bluuebunny/crossref_metadata_2025 huggingface dataset:
Deletion of Smooth Muscle, but not Endothelial, Mineralocorticoid Receptors Prevents Obesity‐Associated Coronary Vascular Dysfunction in Females
Authors: Brown Scott M. , Meuth Alex I. , Jaffe Iris Z. , Bender Shawn B.
Published: June 2021

Coronary vascular dysfunction is an independent predictor of cardiac mortality in obesity and diabetes, both of which are associated with inappropriate activation of the renin‐angiotensin‐aldosterone system (RAAS). We recently demonstrated that systemic mineralocorticoid receptor (MR) blockade with spironolactone treats coronary vascular dysfunction in male Zucker Obese rat model. The aim of the present study was to investigate MR involvement in coronary dysfunction induced by western diet (WD) feeding in female mice, via both systemic blockade and using vascular cell‐specific MR knockout (KO) mice. Female C57BL/6J, endothelial cell (EC)‐specific MR KO mice, and smooth muscle cell (SMC)‐specific MR KO mice were fed either control diet or WD for 16 weeks. Systemic MR blockade was achieved in a group of WD fed C57BL/6J mice via spironolactone (Spiro; sc, 20 mg/kg/d) treatment for 16 weeks. Mice were 28–32 weeks of age at study completion. WD feeding induced obesity, hyperinsulinemia, hyperglycemia, glucose intolerance and adipose inflammation, but did not change blood pressure. Coronary vascular function was assessed via wire myography of left ventricular coronary arteries. Coronary endothelium‐dependent vasodilation to acetylcholine (ACh) was impaired by WD feeding and this was prevented by Spiro treatment and in SMC MR KO mice fed a WD, independent of blood pressure. Pretreatment of coronary arteries with the superoxide dismutase mimetic Tempol restored maximal dilation to ACh in WD fed mice. EC MR KO had no effect on coronary function in mice fed control diet or WD. Endothelium‐independent vasodilation to sodium nitroprusside was principally unaffected by WD feeding. Furthermore, in SMC MR KO mice, WD‐induced enhancement of coronary vasoconstriction to the thromboxane mimetic U46619 was prevented. Additional studies revealed that WD feeding increased gene markers of endothelial inflammation (ICAM‐1, PECAM) and fibrosis (collagen I) in aorta and that this is prevented in SMC MR KO mice fed a WD. SMC MR deletion did not, however, attenuate WD‐induced visceral adipose inflammation or glucose intolerance. Taken together, this study confirms and extends our previous findings regarding MR involvement in obesity‐associated coronary vascular endothelial dysfunction. Specifically, these data provide further insight into the mechanisms underlying the beneficial effects of MR antagonism in obesity, in particular highlighting a novel role of SMC MR, but not EC MR, as an important mediator in the development of obesity‐associated coronary vascular dysfunction.

Support or Funding Information

Funded by VHA BLR&D BX002030 (SBB) and NIH NHLBI R01 HL119290 (IZJ).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Microarray Analysis of Long Noncoding RNAs in the Heart and Plasma of Type 2 Diabetic db/db Mice
Authors: Pant Tarun , Dhanasekaran Anuradha , Bosnjak Zeljko , Ge Zhi‐Dong
Published: June 2021

Objective

Diabetic cardiomyopathy (DCM) refers to diabetes‐associated changes in the structure and function of the myocardium that is not directly attributable to other confounding factors such as coronary heart disease or hypertension. Long noncoding RNAs (lncRNAs) are emerging as the regulator of the development, proliferation, and aging of cardiovascular cells and the pathogenesis of cardiac hypertrophy and heart failure. Little is known regarding lncRNA expression profiles in DCM. The present study was to develop lncRNA expression profiles of the heart and serum of type 2 db/db mice with and without DCM and identify candidate genes for DCM.

