bluuebunny/crossref_metadata_2025 huggingface dataset:
Aerobic Exercise Training Attenuates Differences between Black and White Adults in Left Ventricular-Vascular Coupling and Wasted Pressure Effort
Authors: Maroco Joao , Lane Abbi , Ranadive Sushant , Yan Huimin , Baynard Tracy , Fernhall Bo
Published: May 2024

Background: Black adults have a higher risk for left-ventricular hypertrophy and heart failure, when compared to white adults. This stems, in part, from their frequent potential alterations in ventricular-vascular coupling indexed by the arterial (Ea) to ventricular elastance (Ev) ratio and heightened wasted pressure effort (Ew). Exercise training preserves ventricular-vascular coupling and attenuates Ew, but whether this applies to black adults is unknown. Purpose: We hypothesized that aerobic training would attenuate reported racial differences in both left ventricular-vascular coupling and Ew. Methods: Fifty-four young adults [blacks= 24 (14 females); whites= 30 (15 females), aged: 19-35 years] completed an 8-week aerobic training intervention (3 times/wk, 65-85% peak oxygen uptake). Pre-and post-training systolic function and ventricular-vascular coupling were assessed via echocardiography. The Ew was estimated from pulse contour analysis. Pre-and-post-training changes were examined with linear mixed models. Results: Pre-training, blacks had higher Ev (difference (d) = 0.49, 95% CI: 0.14 to 0.84 mmHg/ml, p=0.007) and Ew (d= 1130, 95% CI: 477 to 1784 dyne cm−2 s, p<0.001). After training, both groups exhibited similar reductions in Ea (d= -0.22, 95% CI: -0.32 to -0.13 mmHg/ml, p<0.001). In white, but not black adults, Ev increased (dwhite= 0.30, 95% CI: 0.04 to 0.56 mmHg/ml , p=0.027) and Ea/Ev was reduced (dwhite= -0.21, 95% CI: -0.29 to -0.12 mmHg/ml, p<0.001). Conversely, black but not white adults exhibited reductions in Ew after training (dblack= -699, 95% CI: -1209 to -189 dyne cm−2 s, p=0.008). Systolic function markers (i.e., race-independent increases in ejection fraction) supported ventricular-vascular coupling results. Controlling for cardiorespiratory fitness, and body mass index attenuated training-induced changes in Ev and Ew, while controlling for sex did no change results. Conclusions: In black adults, Ew was reduced following 8 weeks of aerobic training, while Ea was reduced in both black and white adults. Although ventricular-vascular coupling was only altered in white adults, there was no difference between white and black adults in coupling or its components following training. Despite not controlling for social determinants of health shown to partly explain biological racial disparities, our data suggests a positive effect of aerobic training on risk factors associated with the development of left ventricular hypertrophy and heart failure in black adults.

This study was funded by the National Instituteof Health (NHLBI 1R01HL093249-01A1 awarded to Bo Fernhall).

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Vitamin B1 supplementation ameliorates high-fat diet induced exercise fatigue and improves grip strength in male mice
Authors: Luna Crystal , Leano John , Kozlova Elena , Raut Gayatri , Martinez-Lomeli Jose , Degnan Patrick , Deol Poonamjot
Published: May 2024

Dietary deficiencies in vitamins such as thiamine (Vitamin B1) are common even in developed countries and can have a range of deleterious health effects. This trend in Vitamin B1 deficiency coincides with increased fat consumption in the American diet, particularly of soybean oil, the most widely consumed cooking oil in the U.S. which is also present in many processed foods. Here, we hypothesize that the concurrent malnutrition caused by a soybean oil-based high fat diet (SO-HFD) and a physiological deficiency in thiamine can impact regional gene expression in the brain and behavior. To test this, C57BL/6N male mice (N=10-12 per group) were fed either a low-fat chow (OSD) or an SO-HFD, with or without supplementation with 640 mg/kg of the thiamine analog thiamine tetrahydrofurfuryl disulfide (TTFD), for 18 weeks. Mice were subjected to a series of behavioral tests designed to evaluate cognition (passive avoidance test, PAT), strength (modified grip strength test, MGS), exercise endurance (treadmill test, EE), and locomotor/habituation activity (open field test, OFT). Our results showed no difference across groups on the PAT. On the MGS test, the force generated when normalized to body weight was lesser on all test days for SO-HFD as compared to OSD (p<0.05-0.0001). The TTFD supplementation improved MGS only in the SO group (p<0.05). On EE, OSD ran significantly longer before exhaustion as compared to SO (p<0.05-0.001). For one subset of animals TTFD supplementation improved the EE score in SO but not OSD (p<0.05-0.001). During the one-hour OFT, distance traveled decreased over time for both TTFD-supplemented groups only (p<0.05-0.01), indicating improvement in habituation/learning. Transcriptomic analysis of the hypothalamus and hippocampus from these mice revealed differentially expressed genes (p<0.05) that may contribute to alterations observed in the behavioral tests. Our results indicate that TTFD supplementation ameliorates HFD-induced deficits in strength and exercise endurance. TTFD supplementation improved habituation/learning on OFT regardless of diet.

