bluuebunny/crossref_metadata_2025 huggingface dataset:
Alpha-7 Nicotinic Acetylcholine Receptors Contribute to the Combined Electroacupuncture Modulation of Hypertension in Salt-Sensitive Rats
Authors: Gong Yiwei , Fu Liang-Wu , Nguyen Anh , Guo Zhi-Ling , Malik Shaista , Tjen-A-Looi Stephanie
Published: May 2023

Elevated sympathetic activities and low-grade chronic inflammation are observed in hypertensive (HTNive) patients and animals including dahl salt-sensitive hypertensive (DSSH) rats. We have shown that stimulation of the deep peroneal nerve and the tibial nerve by combined electroacupuncture (cEA) at the combination of two sets of acupoints ST36-37 and SP6-7 decreased blood pressure (BP) and proinflammatory cytokines in HTNive subjects through sympathoinhibition and anti-inflammation. Acetylcholine (ACh), the primary neurotransmitter of parasympathetic nerves, is known to participate in modulation of inflammation. We hypothesized that α-7 nicotinic acetylcholine receptors (α7nAChR) play an important role in the BP lowering effects of cEA in DSSH rats. DSS rats were fed with 4% salt diet and randomly allocated into three groups (4 rats/group). Once they developed moderate hypertension (SBP 160±5 mmHg), one group was treated with Sham-EA (no electrical stimulations), and two groups were treated with cEA. Both cEA and Sham-EA groups were given twice weekly for eight weeks. Methyllycaconitine (MLA) is a α7nAChR antagonist. MLA (2.4 mg/kg) was injected intraperitoneally (ip) daily into one group of cEA treated rats (n=4) during the last three weeks with cEA treatments. In a similar manner, the other cEA group and the Sham-EA group received daily saline ip injection for three weeks. Another four DSS rats were fed with standard rat chow and treated as the normotensive (NTN) controls. Systolic/diastolic BP (SBP/DBP) of rats were measured with Tail-cuff via CODA system once a week. At the end of the experiment, compared to Sham-EA rats (207.8±2.5 mmHg, DBP 144.6±3.2 mmHg), cEA decreased SBP (138.8±0.8 mmHg) by 33.2% and DBP (98.6±1.7 mmHg) by 24.25%. Blockade of α7nAChR with MLA partially reversed the cEA BP lowering effects (SBP 193.4±2.6 mmHg and DBP 136.5±2.4 mmHg), and BPs in cEA+MLA treated rats were still significantly lower than Sham-EA-treated rats after the reveral. BPs of NTNive rats remained in the normal BP ranges throughout the 13 weeks of the experiment (from 135.9±2.8 to 134.2±1.1 mmHg). In conclusion, systemic antagonism of α7nAChR with MLA partially reversed the BP lowering effects of cEA in DSSH rats.

National Institute of Health National Center for Complementary & Integrative Health Grant (1RO1AT011306).

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.
Attractor dynamics that govern breathing are differentially perturbed by inhibitory and excitatory populations of the Ventral Respiratory Column
Authors: Bush Nicholas , Ramirez Jan-Marino
Published: May 2023

Distributed and diverse populations of neurons throughout the Ventral Respiratory Column (VRC) are involved in the generation and maintenance of breathing. We have recently shown that the network-wide dynamics of these populations evolve through rotational trajectories in a low-dimensional latent neural space. These rotations evolve continuously through both inspiration and expiration, and they target a low-dimensional inspiratory-off attractor. It remains unknown how these rotational dynamics respond to perturbations of specific subsets of VRC populations. Here we record from the rostrocaudal extent of the VRC using high-density Neuropixel probes in-vivo in anesthetized mice while optogenetically stimulating subsets of neurons by Cre-driven expression of channel rhodopsin. These stimulations cause both widespread activation and deactivation of recorded populations. We find that brainstem wide stimulation of inhibitory neurons perturbs low-dimensional population trajectories towards the inspiration-off attractor, regardless of trajectory location at the time of stimulation. After cessation of stimulation, all trajectories proceed inexorably toward the inspiration-off point, and the cycle resets. When inhibitory populations are stimulated during the expiratory period, the population dynamics are clamped close to the inspiration-off attractor. Stimulation of glutamatergic populations, in contrast, directs the trajectories to a different region near the center of the rotation. However, upon cessation of excitatory stimulation, the trajectories immediately relax to the closest point along the rotational manifold, and the cycle resumes. Stimulation of either GABA-ergic or glutamatergic populations perturbs the dynamics perpendicular to the ongoing rotations; however stimulation of either Dbx1+ or cholinergic populations perturbs the populations along the current heading of the trajectories. Together, these data highlight a critical role of inhibition in the procession of VRC population dynamics, and suggest that the inspiration-off attractor is targeted by inhibitory mechanisms.