Results

Echocardiography results indicate that there was no significant differences in the thickness of left ventricular wall, left ventricular end‐diastolic volume, the peak velocity of mitral E and A waves, isovolumic contraction time of the left ventricle, ejection time of the left ventricle, and myocardial performance index between type2 db/db mice and C57BL/6 controls at 6–8 weeks of age. Left ventricular end‐systolic volume was significantly increased, and ejection fraction and mitral E/A ratio were significantly decreased in db/db mice with DCM at 18–20 weeks of age compared with age‐matched controls. Profiling revealed differentially expressed (DE; adjusted P –value<0.05) lncRNAs in heart and plasma were 663 and 152 whereas the mRNA expressions in the same order were 447 and 127 of Wild type (C57BL/6, db/db) mice vs type 2 db/db (C57BL/6, db/db) whereas in the Wild Type old (C57BL/6, db/db) mice vs type 2 db/db with DCM (C57BL/6, db/db) total LncRNA and mRNA deregulated in heart were 816 and 662 whereas the mRNA expression in the same order were 662 and 2580.

Conclusion

DCM is associated with changes in global patterns of lncRNA expression. Our study lays the foundation for further studies defining the role of individual lncRNAs in the pathogenesis of DCM.

Support or Funding Information

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mitophagy Must Be Maintained at a Certain Level in Order to Provide Cardioprotection in Mice During Fasting
Authors: Bantis Katrina , Zhang Yawen , Kobayashi Satoru , Liang Qiangrong
Published: June 2021

Previous literatures have shown a clear yet undefined relationship between caloric restriction, or fasting, and preserved cardiac function. Indeed, it has been demonstrated that fasting attenuates acute ischemic injury, chronic cardiac remodeling, and heart failure in mammalian models. Mitophagy, or mitochondrial degradation, has been implicated in mediating such cardioprotection, however the underlying molecular mechanism remains uncharacterized. Mitophagy plays a homeostatic role in mammalian cells, targeting excessive or damaged mitochondria for lysosomal degradation. Such degradation is essential in both dictating mitochondrial turnover during a cell's basal state as well as during times of stress when oxygen free radical species threaten a cell's ability to appropriately perform. We previously showed that one‐day fasting accelerated while two‐day fasting reduced mitophagy flux in the mouse heart, suggesting time‐differential effects of fasting on cardiac mitophagy. In the present study, we set out to determine if manipulating the level of mitophagy could mediate cardiac function during fasting. We subjected genetically altered transgenic (TG) mice with moderate‐ and high‐expression levels of Parkin, an E3 ubiquitin ligase that tags damaged mitochondria for degradation in order to promote mitophagy, in the heart as well as Parkin knockout (KO) mice and wild‐type (WT) mice to 48‐hours of complete caloric restriction. We then determined their cardiac function using echocardiography and invasive left ventricular (LV) catheterization. The results showed that 48‐hour fasting triggered cardiac dysfunction in WT mice, as indicated by significantly reduced heart rate, fractional shortening, maximal left ventricular pressure, and left ventricular contractility. Moreover, between the WT control (fed) and fasted KO mice, the latter group showed a significant reduction in these same cardiac parameters, suggesting that mitophagy is essential to the maintenance of cardiac function during fasting. Interestingly, between the WT control and the fasted TG mice which expressed moderate levels of Parkin, a significant change in cardiac function was not observed whereas significant cardiac dysfunction was observed between the WT control and TG mice that expressed high levels of Parkin. Taken collectively, our findings suggest that the downregulation of mitophagy under prolonged fasting mediates cardiac dysfunction and, thus, a specific level of mitophagy is required in order to be cardioprotective in mice.

Support or Funding Information

This study was supported by an NIH grant.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sodium Butyrate Attenuates Angiotensin II‐Induced Cardiac Hypertrophy by Inhibiting COX2/PGE2 Pathway via a HDAC5/HDAC6‐Dependent Mechanism
Authors: Zhang Linlin , Deng Mokan , Lu Aihua , Chen Yanting , Chen Yang , Wu Chunying , Wang Weidong , Tan Zhi , Yang Tianxin , Zhu Qing , Wang Lei
Published: June 2021