The Thiamine Advocacy Foundation, NIH R01DK127082 (FMS), DOD GW180072 (MCC).

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Inspiratory Pressure Threshold Loading: Effects on Inspiratory Pattern, Perception and Prefrontal Cortical Activity
Authors: Miranda Andre , Burt Juliana , Davenport Paul , Davenport Matthew
Published: May 2024

Cognitive awareness of breathing can lead to behavioral ventilatory compensation, respiratory interoception and activation of brain regions associated with decision processes, including the dorsal prefrontal cortex (dPFC). The dPFC is a critical cortical region mediating executive functions and dPFC activity is modulated during increased breathing load. This study investigated load compensation and perception response to sustained breathing against inspiratory pressure threshold (PT) loads. We hypothesized that increasing magnitudes of PT loads require increasing time to valve opening resulting in; greater inspiratory motor drive, increased perception of breathing effort (INT), increased perception of unpleasantness (UPL) and increased dPFC oxygen consumption (OXY, a measure of increased neural activity). Functional near-infrared spectroscopy (fNIRS) was used to measure OXY changes in the dPFC. Healthy subjects were exposed to 5 cmH2O (LoPT) and 20 cmH2O (HiPT) inspiratory PT loads for 1 minute load-on and 1 minute load-off trials. A total of 8 trials for each load were presented, 4 INT trials and 4 UPL trials. Perception of inspiratory INT and UPL was rated with a 0-10 modified Borg scale. There was a significant PT magnitude dependent increase in valve opening duration (0.18±0.15 LoPT vs 0.57±0.17 HiPT) and pressure (-4.4±0.75 LoPT vs -21.3±2.2 HiPT, p<0.001). The pressure-time-product (PtP), a measure of inspiratory motor drive, significantly (p<0.001) increased with PT magnitude. A significant PT magnitude dependent increase in INT (2.8±1.3 vs 7.9±1.2, p<0.001) and UPL (1.9±1.4 vs 7.8±1.4, p<0.001) ratings occurred but perception ratings did not significantly change throughout the 1-minute trial. The average 1-minute trial OXY LoPT was significantly (p<0.02) less than HiPT. The right dPFC OXY did not significantly change between trial Breath 1 and Breath 10. The left dPFC OXY significantly (p<0.01) increased from trial Breath 1 to Breath 10. These results suggest increased PT load magnitude required greater inspiratory drive to breathe. Breathing against a HiPT load was perceived as highly effortful and unpleasant. Sustained breathing against PT loads progressively increased left dPFC neural activity.

Supported by the University of Florida, College of Veterinary Medicine.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Day-to-day repeatability of total and regional cerebral blood flow
Authors: Ortiz Andrés , Muer Jessica , Didier Kaylin , Wannebo Brett , Sanchez Sophie , Wieben Oliver , Eldridge Marlowe
Published: May 2024

Background: Measuring cerebral blood flow (CBF) has been crucial in understanding brain function and health. Most studies use a resting CBF value for comparison when testing different experimental conditions on different days; however, it is unclear whether resting condition values can be repeated between days. This has important implications for intervention or mechanistic studies. We hypothesize that resting CBF will be repeatable across different days in a well-controlled setting using MRI based pseudo-continuous arterial spin labeling (pcASL). Methods: Seven subjects (1F, 6M) were studied on two separate occasions after abstaining from caffeine, NSAIDs and exercise for 24 hours, and fasting for 8 hours. The end tidal CO2 had to be within 2mmHg between visits. Female subjects were on days 1-7 of their menstrual cycle and were not taking any hormonal contraception. CBF was quantified via MRI based pseudo-continuous Arterial Spin Labeling (pcASL) during both visits and expressed relative to gray and white matter (mL/min/100g). Data focuses on total grey matter, total white matter, and 8 emotional and memory regions. The repeatability of all CBF values was tested between both MRI visits using linear regression. Results: Scans were completed 113± 81 days apart. R2 values showed a weak effect size for grey matter (R2 =0.454) and a moderate effect size for white matter (R2 =0.527). When measuring for the 8 regions of the brain, there were no significant p-values, and weak R2 effect size for the accumbens (p=0.107, R2 =0.454), amygdala (p=0.204, R2 =0.299), anterior cingulate (p=0.092, R2 =0.463), caudate (p=0.122, R2 =0.409) hippocampus (p=0.175, R2 =0.332), and parahippocampus (p=0.183, R2 =0.323). In brain regions involved with memory, the entorhinal cortex indicated a R2 value of moderate effect size (p=0.068, R2 =0.519) t (p=0.068), as well as the precuneus (p=0.060, R2 =0.54) Conclusion: The results suggest that resting CBF demonstrates low repeatability between days. Noteworthy trends exist in the entorhinal cortex and precuneus, which both are involved in memory. These findings suggest that when comparing resting CBF, researchers may want to consider collecting new resting CBF measurements every time they are testing for reactivity since there might be variability in areas such as the accumbens, amygdala, anterior cingulate, caudate, hippocampus and parahippocampus.