R01 HL151389; R01 HL126523; R01 HL144801; F32HL159904

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.
Student performance and satisfaction in the first iteration of an integrated renal and respiratory systems course in a redesigned one-pass preclinical curriculum
Authors: Villalobos Alice , Kruczek Cassandra , Bobulescu I. Alexandru
Published: May 2023

Texas Tech University Health Sciences Center School of Medicine converted its legacy two-pass preclinical curriculum to a one-pass organ system-based format and changed the grading system from categorical to pass/fail (>70%). Our objective was to assess first-year medical student (MS1) performance and satisfaction in the first iteration of Organ Systems-2:Renal and Respiratory ( RNR), an 8-week block taught at the end of Year I. RNR integrates the physiology, pathophysiology, infectious diseases, and pharmacology of the renal system (Weeks 1-4) and respiratory system (Weeks 5-8), using reorganized and updated material from legacy Year-I blocks ( General Principles & Infectious Diseases and Structure & Function of Major Organ Systems) and Year-II blocks ( Immunity & Multisystem Disorders and Systems Disorders). Instruction was delivered via didactic lectures, team-based activities, case-based reviews, dry labs, cognitive integration of clinical reasoning (CICR) sessions, and simulations. Formative weekly quizzes and practice exams were assigned before each exam. Learning in the renal physiology, renal pathophysiology, and respiratory physiology units was assessed by instructor-generated exams at the end of Weeks 2, 4 and 6, respectively, and a final customized, comprehensive NBME exam at the end of Week 8. Aggregate performance on instructor-generated renal and respiratory exam questions was compared to that on similar questions from legacy curriculum exams. Aggregate performance on the NBME exam was compared to USMLE Step 1 exam difficulty, as the legacy curriculum did not include a dedicated renal/respiratory NBME exam. Aggregate performance on instructor-generated renal physiology and pathophysiology and respiratory physiology questions was comparable to that in the legacy curriculum. Average performance on the renal portion of the NBME exam was 0.76 vs. Step 1 exam difficulty of 0.78; average performance on the respiratory portion of the exam was 0.77 vs. Step 1 exam difficulty of 0.78. Per end of block survey and student focus group feedback, overall student satisfaction with RNR was 73%. Thus, the first iteration of the integrated organ systems-based renal and respiratory systems course in Year I yielded a MS1 performance on the NBME that was comparable to USMLE Step 1 source difficulty, and student satisfaction was positive overall. More detailed analysis of exam performance is needed. Further modifications of RNR will include additional simulations and flipped-classroom sessions.

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.
Topographical Distribution and Morphology of Calcitonin Gene-Related Peptide (CGRP) Axons in the Flat-Mounts of the Whole Heart in Male and Female Mice
Authors: Bendowski Kohlton , Zhang Yuanyuan , Bizanti Ariege , Heal Maci , Christie Richard , Hunter Peter , Chen Jin , Cheng Zixi
Published: May 2023

It is important to understand the topographical distribution of nociceptive axons in the heart to treat cardiac pain. While previous studies have detected nociceptive axons in the sectioned heart, their full distribution has not been fully explored, in particular, the pattern differences in male and female mice have not been determined. In this study, we performed a topographical mapping of the nociceptive afferent axons in flat-mounts of the whole heart of mice (C57BL/6J, male & female, 3-5 months, n=6 for each gender) using calcitonin gene-related peptide (CGRP) as a marker. Then, we used a confocal microscope and a Zeiss M2 Imager microscope to scan all tissues of the heart and assemble the images into complete photo montages of the heart. Furthermore, a Neurolucida 3D Digitization and Tracing System was used to trace CGRP-immunoreactive (CGRP-IR) axons and terminals in the whole heart of the male and female mice. We found that 1) CGRP-IR axons entered as large bundles near the superior/inferior vena cava, left pre-caval vein and the pulmonary veins before bifurcating into small branches, and finally formed single varicose axons and terminals which distributed throughout the tissue, including the cardiac ganglia, SA/AV nodes, auricles, and blood vessels in the right/left atria. 2) CGRP-IR axons particularly accumulated in the SA node region. 3) CGRP-IR axons entered the right/left ventricles and interventricular septum as large bundles through the base before bifurcating into small branches towards the apex. 4) CGRP-IR axons innervated the intrinsic cardiac ganglia (ICG) neurons. 5) CGRP-IR axons wrapped around the blood vessels in the atria and ventricles. 6) CGRP-IR axons presented heavily in the epicardium layer and less in the myocardium and endocardium. 7) CGRP-IR axons had a similar innervation pattern in male and female mice. 8) The representative CGRP-IR axon innervation maps will be integrated into 3D heart scaffolds (male and female). For the first time, our data provide a comprehensive topographical map for CGRP-IR axons in the hearts of male and female mice with single cell/axon/synapse resolution. Our work lays out a novel anatomical foundation for the functional mapping of nociceptive afferent axons and their pathological remodeling in cardiovascular diseases. This work will also contribute to the development of a 3D representation of a brain-heart nociceptive afferent atlas.

This study was supported by NIH HEAL/SPARC U01 NS113867-01, NIH R15HL137143-01A1. NIH SPARC OT3OD025349-01 (PH).