Sodium butyrate (NaBu) is reported to play important roles in a number of chronic diseases. The present work is aimed to investigate the effect of NaBu on angiotensin II (Ang II)‐induced cardiac hypertrophy and the underlying mechanism in in vivo and in vitro models. Male SD rats were infused with vehicle or Ang II (200 ng/d) and oral administrated with or without NaBu (1g/kg/d) for two weeks and blood pressure was monitored by the telemetry system. After two weeks, cardiac hypertrophy parameters and COX2/PGE2 pathway were analyzed by Real‐time PCR, immunohistochemistry and Western blot. The content of ANP, PGE2 and activity of HDACs were measured by ELISA. The cardiomyocyte H9C2 cells were used to investigate the underlying mechanism by which NaBu inhibiting Ang II‐mediated hypertrophy. NaBu significantly attenuated Ang II‐induced increase in the mean arterial pressure from 159 ±8 mmHg to 127 ± 7 mmHg (P<0.01). Ang II treatment remarkably increased cardiac hypertrophy as indicated by increased ration of heart weight/body weight and enlarged cardiomyocyte size, extensive fibrosis and inflammation, as well as enhanced expresssion of hypertrophic markers, whereas hearts from NaBu treated rats exhibited a significant reduction in these hypertrophic responses. Mechanistically, NaBu suppressed the expression of COX2/PGE2 along with the production of ANP and phosphorylated ERK (pERK) stimulated by Ang II in vivo and in vitro, which is mediated by the inhibition of HDAC5 and HDAC6 activities. Additionally, expression knockdown of HDAC5 and HDAC6 via gene editing strategy dramatically blocked the hypertrophic response of COX2/PGE2 pathway induced by Ang II in vitro. These results provide solid evidence that NaBu attenuates Ang II‐induced cardiac hypertrophy by inhibiting the activation of COX2/PGE2 pathway in a HDAC5/HDAC6‐dependent manner.

Support or Funding Information

National Natural Science Foundation of China (No. 81600322, No. 81770707, No. 81603587)

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Circulating transcriptome as a signature for the diagnosis of pulmonary arterial hypertension.
Authors: Qi Xinshuai , Gonzalez‐Garay Manuel J. , Vanderpool Rebecca , Song Shanshan , Tang Haiyang , Ayon Ramon J. , Desai Ankit , Yuan Jason X.‐J.
Published: June 2021

Introduction

Pulmonary Arterial hypertension (PAH) is a rare disease that progressively leads to right heart failure and risk of mortality. However, the diagnosis of PAH in clinic largely depends on hemodynamic data. Circulating transcriptomic profiles have been developed as biomarkers in multiple cardiovascular diseases and thus can be potentially used to detect the signature of PAH. Here we aim to develop a robust approach for the diagnosis and prediction of PAH and its severity by integrate genotype, phenotype, and gene expression data.

Methods

We analyzed 96 peripheral blood mononuclear cell transcriptomes from PAH patients and control cohort. Gene expression analysis was performed using Rsubread, limma, and EdgeR package in R. Variation calling, filtering. The comparison was performed between PAH, idiopathic PAH with control, and different PAH severity groups. GWAS was performed using Samtools, Vcftools, and PLINK.

Results

A total of 72 genes with significant differential expression and 150 genes associated with PAH severity were identified. In addition, 405 of the 4.1 million identified SNPs are associated with PAH.

Conclusion

Circulating transcriptome can be used to identify genetic signatures for the diagnosis of pulmonary arterial hypertension based on our preliminary results. Once validated in a larger cohort, the identified genes and SNPs can provide a molecular marker system for the PAH diagnosis in addition to hemodynamic data.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Acute Effect of Aerobic Exercise on Carotid Strain in Individuals with Multiple Sclerosis
Authors: Grigoriadis Georgios , Rosenberg Alexander J. , Wee Sang Ouk , Schroeder Elizabeth C. , Griffith Garett , Baynard Tracy
Published: June 2021

INTRODUCTION

Individuals with multiple sclerosis (MS) have increased arterial stiffness, a known risk factor for cardiovascular disease. Acute aerobic exercise is a stressor affecting markers of arterial stiffness, such as carotid strain (CS) and beta stiffness index, which provides insight into aspects of arterial function. Individuals with MS may have different responses to exercise compared to healthy individuals due to arterial dysfunction, which can be evaluated via markers of arterial stiffness.