Funding: NIH R01 HL150361.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
A Timeline of Cardiac Maturation
Authors: Mikkila Jennifer , Wang Ruchen , Torniainen Andrea , Nelson Gabrielle , Rajvansh Neal , Meyer Markus , van Berlo Jop
Published: May 2024

Background: Much is known about the differences between adult and immature fetal cardiac myocytes. For example, the switch from glycolysis to oxidative phosphorylation, the increase in sarcomere distance and cell size, along with changes in mitochondrial structure and organization are all known to occur at some point between late embryonic development and adulthood. However, the precise timing of when these changes take place is ill-defined. Here, we report in high temporal resolution when hallmarks of maturation develop to provide a timeline and the order of events that are necessary for structural and physiological cardiomyocyte maturation. Methods and Results: Using murine samples from embryonic day 15 all the way to adulthood, we performed characterization of basic organelles, contractile machinery, and extracellular matrix composition, all shown to be necessary for cardiac maturation. We observed clear differences in when maturation hallmarks became established. Features that increased continuously include growth of the size of the heart and cardiomyocytes. Accompanying cell size changes, an increase in endothelial cell count was observed, although cardiomyocyte growth continued after the endothelial cell population reached a plateau. Seahorse assays revealed that mitochondrial respiration increased continuously over time for Complex 1 and 2 until about postnatal day 15, with complex 4 being relatively stable throughout maturation. Lipid droplets appeared at a higher frequency in ventricular tissue starting at postnatal day 5, coinciding with an increase in sarcomere length. T-tubules began to appear at postnatal day 7 alongside changes in calcium handling genes. Mitochondrial size was found to increase rapidly at postnatal day 19. Discussion: Overall, we found that multiple stages of development seem important to target for enhancing maturation as not all changes occur in a linear fashion. Ultimately, knowledge of when maturational hallmarks develop might inform strategies to enhance maturation of human induced pluripotent stem cell derived cardiomyocytes.

T32 Minnesota Muscle Training Grant; Summer’s Wish; Regenerative Medicine Minnesota; Stem Cell Institute Predoctoral Infuse Award.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Sudden Death Induced by Rapid Intravenous Injection of Fentanyl in Conscious Rats
Authors: Zhuang Jianguo , Gao Xiuping , Shi Shan , Xu Fadi
Published: May 2024

The sudden death induced by rapid intravenous (IVr) injection of overdose FNT in clinical settings is commonly observed in conscious humans and more often in the males than females. Our previous study has shown that IVr injection of FNT induces a long-lasting apnea associated with bradycardia and hypotension in anesthetized rats (Zhuang et al. 2023 EB). This study aimed to determine whether a lethal dose of FNT could cause sudden death with the mortality being higher in male rats than female ones and whether the FNT-induced respiratory disorder, especially ventilatory arrest, but not cardiac arrest, was the trigger of the death. The rat previously instrumented with ECG electrodes and jugular vein cannulation was placed in a restraint tube that was connected to a plethysmograph chamber to record cardiorespiratory activities. We found that FNT at doses <2 mg/kg induced an immediate persistent apnea, lasting less than 1 min, associated with bradycardia. Following restoration of respiratory rhythm, the rats showed depressed VE and bradycardia for several hours and the cardiorespiratory variables recovered next day. A lethal dose of FNT at 3 mg/kg, compared to FNT at <2 mg/kg, induced an even longer apnea (lasting >1.5 min) accompanied with more severe bradycardia. This sustained apnea was usually interrupted by brief restoration of breathing, which was followed by ventilatory and cardiac arrest occurring at approximately 5 min and 10 min post injection respectively. Although the initial cardiorespiratory response to FNT appeared to be similar in both genders, the death rate was relatively higher in male rats than female ones. In conclusion, our study establishes an animal model of IVr injection of overdose FNT-induced sudden death occurring within minutes. The sudden death is the result of ventilatory, but not cardiac, arrest following a brief restoration of respiratory activity from a sustained apnea.

Supported by NIH R01 grants HL163512 and DA059063.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Pressure regulation of L-type Ca2+ channels and its role in myogenic response
Authors: Mironova Galina Yu. , Baudel Miguel Martín-Aragón , Flores-Tamez Victor A. , Brett Suzanne E. , Navedo Manuel F. , Welsh Donald G.
Published: May 2024