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.
The beneficial effects of SS-31 on aging mice cerebral microvasculature
Authors: Rutkai Ibolya , Seman Abigail , Chandra Partha , Byrum Stephanie , Mackintosh Samuel , Gies Allen , Busija David
Published: May 2023

Aging-associated structural alterations and functional decline of the brain microvasculature contribute to the development of cognitive impairment and dementias such as Alzheimer’s disease. The mitochondrial loss and dysfunction appear to play a major role in mechanisms leading to aging-associated changes of the microvasculature, including increased blood brain barrier permeability, vascular rarefication, or decreased branching. SS-31, a small, water-soluble tetra-peptide has been shown to be effective in improving the aging phenotype in healthy, aged rodents as well as in models of neurodegenerative disease. However, the beneficial effects of SS-31 have not been examined on the brain microvascular proteome.We tested the hypothesis that targeting mitochondria with SS-31 rescues aging-associated changes in the brain microvascular proteome.Aged male (> 18 months) C57Bl6/J mice were randomly assigned to the SS-31 treatment (10 mg/kg; i.p.; n = 5) or vehicle saline (n = 5) groups. Mice were treated daily for two weeks. Cerebral blood flow (CBF) was measured using laser speckle imaging at four time points (0, 3, 7, 14 days). Then, cortical microvessels (MVs) containing a mixture of end arterioles, capillaries, and venules, < 70mm, were isolated and used for Orbitrap Eclipse Tribrid mass spectrometry.During the two-week period, baseline CBF was similar between SS-31 and vehicle groups. Bioinformatic analysis showed that treatment with SS-31 resulted in significant differences in protein abundance of cortical MVs vs. vehicle. Twelve percent (107) of the identified 6,266 proteins were mitochondria associated (oxidative phosphorylation, metabolism, the antioxidant defense system) and mitochondrial dynamics were significantly differentially expressed, Our findings suggest that mitochondria are potential therapeutic targets in the aging brain microvasculature, and that changes in the proteome may contribute to the beneficial effects of SS-31 in aging. Our results warrant further study with the inclusion of female animals to investigate the role of sex-differences in the effects of SS-31.

This research was supported in part by: IDeA National Resource for Quantitative Proteomics Voucher Program (R24GM137786), Tulane Brain Institute Research Fund Award to IR, NIH HL-148836, NIH AG-063345, NIH AG-075988, the Louisiana Board of Regents Endowed Chairs for Eminent Scholars program to Dr. Busija, P30GM145498, U54 GM104940. The University of Arkansas for Medical Sciences Bioinformatics Core Facility is supported by the Winthrop P. Rockefeller Cancer Institute and National Institutes of Health grant P20GM121293.

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 gene therapy restores breathing in a rat model of Pompe disease
Authors: Fuller David , Rana Sabhya , Pope Megan , Thakre Prajwal , Corti Manuela , Byrne Barry
Published: May 2023

Pompe disease is a neuromuscular disorder resulting from mutations in the gene for acid a-glucosidase (GAA) – an enzyme necessary to degrade lysosomal glycogen. Early-onset disease occurs in the absence of functional GAA, which leads to cardiorespiratory failure early in life. Late-onset disease is associated with reduced GAA activity and gradual respiratory failure with preserved cardiac function. The standard of care – intravenous enzyme replacement therapy (ERT) using recombinant GAA does not effectively target the central nervous system, and can delay but not prevent respiratory failure. We used a Pompe rat model ( Gaa null) to test the hypothesis that a single intravenous AAV-GAA dose in neonate Pompe rats can drive persistent and widespread GAA expression and prevent respiratory decline over the lifespan. Male Gaa-/- rats received a single intravenous administration of AAV9-DES-hGAA (1x1014 vector genomes/kg; n=6), temporal vein injection) or sham injection (1xPBS; n=6) on post-natal day one. Ventilation was measured using a whole-body plethysmograph at age 3-, 6-, and 9-months. Rats treated with the gene therapy vector showed a striking increase in body mass over the duration of the study (2-way repeated measures analyses of variance, treatment effect, p<0.001). At age 9 mo, treated rats weighed 402±25 g and sham rats weighed 293±27 g. As rats progressed from 3- to 9-months age, tidal volume, minute ventilation, and the ratio of minute ventilation to CO2 production (i.e., VE/VCO2) were all greater in the gene therapy treated rats as compared to sham (each of these variables showed an age x treatment interaction, all p<0.001). We conclude the neonatal gene therapy with AAV9-DES-hGAA can prevent decline in body mass and preserve breathing ability over the lifespan of a Pompe rat model. Gene therapy is a promising approach for treating Pompe disease.