PURPOSE

To evaluate the acute effect of aerobic exercise on CS in individuals with MS.

METHODS

Sixteen individuals with MS (42 ± 8 yrs; 27.5 ± 6.9 kg/m2) underwent treadmill walking at 60% of their peak aerobic capacity for 20 min. Images of the carotid artery were obtained in the radial view with ultrasonography at baseline, immediate and 30 min post‐exercise. Speckle tracking software was used to calculate the following variables of arterial function: CS, CS time to peak (TPK), CS rate, CS rate TPK, radial velocity (RV), RV TPK, radial displacement (RD) and RD TPK. Carotid systolic blood pressure (cSBP) was measured via applanation tonometry and longitudinal carotid beta stiffness index via ultrasonography.

RESULTS

See Table. CS rate, RV and carotid systolic blood pressure (cSBP) increased immediate post‐exercise (p<0.05). CS TPK and RD TPK decreased immediately post‐exercise and RD TPK remained decreased at 30 min post‐exercise (p<0.05). HR and beta stiffness index increased immediately post‐exercise (p<0.05) and returned to baseline at 30 min (p>0.05).

CONCLUSION

The baseline levels of CS in individuals with MS are lower than values reported for middle‐aged adults in the literature, indicative of baseline arterial dysfunction. Beta stiffness index increased immediately after exercise. While CS rate increased after exercise in individuals with MS similar to beta stiffness index, the difference disappeared after statistically controlling for HR. Our results suggest that individuals with MS do not improve arterial stiffness with acute aerobic exercise, providing more evidence for arterial impairment.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Influence of Sex and Exercise Intensity on Acute Flow‐Mediated Dilation Response to Aerobic Exercise in Healthy Young Adults
Authors: Kim Han‐Kyul , Hwang Chueh‐Lung , Lim Jisok , Yoo Jeung‐Ki , Perez Hannah , Handberg Eileen M. , Christou Demetra
Published: June 2021

Brachial artery flow‐mediated dilation (FMD), a measure of endothelial function, is an independent predictor of future cardiovascular events. Sex and exercise intensity influence the acute FMD response to aerobic exercise in older adults, but in young adults this has not been investigated. Therefore, the purpose of this study was to compare the acute FMD response to a single bout of high‐intensity interval training (HIIT), moderate‐intensity continuous training (MICT) and low‐intensity continuous training (LICT) in young men vs. women. Twenty‐eight healthy young adults (14 men and 14 premenopausal women, 21.2±0.3 vs. 21.5±0.8 years of age, means ± SE, P =0.7) participated in this randomized crossover study. Brachial artery FMD was measured in response to reactive hyperemia following 5‐min forearm occlusion using high resolution ultrasonography. FMD measures were obtained prior to exercise, at the end of a single bout of HIIT (40 min, 4 × 4‐min intervals at 90% peak heart rate (HRpeak), MICT (47 min, 70% HRpeak) and LICT (47 min, 50% HRpeak) on the treadmill and following 60‐min recovery from exercise. The acute FMD response was influenced by exercise intensity but not sex (P=0.006 for exercise intensity × time and P=0.9 for sex × exercise intensity × time), thus the results are presented for men and women combined. FMD was attenuated by 20.7% following the end of HIIT (6.96±0.51 vs. 5.47±0.48%, pre‐ vs. end of exercise; P=0.001) and returned to pre‐exercise levels following 60‐min recovery (P>0.99). However, FMD did not change in response to MICT(7.10±0.53 vs. 6.32±0.57 vs. 7.26±0.37%; P≥0.3) and LICT (7.14±0.41 vs. 7.46±0.56 vs. 7.15±0.43%; P>0.99). In conclusion, exercise intensity, but not sex, significantly impacts the acute FMD response to aerobic exercise in young adults.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effects of Resistance Exercise on Intracranial Pressure
Authors: Fischman Jessica Jayne , Cowen Robin , Petersen Lonnie , Healey Robert , Hargens Alan
Published: June 2021

Introduction

One of the primary health concerns faced by NASA astronauts on board the International Space Station is a decline in visual acuity. It is believed that increases in intracranial pressure (ICP) due to resistive exercise performed on the station's Advanced Resistive Exercise Device (ARED) may contribute to Spaceflight Associated Neuro‐Ocular Syndrome (SANS), also referred to as the Visual Impairment and Intracranial Pressure (VIIP) syndrome. In a manner similar to low level Valsalva exertion, it is hypothesized that ICP would increase during low level resistance exercise.