L-type calcium (Ca2+) channels hold a pivotal position in governing intracellular Ca2+ concentration within smooth muscle and the establishment of myogenic tone. Their primary regulatory mechanism has historically been linked to voltage. Nevertheless, it remains a subject of inquiry whether voltage represents the exclusive modulator or whether these channels also exhibit mechanosensitivity. This study seeks to elucidate the influence of pressure stimuli on L-type Ca2+ channels in the resistance arteries of rodents (rats and mice). The investigative approach spans from the scrutiny of individual smooth muscle cells employing methodologies such as whole-cell and cell-attached patch-clamp electrophysiology, immunohistochemistry, proximity ligation assay, and super-resolution microscopy to the evaluation of intact arteries utilizing pressure myography. The findings obtained through whole-cell patch-clamp electrophysiology unveil a notable augmentation in L-type Ca2+ current in response to pressure stimuli. Subsequent scrutiny at the level of single-channel activity discloses that this augmentation is ascribed to an enhancement in functional coupling. Further inquiry reveals that the intensified functional coupling in response to pressure is contingent upon two principal factors: 1) the facilitation of cooperative gating mediated by protein kinase C (PKC), and 2) the traffcking of subunits to caveolae. Notably, functional experiments, involving depolarization elicited through the application of 30 mM KCl, underscore that arterial tone and cytosolic Ca2+ concentration responses are markedly more pronounced when the arteries are subjected to a pressure of 80 mmHg, as opposed to 20 mmHg. The culmination of these observations from both patch-clamp experiments and functional investigations supports the assertion that L-type Ca2+ channels are indeed amenable to mechanosensory influences, in addition to their well-documented voltage-dependent behavior. In summation, this investigation underscores that the regulatory landscape of L-type Ca2+ channels transcends the confines of voltage control, emphasizing the significance of considering pressure sensitivity in both physiological and pathological contexts. Ongoing research endeavors aim to delineate with precision the signaling complexes within vascular smooth muscle that respond to mechanical forces.

Supported by the Canadian Institute for Health Research, National Institute of Health and the Rorabeck Chair in Vascular Biology and Neuroscience.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Cross-sexual Effects of Testosterone on Mesenteric Arterial Reactivity in Ovariectomized Female Rats
Authors: Rahman Mohammad Moshiur , Islam Rifat Ara , Razan Md Rahatullah , Esfandiarei Mitra , Felmlee Melanie , Rahimian Roshanak
Published: May 2024

The number of transgender individuals is on the rise in the United States. Although there are studies on the effects of sex hormones on cardiovascular function of cisgender male and female, still much is not known about the effects of cross-sex hormone therapy (CSHT) on cardiovascular function in transgender individuals. It has been shown that the risk factors of cardiovascular diseases (CVD) are increased in transgenders after they undergo CSHT. Epidemiological studies suggest that transgender females (male to female, MtF) on estrogen therapy develop higher risk of CVD compared to transgender males (female to male, FtM) taking testosterone. This study investigates the effects of testosterone or estrogen treatment on the third branch of mesenteric arterial reactivity in ovariectomized female rats. Briefly, 8-10 weeks old female Sprague Dawley (SD) rats were ovariectomized (OVX) and subcutaneously implanted with placebo (OVX + PL) or testosterone (OVX + T, 7.5 mg) or 17β- estradiol (OVX + E2, 1.5 mg) pellets for about 35 days. Age matched intact female SD rats were also included in the experimental groups. Endothelium-dependent vasorelaxation (EDV) to acetylcholine (ACh) was measured in the precontracted mesenteric arteries with phenylephrine (PE), using wire myography. Responses to sodium nitroprusside (SNP)-induced vasorelaxation, and PE- and endothelin-1 (ET-1) induced vasocontraction were also determined. We demonstrated that the responses to ACh in rat mesenteric arteries were not altered by either ovariectomy or estrogen treatment. However, testosterone treatment of OVX female rats significantly enhanced the sensitivity to ACh-induced vasorelaxation compared with those in other experimental groups. Moreover, the mesenteric arteries of OVX + T exhibited a trend of reduced sensitivity to PE responses compared to other groups. Furthermore, the maximum tension to ET-1 was significantly reduced in mesenteric arteries of OVX + T compared to OVX+E2 and OVX+PL groups. The vasorelaxation responses to SNP were not altered in any of experimental groups studied. These data suggest that elevated sensitivity to ACh in testosterone-treated ovariectomized female rats might be, in part, due to reduced vessel responses to contractile agents, but not altered sensitivity of smooth muscle to nitric oxide (NO) in this group. Additional studies are needed to investigate the underlying mechanisms and document the consequences for the improvement of EDV observed in OVX + T rats.

NIDA/NIGMS, 1SC1DA052120-01 to MF, Bridge Grant from University of the Pacific to RR.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Role of the caudal Nucleus Tractus Solitarius and the Postinspiratory Complex in swallow production
Authors: Huff Alyssa , Karlen-Amarante Marlusa , Oliveira Luiz , Ramirez Jan Marino
Published: May 2024