Funding: R01HD052682

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.
Development of an in vivo correlate of lung mechanics in a rat model of spinal cord injury
Authors: Sunshine Michael , Taylor Chase , Little Brittany , Waters Christopher , Alilain Warren
Published: May 2023

High cervical spinal cord injuries (SCI) damage of bulbospinal inputs to phrenic motor neurons results in diaphragm paresis and paralysis. Additionally, acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) is prevalent in individuals with SCI (Veeravagu et al., 2013). We have recently shown that a rat model of SCI recapitulates inflammatory and metabolic symptoms of ARDS/ALI (Huffman et al., 2021). Measurements of lung damage are typically performed at endpoint, and therefore do not allow researchers to perform longitudinal or repeated evaluations. Conversely, whole body plethysmography (WBP) is used commonly in longitudinal studies to assess changes in ventilation. WBP systems collect complex pressure waveforms, which are derived to estimate flow, and tidal volumes (Drorbaugh & Fenn, 1955). Recently, methods have been developed to capture more subtle characteristics within respiratory waveforms (Sunshine & Fuller, 2021). By grouping respiratory waveforms into clusters using principle component analysis we can track the prevalence of waveforms with similar patterns between treatment groups and across experimental protocols. In the present study we recorded WBP in adult female Sprague-Dawley rats prior to assessing lung mechanics with a flexivent. Animals were grouped into either, Shelf, Sham, C2Hx and measurements were performed at 6, 12, or 64+ weeks post-surgery. We correlated waveform cluster prevalence with metrics of lung mechanics. The waveform analysis revealed a subset of clusters with moderate correlation to lung compliance, and resistance. This suggests that this waveform analysis method may serve as an in vivo surrogate to estimate lung mechanics during longitudinal studies.

NIH R21NS121966

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.
Appetite control and feed intake- Can AgRP serve as a biomarker for appetite in the teleost Atlantic salmon, Salmo salar?
Authors: Ronnestad Ivar , Lai Floriana , Kalananthan Tharmini , Tolås Ingvill , Norland Sissel , Gomes Ana
Published: May 2023

In mammals, the main center for appetite control is the arcuate nucleus (ARC), which contains different neuronal populations. Anorexigenic neurons co-express cocaine- and amphetamine-regulated transcript ( cart) and proopiomelanocortin ( pomc) neuropeptides. The pomc peptide undergoes posttranslational modifications and one of its products, α-MSH, is released together with CART to inhibit appetite. The orexigenic neurons co-express and release neuropeptide Y (NPY) and agouti-related peptide (AgRP) to stimulate appetite. Together, these two ARC neuronal populations comprise the key neuropeptide expression of the melanocortin system (MCS).The MCS is relatively well-conserved among vertebrates, including teleost species. However, in Atlantic salmon ( Salmo salar), the salmonid-specific fourth round whole-genome duplication has resulted in the presence of several paralogous genes, some of which may have resulted in divergent functions. Our in-silico analyses have shown that in Atlantic salmon the key potential neuropeptides of the MCS repertoire comprises three npy, one agrp, ten cart and three pomc genes.Analyses of mRNA distribution of the genes for the MCS neuropeptides across brain regions in salmon reveal significant spatial and quantitative differences in their expression profile between paralogs. In situ hybridization analyses show that agrp1 is only expressed in the nucleus lateralis tuberis (NLT) region of the Atlantic salmon, the putative homolog to the mammalian ARC. In this NLT area, npya, agrp1, cart2b, and pomca are predominantly localized in distinct neurons, however, some neurons co-express cart2b/ pomca. This contrasts with what is known for higher vertebrates and show that co-expression is not required for homeostatic feeding control. Further, studies of fed and fasted fish support that agrp1 acts as an orexigenic signal in Atlantic salmon. In addition, the distinct and well-defined localization of agrp1 in the NLT region suggest that the hypothalamic agrp1 gene may serve as a biomarker for appetite and feed intake in the Atlantic salmon.

Research Council of Norway (Projects# 221568; 254894, 267626, 268987, 315106, 317770)

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 lower body negative pressure on critical closing pressure and brain tissue mechanics in healthy young adults
Authors: Horvat Fiona , Kramer Mary , Johnson Curtis , Martens Christopher
Published: May 2023

BACKGROUND: Elastography has emerged as a powerful tool for assessing the viscoelastic mechanical properties of the brain which are believed to reflect the microstructural integrity of neuronal tissue. Little is known about the influence of hemodynamic properties, including alterations of intracranial pressure (ICP) on brain tissue properties, which may be important for proper brain functioning. PURPOSE: The purpose of this study was to determine whether acute application of lower body negative pressure (LBNP) alters brain tissue mechanical properties via reductions in ICP. METHODS: 10 participants (8F/2M, age: 23±2 y; BMI: 24±2 kg/m2; BP: 111±6/73±6 mmHg) were included in this study. All participants laid supine with their lower limbs in a negative pressure chamber. Arterial blood pressure (ABP) was measured by finger plethysmography and heart rate was recorded using a 3-lead electrocardiogram (Finapres, NOVA, Medical Systems, Enschede, the Netherlands). Right middle cerebral artery blood velocity (MCAv) was assessed by transcranial Doppler ultrasound. All measures were made at rest and in response to -30mmHg LBNP, which was applied over three repeated 10-minute intervals with 10 minutes of rest in between each interval. Critical closing pressure (CrCP) was calculated as a surrogate measure of ICP using the X-intercept from a best-fit line between ABP and MCAv. The same LBNP protocol was then repeated inside a Siemens 3T Prisma MRI scanner to measure global brain tissue stiffness using magnetic resonance elastography (MRE; 3-min sequence). The last 2-minutes of vascular data for each interval was averaged for all outcomes and the effects of LBNP (off vs. on) and repeated interval (1, 2, 3) were examined using a mixed effects model. RESULTS: Heart rate was significantly elevated during application of LBNP (off: 66±23 vs. on: 76±12 BPM; p-value=0.001) confirming expected vascular effects of LBNP. There was no main effect of LBNP on either stiffness or CrCP; however, stiffness increased with each subsequent application of LBNP, resulting in a main effect of interval on brain stiffness (p-value=0.018). CONCLUSION: These preliminary data suggest brain stiffness increases with repeated application of -30 mmHg LBNP; however, this does not appear to be caused by a change in critical closing pressure and thus ICP. Future studies should further examine alternative mechanisms by which vascular function relates to brain tissue properties.

