physiology Summit 2023 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.
Endothelial-endothelial signaling as a mechanism for neurovascular coupling
Authors: Krolak Trevor , Kaplan Luke , Chen Lujing , Navas Kathleen , Birmingham Austin , Ryvkin Daniel , Izsa Victoria , Gu Chenghua
Published: May 2023

The brain is an energetically expensive organ, consuming 20% of the body’s cardiac output at rest while only accounting for 2% of its mass. Unable to store long-term energy reserves, the brain rapidly redistributes blood flow to active regions in order to meet moment-to-moment changes in metabolic demand. This dynamic process, known as neurovascular coupling, is the basis of most non-invasive human imaging and plays a crucial role in maintaining brain health. However, despite its broad-ranging importance, the cellular mechanisms that underlie neurovascular coupling remain elusive. During neurovascular coupling, activity-evoked signals drive smooth muscle relaxation, resulting in arterial dilation and a robust increase in downstream capillary blood flow. These dilation events occur quickly – on the order of milliseconds – and spread rapidly through the arterial network to effectively recruit perfusion. Electrical signals propagated along the cerebrovascular endothelium are increasingly speculated to underpin this phenomenon, but this idea remains fundamentally untested. Here, we leverage a combination of mouse genetics, molecular biology techniques, and in vivo imaging in awake mice to evaluate the role of propagated electrical signals in the neurovascular coupling response. Our preliminary results indicate that brain endothelial cells are capable of electrical communication and establish a foundation to test the physiological significance of the signals they relay.

R01 HL153261/HL/NHLBI NIH HHS/United States; HHMI/Howard Hughes Medical Institute/United States

This is the full abstract presented at the American Physiology Summit 2023 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.