The production of swallowing and its coordination with breathing is essential for homeostasis in most organisms. The postinspiratory complex (PiCo) is thought to regulate the transition between swallowing and breathing. Activation of PiCo triggers swallow production and stimulates laryngeal activation in a respiratory phase specific manner. However, little is known about PiCo’s role in swallow generation, which is thought to be controlled by the caudal portion of the Nucleus Tractus Solitarius (cNTS), presumably the swallow pattern generator (SPG). We hypothesize the cNTS is necessary for PiCo to trigger a swallow. Using both male and female Vglut2cre mice, a cre-dependent ChR2 AAV was bilaterally injected into PiCo and a cre-dependent inhibitory DREADD was bilaterally injected into the cNTS, specifically targeting the interstitial (SolI) and intermediate (SolIM) solitary nucleus. Twenty-one days after injection, using our freely breathing urethane anesthetized mouse model, swallows were stimulated by 1) injection of water into the oral cavity and 2) optogenetic stimulation of PiCo neurons; before and after DREADD activator, clozapine-N-oxide (CNO). Swallow and laryngeal activity were measured via monopolar suction electrodes of the hypoglossal (XII) and vagus (X) nerves as well as bipolar electromyogram (EMG) of the submental, laryngeal complex and costal diaphragm muscles. Post-hoc histological analysis was done to confirm areas of interest were targeted. We found that after activation of the inhibitory DREADD, located in the cNTS, swallow was not evoked by water stimulation nor optogenetic stimulation. We propose that PiCo relies on direct feedback from the cNTS in order to trigger swallow production.

NIH F32 HL160102.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Differential Downregulation of Subcellular Specific adrenoceptor Signaling in The Heart
Authors: Xu Bing , Bahriz Sherif , Salemme Victoria , Zhu Chaoqun , Wang Ying , Zhao Meimi , Xiang Yang k
Published: May 2024

Objective: Recent studies have shown that intracellular b1- adrenoceptors (b1ARs) are associated with the (Sarco)endoplasmic reticulum calcium ATPase 2a (SERCA2a) on the sarcoplasmic reticulum (SR) membrane. However, the mechanism of how this plasma membrane- and SR-associated pool of b1ARs signals downregulation under chronic sympathetic stimulation is not well understood. We aim to study these subcellular β1AR signals in different cellular compartments in a heart failure (HF) mouse model with chronic infusion of isoproterenol (ISO). Results and Methods: We investigated the association of b1AR with L-type calcium channel (LTCC), ryanodine receptor 2 (RyR2), and SERCA2a by utilizing proximity ligation assay (PLA) and confocal imaging in HF induced by chronic ISO infusion (30 mg/kg/day, 2 weeks). Chronic ISO infusion resulted in a downregulation of b1AR, and decreased receptor association with LTCC and RyR2 at the tubular membrane. In comparison, the b1AR association with SERCA2a was increased; however, the local cAMP-PKA mediated phospholamban phosphorylation is downregulated. Using Förster Resonance Energy Transfer (FRET) with genetically encoded biosensors to probe subcellular β1AR-PKA signaling, we observed reduced local ISO-induced PKA signaling at the RyR2 but not the SERCA2a nanodomains. Meanwhile, the expression of phosphodiesterases (PDEs) was altered including the downregulation of PDE4D and PDE3A and the upregulation of PDE2A, PDE4A, and PDE4B, which alters the local PKA activities in individual subcellular nanodomains. Interestingly, the localized PKA signal induced by endogenous norepinephrine at the SERCA2a nanodomain was impaired. Inhibition of monoamine oxidase A rescued the norepinephrine-induced local PKA signaling at the SERCA2a nanodomain and myocyte sarcomere shortening. Conclusion: We have uncovered distinct remodeling of b1AR signaling at the RyR2 and SERCA2a nanodomains in mouse HF after a chronic infusion of ISO. Our study offers strategies to restore the subcellular nanodomain cardiac b1AR signaling and contractile function in HF associated with chronic adrenergic stress, pointing toward potential therapeutic targets.

National Institutes of Health grants R01-HL147263 and HL162825, Veteran Affair Merit grants IK6BX005753, 01BX002900 and BX005100.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Upregulation of miR-361-3p Is Associated With Impaired AT2 Receptor Expression in Cardiometabolic Diseases
Authors: Miao Kevin , Alnoud Mohammed , Elgazzaz Mona , Martinez Alexa , Lazartigues Eric
Published: May 2024

Cardiometabolic homeostasis has been shown to be regulated by the brain Renin-Angiotensin System (RAS), including via epigenetic mechanisms. MicroRNA (miRNA) regulation is one of the most common mechanisms controlling the expression of RAS genes and has previously been implicated in hypertension, cardiac ischemia, and aging. Recently, we observed that hypercaloric diet (HCD) programming resulted in differentially expressed miRNA in the hypothalamus of only the male progeny, including miR-361-3p which is thought to target angiotensin-II type 2 receptors (AT2R). Here, we aimed to investigate whether miR-361-3p regulate AT2R expression in a mouse model of cardiometabolic disease (CMD) exhibiting hypertension, diabetes and obesity. C57BI/6J mice (3-week-old, both sexes, n=10) were fed a HCD (D12492. 60 kcal% Fat, Research Diets, USA) while weight and fasting blood glucose levels were measured weekly to ensure the acquisition of metabolic syndrome. At 12 weeks of age, the mice were infused subcutaneously (osmotic pump model 1004, Alzet) with Ang-II (600 ng/kg/min/4 weeks). BP, food intake and glycemia were recorded weekly while intraperitoneal glucose (GTT), insulin (ITT) tolerance tests and body composition (EchoMRI) were assessed at the end of the study. Gene expression of miR-361-3p (QRT-PCR) was increased in the hypothalamus of CMD male mice (2.0 ±0.5 vs.1.2 ±0.2, p<0.05) but not in females (2.7 ±0.8 vs.2.5 ±0.4, P>0.05). However, both sexes showed an increase in the heart (Males: 2.0 ±0.5 vs.1.0 ±0.3; Females: 1.6 ±0.4 vs. 0.8 ±0.2, p<0.05) which was associated with decreased AT2R cardiac expression (Capillary Western) in CMD male (0.9 ±0.0 vs.1.0 ±0.0, p<0.05) and females (0.1 ±0.0 vs.0.6 ±0.1, p<0.001). Together, our data suggest that in CMD, upregulation of miR-361-3p is associated with the decrease of AT2R in the heart, possibly contributing to impaired cardiac function in this model. This positions inhibitors of miR-361-3p as a possible new therapeutic strategy to control RAS overactivity in CMD.