University of Delaware Research Foundation

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.
Mentoring is not “Short-Term”: effective continuing mentoring strategies for undergraduate short-term summer program participants after the research experience
Authors: De Miguel Carmen , Becker Rena , Hollowell Cheyenne , Wilson Christopher , Pollock Jennifer
Published: May 2023

Short-term summer research experiences are a “crash-course” in unique research and mentoring opportunities. Mentoring by research faculty is a key component to short-term summer undergraduate research experiences through laboratory training, one-on-one mentoring, and overall engagement in the program. Faculty members also encourage retention of these scholars in research areas. However, continuing mentorship beyond the brevity of the experience is often difficult for both the faculty mentor and the mentee, particularly if they are at different institutions. The UAB kidney, urology, and non-malignant hematology (KUH) undergraduate research experience (KURE) has been active since 2014 and since 2018 as an NIH-funded R25 Program focused on kidney research and interdisciplinary KUH experiences. UAB KURE has trained over 99 scholars (33% underrepresented in biomedical sciences) in individualized kidney physiology and pathophysiology research as well as clinical experiences. The KURE scholars were individually matched with a faculty mentor and daily supervisors or near peers to support the project and research experience. Over 32 UAB faculty members have mentored a KURE scholar in this short-term experience with 72% (23 of 32) faculty members being a mentor for 2 or more summer experiences. Many in the UAB KURE cohorts have developed a strong bond with the mentor and KUH community at UAB. Those scholars continue in research either at a distance or in future summers, a number return as gap year interns, and many are in communication for future career direction or support. This on-going mentoring and engagement with KURE Scholars as a near peer and a faculty mentor requires time and focus. Determining the most effective means and resources to continue mentoring summer scholars in the long-term is an important consideration. Continual mentoring of summer undergraduate KURE scholars has a critical impact in retaining these scholars and increasing the diversity of researchers and clinicians in the KUH larger community. Through one-on-one qualitative interviews and quantitative survey analysis, we investigated the key aspects of ongoing mentoring of short-term research scholars. We will present methods, metrics, and models for ongoing mentoring, as well as the complex nature and significance of this ongoing mentoring after the summer experience to those scholars who are underrepresented in medicine.

Funded by R25 DK115353

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.
Short-chain fatty acids of the intestinal microbiota reduce mesenteric lymphatic pumping
Authors: Singh Reetu , Heaps Cristine , Muthuchamy Mariappan , Stewart Randolph , Laine Glen , Dongaonkar Ranjeet
Published: May 2023

Short-chain fatty acids (SCFAs; acetate (AC), propionate (PP), and butyrate (BT)) are the primary metabolites of the intestinal microbiota. In addition to being an epithelial energy source, SCFAs exert numerous local effects, including maintenance of the epithelial barrier integrity and protection against inflammation, and are commonly assumed beneficial. It is also well understood that mesenteric lymphatic function is vital for normal gut health; impaired pumping leads to interstitial accumulation of fluid and immune cells, inducing intestinal edema and inflammation. Mesenteric lymphatic vessels are exposed to significantly high concentrations of SCFAs, yet the acute effects of SCFAs on lymphatic function have remained unexplored. Following earlier reports of SCFAs-induced relaxation of vascular smooth and cardiac muscle, in the present study, we tested the hypothesis that AC, PP, and BT reduce lymphatic pumping.Following our recently reported methods, pumping was characterized in vitro using rat mesenteric lymphatic vessels. Briefly, isolated vessels were cannulated, perfused, and bathed with warmed APSS. Following 60-min initial equilibration, in spontaneously contracting vessels, the effects of acute treatment with AC (10 mM), PP (10 mM), BT (10 mM), or AC+PP+BT were determined. In an additional set of vessels, the effects of short-chain fatty acid receptor antagonists (GLPG0974, FFAR2 antagonist, 1 μM and ((R)-3-Hydroxybutyric acid, FFAR3 antagonist, 1 μM) on lymphatic acute responses to AC+PP+BT were determined. Lymphatic responses were characterized using contraction frequency (CF), normalized stroke volume (difference in diastolic and systolic volume normalized to passive volume, NSV), normalized pump flow (CF*NSV, NPF), and diastolic tone (difference in passive and diastolic diameters normalized to passive diameter, DT).Treatment with AC, PP, or BT alone decreased CF and NPF significantly. Accordingly, CF and NPF were also lowered significantly after the combined treatment with the three SCFAs. Nevertheless, both indices were completely restored after FFAR2 and FFAR3 inhibition. Changes in NSV and DT after treatment with AC, PP, or BT, however, were not significant.To our knowledge, the present study is the first to demonstrate adverse chronotropic effects of the three primary SCFAs produced by intestinal microbiota on lymphatic pumping. The lymphatic responses are consistent with reports of reduced heart rate and cardiac contractile indices more than the dilation of blood vessels induced by SCFAs. Further studies are needed to reconcile the apparent conflict between the beneficial effects of SCFAs and the damaging effects of impaired lymphatic pumping.