This work was supported in part by a research grant from the National Institutes of Health (HL163588).

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
A Novel Mouse Model of Physical Inactivity to Study the Role of Mitochondria in Chronic Kidney Disease
Authors: Opurum Precious
Published: May 2024

Chronic kidney disease (CKD) is a progressive disorder marked by a decline in kidney function. It is thought that a decline in mitochondrial function likely contributes to the pathogenesis of CKD, but the detailed mechanisms remain unclear. This gap in knowledge is contributed by a lack of a murine CKD model that does not rely on injury, toxin, or gene deletion to induce reduced kidney function. In humans, obesity and sedentary behavior strongly contribute to the development of CKD. The aim of the study was to employ small mouse cage (SMC) housing, a novel mouse physical inactivity model that was recently developed in our lab, and test whether it can be used to reliably induce CKD in mice. Wildtype C57BL6J mice were given standard chow or Western high-fat diet (HFD) with or without SMC intervention for 24 weeks to examine the effects of HFD and SMC on glomerular filtration rate (GFR) and respiration on isolated mitochondria from kidney cortex. Although the GFR values of the HFD+SMC group trended higher than other groups, the kidney function was still considered to be normal. Neither HFD nor HFD+SMC group had developed CKD, but mitochondrial respiration of SMC+HFD (1512.64 ± 77.86 pmol·sec−1·mgprotein−1) was significantly greater than that of the HFD-only group (1307.82 ± 79.08 pmol·sec−1·mgprotein−1, p = 0.0017) or the standard chow group (1104.69 ±143.12 pmol·sec−1·mgprotein−1, p = 0.0314. One-way ANOVA followed by Tukey’s test for multiple comparisons). Increased mitochondrial respiration may suggest a hyperfiltration-induced stress response, as commonly observed in the early stages of CKD in humans, and/or an increase in respiration to compensate for reduced effciency of oxidative phosphorylation. We interpret these data to mean that HFD and HFD+SMC are beginning to show adaptations that are in an early phase of CKD development. However, this model requires further optimization to yield the CKD phenotype. Therefore, we intend to further adapt the intervention to induce symptomatic CKD. We envision that developing preclinical models of CKD will help better elucidate its molecular mechanism and identify therapeutic targets for treating CKD in human patients.

DK107397, DK127979.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Regulation of Inflammation, Without Impacting Heart Rate, via Electrical Stimulation of the Dorsal Motor Nucleus of the Vagus
Authors: Falvey Aidan , Palandira Santhoshi , Chavan Sangeeta S. , Brines Michael , Tracey Kevin J. , A. Pavlov Valentin
Published: May 2024

The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. Recently, using optogenetics it has been demonstrated that the brainstem’s dorsal motor nucleus of the vagus (DMN) is a significant source of efferent vagus nerve fibers that control inflammation. In contrast to optogenetics, electrical neuronal stimulation is an approved therapeutic approach. However, the anti-inflammatory effectiveness of electrical stimulation of the DMN (eDMNS) and the possible heart rate (HR) alterations associated with this approach have not been investigated. Here, we examined the effects of eDMNS on the HR and cytokine levels in murine endotoxemia as well as the cecal ligation and puncture (CLP) model of sepsis. C57BL/6 mice (8-10 weeks old), under anesthesia and secured in a stereotaxic frame, received eDMNS via a concentric bipolar electrode in the left or right DMN, or sham treatment. eDMNS (50, 250 or 500 μA and 30 Hz, for 1 min) was performed and HR recorded. In endotoxemia experiments, mice underwent sham or 5-minute eDMNS (250 μA or 50 μA) followed by LPS (0.5 mg/kg) i.p. injection. eDMNS was also studied on mice with cervical unilateral vagotomy or sham surgery. In CLP experiments sham or left eDMNS was performed immediately post CLP. Cytokines and corticosterone were measured 90 mins after LPS administration or 24h after CLP. CLP survival was monitored for 14 days. Both left and right eDMNS at 250 μA and 500 μA significantly reduced HR, compared with pre- and post-stimulation, while 50 μA did not. Left-side eDMNS at 50 μA decreased serum and splenic TNF levels, and increased serum IL-10 during endotoxemia. The anti-inflammatory effect of eDMNS was abrogated in mice with ipsilateral unilateral vagotomy, which was also not associated with serum corticosterone alterations. Right-side eDMNS lowered serum TNF levels and increased IL-10 but had no impact on splenic cytokines. In CLP, left eDMNS decreased serum TNF and IL-6 levels, lowered splenic IL-6 and increased splenic IL-10, and improved survival in mice. For the first time, we demonstrate that an eDMNS regimen, which does not cause bradycardia, mitigates LPS-induced inflammation. These effects are dependent on an intact vagus nerve and are unrelated to corticosteroid alterations. Additionally, eDMNS reduces inflammation and enhances survival in a polymicrobial sepsis model. These findings hold promise for further research into bioelectronic anti-inflammatory strategies aimed at the brainstem DMN.