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.
The “forgotten circulation”: Sympathetic control of mesenteric venous capacity in conscious hypertensive rats
Authors: McBryde Fiona , Emans Tonja , Barrett Carolyn , Paton Julian
Published: May 2023

The venous circulation is often “forgotten,” as cardiovascular research and therapeutic intervention focusses predominantly on arteries. However, systemic veins store two-thirds of blood volume at rest, with reservoir beds such as the mesenteric circulation receiving dense sympathetic innervation, suggesting a critical neurogenic role for the mobilization of blood. The impact of hypertension on sympathetic regulation of venous circulation remains unclear. We hypothesized that capacity of mesenteric vasculature is impaired in spontaneously hypertensive rats (SHR) and that reducing sympathetic drive will increase mesenteric buffering of excess volume.SHR (n=6) and Wistar rats (n=7) were instrumented with telemeters recording arterial and venous pressures, and an atrial balloon for assessment of mean circulatory filling pressure (MCFP). Arterial (inflow) and venous (outflow) mesenteric flow probes were implanted to measure total mesenteric volume fluctuation. Mesenteric vascular capacity was challenged with 20% volume load of intravenous saline. In SHR sympathetic drive was reduced via hexamethonium (10mg/kg) or via carotid body denervation (CBD).MCFP was elevated in SHR (+2.7±0.5mmHg, p<0.01 vs Wistars). MCFP in SHR was reduced by hexamethonium (-2.6±0.6; p=0.01 vs Baseline, n=5) and CBD (‑2.0±0.7mmHg; p=0.04 vs Baseline, n=5). In normotensives volume load was accommodated by the mesenteric bed, with a net total influx of blood (+5.4±2.2ml; n=7). In contrast, SHR showed a counter-intuitive net efflux of blood from the mesenteric bed (-1.6±1.4ml; p=0.04 vs Wistars, n=6). Preliminary results indicate that hexamethonium and CBD tended to increase the ability of the mesenteric bed to accommodate volume (hexamethonium: +1.9±1.5, n=6; CBD: +0.8±0.6ml, n=3).We show that SHR have higher venous tone and reduced capacity to accommodate excess volume within the mesenteric vascular bed. Reductions in sympathetic drive reduced venous tone and improved the ability to accommodate volume load. Inhibiting sympathetic activity may provide a novel therapeutic opportunity to restore venous mesenteric capacity and potentially ameliorate hypertension.

Marsden Fund, Royal Society of New Zealand; Health Research Council of New Zealand

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.
The role of Cola nitida on gastric acid secretion and its mechanism of action in male Wistar rats
Authors: Ayegboyin Olusola , Alada AbdulRasak
Published: May 2023

This study investigated the effect of an aqueous extract of Cola nitida (AECN) and decaffeinated (DECAF) extract of kolanut on gastric acid secretion and its mechanism of action in rats. Previous reporters only speculated that the biological effect of kolanut in causing gastric acid secretion could be ascribed to its caffeine content, also the mechanism is not fully elucidated. In addition, none of the previous reporters has investigated the effect of decaffeinated kolanut extract on gastric acid secretion. Sixty (60) male adult Wistar rats divided into twelve groups of five rats each were used for this study. Groups 1 and 2 received normal saline orally and intravenously respectively at a dose of (1 ml/kg), 3 and 4 received 25 mg/kg of (AECN) orally and intravenously respectively, group 5 received (100mg/kg) AECN orally, groups 6 and 7 received 25mg/kg of (DECAF) both orally and intravenously respectively, group 8 received 100mg/kg of DECAF orally, groups 9 and 10 were pre-treated with cimetidine 12 μmoles/kg intravenously followed by 25 mg/kg AECN and DECAF respectively, groups 11 and 12 were pre-treated with i.v atropine (0.2 mg/kg) followed by 25 mg/kg of AECN and DECAF respectively. Gastric acid secretion was determined by continuous perfusion of rats' stomachs under urethane anesthesia. Data collected were expressed as mean ± SEM. Statistical significance at P≤0.05 was determined using Student’s t-test analysis. The oral administration of AECN (25mg/kg and 100mg/kg) and i.v AECN (25mg/kg) caused a significant increase (P≤0.05) in gastric acid secretion (GAS) with pronounced effect than DECAF group. The oral administration of 25mg/kg and 100mg/kg of DECAF and intravenous administration of (25mg/kg) DECAF caused a significant increase in gastric acid secretion. The administration of cimetidine and atropine significantly reduced gastric acid secretion. In conclusion, aqueous extract of Cola nitida and decaffeinated kolanut extract exert significant gastric acid secretion in this study. Also, the mechanisms exhibited by kolanut in stimulating gastric acid secretion in this study could be attributed to stimulating both the histaminergic H2 and cholinergic (Muscarinic M3) receptors since cimetidine and atropine blocked/reduced its effect.

This research work was self-funded.

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.
Intestinal inflammation caused by anti-cancer drugs is ameliorated by ginsenoside
Authors: Tsujii Taisei , Kato Daisuke , Jonan Shizuka , Amagase Kikuko
Published: May 2023

Background & Aim: It has been reported that 5-fluorouracil (5-FU), a widely used anticancer drug, causes intestinal inflammation due to shortening of small intestinal villi and destruction of the glandular fossa, resulting in diarrhea and weight loss. Although Ginsenoside Rd (GRd) and Ginsenoside Re (GRe) are saponins found in carrots and have been reported to have anti-inflammatory effects on the gastrointestinal tract, these compounds have not been reported to have anti-inflammatory effects on the small intestinal mucositis induced by 5-FU. In the present study, we investigated the effects of GRd and GRe on the 5-FU-induced mucoenteritis. Materials & Methods: Male C57BL/6N mice (20-25 g) were treated with 5-FU (50 mg/kg i.p.) and GRd (60 or 100 mg/kg p.o.) or GRe (100 mg/kg p.o.) once daily for 7~8 days. 5-FU was dissolved in saline and GRd and GRe were dissolved in 0.5 % CMC. The group receiving saline and 0.5% CMC was designated as the Vehicle group. Body weight and degree of diarrhea (score 0: normal stools, 1: soft stools, 2: severe soft stools, 3: diarrhea, 4: severe diarrhea) were measured daily during the treatment period. The degree of intestinal inflammation was evaluated by histopathological examination using hematoxylin/eosin (H&E) staining, measurement of myeloperoxidase (MPO) activity, and mRNA expression of inflammation-related molecules after the end of drug administration. The expression of NF-κB in the small intestine was examined by immunohistochemical staining. Results: Decreased body weight and exacerbation of diarrhea were observed from the third day of 5-FU administration, and combined administration of GRd or GRe had no effect on these symptoms. Histopathological observations showed that 5-FU administration shortened small intestinal villi and reduced the number of small intestinal crypt, compared to the vehicle group. However, co-administration of GRd and GRe, significantly suppressed the decrease in the number of small intestinal crypts and cells in the crypt by 5-FU treatment and tended to suppress the increase in expression of TNF-α mRNA. MPO activity in the small intestinal mucosa were increased by 5-FU treatment, and the increase was clearly suppressed in the GRd or GRe combination treatment groups. In addition, the expression of NF-κB was clearly increased at 24 hours after the last dose of 5-FU compared with the Vehicle group, and the increase of NF-κB expression by 5-FU administration was clearly suppressed by the concomitant use of GRd. Conclusion: The results obtained in this study suggest that GRd and GRe show anti-inflammatory effect against 5-FU-induced enteritis and that NF-κB is involved in their action.

The authors declare no conflict of interest.

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.
Kv7 channel dysfunction is involved in hyperactivity of posterior insular cortex neurons in hypertension
Authors: Sheng Zhaofu , Sheng Zhaofu , Zheng Peiru , Li De-Pei
Published: May 2023

Elevated sympathetic outflow is a key component of pathogenesis of hypertension. However, the source driving increased sympathetic vasomotor tone remain unclear. The posterior insular cortex (PIC) is a brain region involved in regulating blood pressure and sympathetic tone. Neurons in the PIC project to the rostral ventrolateral medulla (RVLM). Neuronal Kv7 channels play a vital role in controlling the excitability of neurons. This study determined the role of Kv7 channels in regulating RVLM-projecting PIC neurons in spontaneously hypertensive rats (SHRs). Kv7.2, Kv7.3, and Kv7.5 subunits expression level were compared between Wistar-Kyoto (WKY) rats and SHRs. Whole-cell recording was used to compare the firing activity and M-current in RVLM-projecting PIC neurons retrogradely labelled by Fluospheres injected into the RVLM. We found that the protein expression levels of Kv7.3 and Kv7.5 in the PIC were significantly lower in SHRs than in WKY rats, while Kv7.2 levels did not differ between WKY and SHRs. Immunofluorescent staining reviewed that Kv7.2, Kv7.3, and Kv7.5 subunits were expressed on retrogradely labeled RVLM-projecting PIC neurons. Electrophysiological recording results showed that the basal firing activity of labeled PIC-RVLM projection neurons was significantly greater in SHRs than in WKY rats. Blocking M-currents with XE-991 increased both spontaneous and depolarization-triggered firing rate of RVLM projecting PIC neurons in WKY rats, whereas XE-991 did not alter either spontaneous or depolarization-triggered firing rate of these neurons in SHRs. These data suggest that hyperactivity of RVLM projecting PIC neurons in SHRs is attributed to reduction of Kv7 channel expression and activity. Our findings revealed a novel mechanism underlying elevated sympathetic vasomotor activity in hypertension.