This work was partially funded by NIGMS.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Sex Differences in Blood Pressure Response to Dietary Salt in Aged Rats
Authors: Sun Fen , Wang Qiu-Xiang , Jin Qi , Jin Shi-Han , Zhang Jin-Yang , Zhao Lu-Ping , Jin Chao
Published: May 2024

Background: The impact of dietary salt intake on blood pressure (BP) and its variability is critical for understanding cardiovascular risks, yet there is a scarcity of data exploring these effects across different sexes, particularly in the context of aging. Methods: This study examined the effects of varying salt diets on BP among aged female and male Sprague-Dawley rats (22-24 months). Subjects were administered either a control (0.4% NaCl), low (0.1% NaCl), or moderate-high (1% NaCl) salt diet for 12 weeks. BP levels and variability were measured at baseline, 2, 4, 8, and 12 weeks after dietary onset. Results: Preliminary findings revealed that, from the eighth week following dietary initiation, aged male rats exhibited a pronounced elevation in systolic BP when exposed to all types of diets, in contrast to aged female rats consuming low-salt diets. Additionally, aged male rats presented with a marked rise in diastolic BP upon consumption of both control and high-salt diets relative to female rats across all diets from the eighth week onward. Although systolic BP variability did not differ significantly between sexes, there were marked sex-specific differences in diastolic BP variability. Conclusions: The study identified sex-specific responses in BP and its variability to dietary salt intake in aged rats, with male rats showing heightened sensitivity. These findings underscore the importance of considering sex as a biological variable in dietary and cardiovascular health research.

This research was funded by the START-UP FUNDING OF HANGZHOU NORMAL UNIVERSITY, grant number 4255C50221204123 (Dr. Fen Sun).

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Pain Relief: Unique Derivatives of Ibogaine Alleviate Both Acute and Chronic Pain Symptoms
Authors: Dey Sanjit , Bhattacharya Tuhin , Sinha Surajit
Published: May 2024

Pain induction results in the initiation of neuroinflammatory and neurodegenerative processes, leading to neuromodulation, while conventional analgesic treatments frequently entail undesirable side effects. This research delves into the potent and selective analgesic attributes of Iboga derivatives in the context of acute and chronic pain models. Specifically, the study explores the effcacy of Iboga-alcohol (C1) against acute pain induced by formalin, and investigates the properties of novel derivatives, including iboga-amide (C2), iboga-methylamide (C3), and iboga ester-exo (C4) in terms of their antinociceptive, anti-inflammatory, and neuromodulatory effects. To assess pain, various methods were employed, such as measuring paw diameter, observing paw licking, conducting tail flick tests, hot plate tests, and Von Frey assessments. Additionally, the study evaluated locomotor activity and anxiety-like behavior through open field and elevated plus maze tests, while motor coordination was assessed via the rotarod test. Inflammatory mediators, neurotransmitters, and neurotrophic factors were quantified in serum, paw tissue, and spinal segments. All animal experiments were conducted following approval from Institutional Animal Ethics Committee, University of Calcutta approved by CCSEA, Government of India. The Iboga derivatives demonstrated a significant reduction in the increase in paw diameter induced by formalin. In acute pain models, ibogaine derivatives (C1, C3) reversed the reduced tail flick latency, and the restricted locomotor activity was notably improved by C1, C2, and C3. Anxiolytic behavior was observed in the groups treated with C1 and C3. The Iboga derivatives also mitigated inflammatory markers (Substance P, CGRP, COX-2, p65 nuclear translocation) and reduced serum IL-6 and TNF-α levels (C1). Iboga-alcohol effectively inhibited mechanical allodynia and heat hyperalgesia in chronic pain, along with ameliorating impaired motor activity. Iboga-analogues reversed BDNF depletion in acute pain and exaggerated GDNF elevation in response to noxious stimuli. These findings suggest that the novel Iboga derivatives, especially iboga-alcohol, demonstrate effective antinociceptive actions, prevent neuroinflammation, and hold promise as evidence-based candidates for drug development, without any psychedelic issues potentially offering unique solutions for clinical applications, including pain management in healthcare and sports performance enhancement.

1. West Bengal Department of Science and Technology Biotechnology, Government of West Bengal 2. Life Science Research Board, DRDO, Government of India.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Exposure to Prenatal Tributyrin Improved Pre-Weaning Growth Performance and Reduced Fat Deposition in the Muscle of Market Age Pigs
Authors: Cooper Elizabeth , Murray Robert , Palou Egoaguirre Rousset , Markley Grace , Stahl Chad
Published: May 2024

Organic acids, including short chain fatty acids, medium chain fatty acids, and tricarboxylic acid, are used as alternatives to antibiotics for the purpose of growth promotion in livestock species. Butyric acid has been used extensively for its various functions in intestinal health and barrier function, as well as its actions as a histone deacetylase inhibitor. Many of the issues related to using butyric acid as a feed supplement are overcome by utilizing tributyrin (TB), a butyrate prodrug. Dietary supplementation of TB to sows during gestation was able to improve pre-weaning litter performance. Sows (n=52, 42 gestational days) were randomly assigned to either a control diet or control diet supplemented with 2% TB. All diets were made isocaloric with the addition of oil and wheat flour. Dietary treatments continued until 112 days of gestation. After farrowing, piglet growth performance was monitored. Once offspring reached 6 months of age, 30 gilts from the most median performing litters were identified for tissue collection and evaluation of meat characteristics. Sows that received tributyrin during gestation tended to have higher total litter weights at birth (P value < 0.1), however, average individual birthweights were not statistically different between control and TB litters. TB piglets tended to be heavier at weaning (P value < 0.1). Pre-weaning average daily gains were higher in piglets exposed to prenatal TB (P value < 0.01). Live weights and hot carcass weights did not differ significantly in gilts at market age. There was, however, a trend of increased dressing percentage from TB treated offspring, accompanied by significantly reduced back fat at the 10th rib (P value < 0.1 and P value < 0.05 respectively). This data suggests that TB supplementation results in both temporary and permanent improvements to growth and development. This study provides further evidence that prenatal TB can have long term effects on muscle growth and meat quality. Further studies are needed to ultimately determine whether prenatal or postnatal supplementation is ideal for improving long-term growth performance.

USDA Grant Funded.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Comparing Integrative Respiratory and Renal Acid-Base Acclimatization in Lowlanders and Tibetan Highlanders During Incremental Ascent to 4,300m
Authors: Johnson Nicole , Dickenson Jessica , Isakovich Rodion , Mackenzie Benjamin , Bouten Janne , Kalker Anne , Strzalkowski Nicholas
Published: May 2024

During sustained exposure to high altitude, integrated respiratory and renal acclimatization protects blood oxygenation and acid-base homeostasis, respectively. A sustained and augmented hypoxic ventilatory response (HVR) protects blood oxygenation with ascent (i.e., ventilatory acclimatization). However, the HVR elicits hypocapnia and respiratory alkalosis. A subsequent renally-mediated compensatory metabolic acidosis partially returns pH back to baseline values, with a high degree of variability, and capacity for full compensation limited to approximately 4000-4500m. In convenience samples of fully-acclimatized participants, indigenous highlanders of Tibetan ancestry (TH; i.e., Sherpa) have been reported to have (a) similar ventilatory acclimatization but, (b) improved renal compensation than lowlanders (LL) at 4300m. However, little work has been performed on the differences in renal acclimatization between LL and TH during acclimatization with incremental ascent to high altitude over a similar ascent profile. We assessed renal acclimatization between acclimatizing LL and TH, and hypothesized that (a) TH would have similar ventilatory acclimatization to LL but (b) larger magnitude renal compensation than LL during incremental ascent from 1400m to 4300m. Age- and sex-matched groups of 15 unacclimatized LL (8F) and 14 unacclimatized TH of confirmed Tibetan ancestry (7F) were recruited at 1400m. Utilizing an average of two finger capillary blood draw samples and a blood gas analyzer, we compared renally-mediated acid-base acclimatization (PCO2, [HCO3−], pH) in both groups before (1400m) and following day 8-9 of incremental ascent to 4300m. We found that following ascent, LL had significantly lower PCO2 (p<0.0001) and [HCO3-] (p<0.0001), and higher pH (P=0.0037), suggesting respiratory alkalosis and only partial renal compensation. However, TH had significantly lower PCO2 (p<0.0001) and [HCO3−] (p<0.0001), but unchanged pH (P=0.1), suggesting full renal compensation. At 4300m, TH had significantly lower PCO2 (P=0.01), [HCO3−] (p<0.0001) and pH (P=0.005) than LL. These data suggest that TH have larger magnitude and more rapid time-course ventilatory and renal mechanisms compared to LL, resulting in fully-compensated pH in TH during incremental ascent to high altitude, despite a larger hypocapnic stimulus. To our knowledge, this is the first study to demonstrate these integrated respiratory-renal responses between acclimatizing LL and TH.

MRU, NSERC, NSF.

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