National Heart, Lung, and Blood Institute grant HL142133 and HL139523, and HL159157 to D-P. L.

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 function of vascular segments that comprise a murine arteriovenous fistula
Authors: Mookherjee Sohom , Hill Nathan , Fairbourn Brayden , He Yuxia , Boudina Sihem , Shiu Yan-Ting , Lee Timmy , Symons John David
Published: May 2023

Approximately 60% of arteriovenous fistulas (AVFs) created in hemodialysis patients in the United States fail to mature. Understanding the underlying pathobiology is requisite to design and implement new treatments. Mechanisms responsible for AVF failure include intimal hyperplasia and poor lumen expansion. Compromised vasoreactivity also might play a role. Our murine AVF model comprises the external jugular vein (EJV) connected to the carotid artery (CA), establishing 3 component parts to the AVF, i.e., proximal CA, EJV, and distal CA. Upon AVF creation, the EJV is acutely exposed to higher pressures and disturbed flow, known causes of endothelial cell dysfunction. First, we tested the hypothesis that endothelial function is impaired in EJVs (193 ± 27 μm i.d.) from AVF mice (i.e., EJV-AVF; n= 5 males and 5 females) vs. EJVs (228 ± 18 μm i.d.) from naïve animals (EJV-Con; n=6 males and 4 females). Three days after creating the AVF, using isometric tension procedures, dose-dependent vasocontraction to the Thromboxane A2 (TxA2) receptor agonist U46619 was robust in the EJV-Con (p<0.05) but was absent in the EJV-AVF segment. Because vasocontraction is necessary to subsequently test endothelium-dependent vasorelaxation, our hypothesis could not be evaluated. Our second hypothesis was that endothelial function is impaired in the distal (185 ± 7 μm i.d.) vs. proximal (230 ± 10 μm i.d.) CA, secondary to disturbed flow patterns. U46619 -evoked vasocontraction was greater (p<0.05) in the proximal vs. distal CA segment of the AVF. Acetylcholine-evoked vasorelaxation was greater (p<0.05) in distal vs. proximal CA, whereas responses to sodium nitroprusside were similar between groups. These findings do not support our hypothesis and suggest that endothelial function is better in the distal vs. proximal CA of the AVF, whereas vascular smooth muscle function is similar between segments. Ongoing studies are evaluating endothelial function in each segment of the AVF 21-days after creation.

Supported by R01HL153244 NIH/NIDDK (TL, YTS, JDS)

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.
Uncovering the relationship between optic atrophy-1 protein and mitochondria function
Authors: Chapa Xavier , Garcia Jorge , Bazil Jason , Javadov Sabzali
Published: May 2023

Mitochondria, known as the powerhouse of the cell, also participate in the regulation of ion homeostasis, redox status, cell growth and differentiation, lipid metabolism, and cell death. The inner mitochondrial membrane (IMM) plays a crucial role in the regulation of mitochondrial metabolism and function. The dynamin-related GTPase optic atrophy-1 (OPA1) localized in the IMM is responsible for mitochondria fusion. In addition, OPA1 has been shown to play an important role in maintaining the structural integrity and functional activity of mitochondrial cristae. We have recently shown that mitochondrial swelling stimulates enzymatic cleavage of OPA1 by OMA1, a zinc metallopeptidase, which converts long-OPA1 (L-OPA1) to short-OPA1 (S-OPA1). Cleavage of L-OPA1 was suggested to diminish mitochondrial fusion and bioenergetics leading to cell death. The role of OPA1 cleavage and OMA1 activation under diverse swelling conditions has not yet been elucidated. In this study, we investigated the role of OPA1 cleavage under various mitochondrial swelling conditions in the presence and absence of Myls22 (an OPA1 inhibitor), and TPEN (a zinc-chelator and OMA1 inhibitor). Cardiac mitochondria were isolated from Sprague Dawley rats and their function was assessed under Ca2+-induced mitochondrial swelling with oxoglutarate and malate (OM) with/without ADP. Our dose-dependent experiments revealed that Myls22 and TPEN exert the maximum effect at 50 and 5 μM, respectively. Next, we found that the maximum respiration rate (state 3) of mitochondria for complex I is diminished by both inhibitors. However, neither Myls22 nor TPEN prevented alterations in mitochondrial respiration rates, swelling, membrane potential, and calcium retention capacity induced by Ca2+. Finally, we evaluated the protein expression of L-OPA1 via western blot and found more OPA1 cleavage under state 3 compared to state 2 respiration rate suggesting the regulatory role of S-OPA1 in mitochondrial respiration. Thus, our data demonstrate that although mitochondrial swelling stimulates L-OPA cleavage associated with mitochondrial dysfunction, inhibition of OPA1 cleavage/OMA1 activity by Mysl22/TPEN is ineffective in ameliorating the effects of Ca2+-induced mitochondria swelling.

This study was supported by the National Science Foundation (Grant 2006477).

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.