Methods

Six healthy subjects (4 male, 2 female, age: 27 ± 10 years, weight: 77 ± 15 kg) were recruited to perform low‐level resistance exercises in both the seated and supine positions. A Cerebral Cochlear Fluid Pressure analyzer (CCFP) was used to noninvasively measure ICP by assessing tympanic membrane displacement (Vm) in the inner ear following an auditory stimulus. Increased values of Vm correspond to a decrease in ICP. After a 10‐minute acclimation period, a baseline measurement was taken with the subject at rest in the seated position. ICP was then measured during randomized, isometric, overhead shoulder holds with weights of 0lbs, 2lbs, and 5lbs (per hand). This procedure was then repeated in the supine position. ICP was also measured in the 15‐degree head down tilt (HDT) position following a 10‐minute acclimation period. Significant differences between groups were determined at p<0.05 using a Student's T‐test.

Results

The relative changes in Vm with increased loading by position are shown in Figure 1. Vm decreased by 40% ± 15% (p=0.001) in the HDT position as compared to the supine baseline, showing a predicted, reliable increase in ICP for positional changes. In the seated position, displacement increased slightly from baseline (12% ± 63%, p=0.412) for all subjects across all weight levels, indicating a statistically nonsignificant decrease in ICP. Measurements in the supine position were more consistent, with decreasing Vm (3% ± 3%, p=0.563) for all subjects across all weight levels, indicating a nonsignificant increase in ICP.

Discussion

Contrary to our hypothesis, measured data showed no significant change in ICP during low level resistance exercise in either the seated or supine positions. Based on these results, resistance exercise may not be the primary contributing factor to the development of SANS in astronauts. This study will form the basis of future investigation into the effects of exercise and ICP in different such as gender, age, and clinical populations. Sensitivity of the CCFP to motion and pulse artifacts will also be addressed to reduce variability between subjects.

Support or Funding Information

Supported by NASA grant NNX13AJ12G

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Individual Differences in Response to Cold‐Pressor Test: Are the Corresponding Blood Pressure, Sympathetic, and Pain Perception Responses Associated to a Family Risk of Hypertension?
Authors: Huang Mu , Yoo Jeung‐Ki , Stickford Abigail S.L. , Hendrix Joseph M. , Moore Jonathon P. , Crandall Craig G. , Fu Qi
Published: June 2021

There is a considerable amount of inter‐individual variability in the perception of pain to a given stimulus. Given that pain, and its management, is a major public health problem, expanding an understanding of the underlying causes of these individual differences is important. Recent studies have demonstrated divergent muscle sympathetic nerve activity (MSNA) responses to physical and mental stressors. Perhaps there is similar variability in the sympathetic responses related to the perception of pain. Therefore, the purpose of this investigation was to test the hypothesis that during a cold‐pressor stimulus in healthy individuals, the sympathetic neural responses correspond with perceived levels of pain. Heart rate (HR), blood pressure (BP), and MSNA were measured at baseline and during a 2‐minute cold‐pressor test (CPT) with subjects in the supine position. Immediately following the CPT, pain was rated on a numeric scale (range 0–10), with two groups being established: subjects who rated their pain ≥7 (HP: high pain, n=10) and those that rated their pain ≤6 (LP: low pain, n=8). The HP group (age: 37±12, 5 females) exhibited greater increases in MSNA during the first 30 seconds (HP: 9±8 vs. LP: −1±3 bursts/min change from baseline, P=0.04) and peak MSNA responses (HP: 25±11 vs. LP: 10±6 bursts/min change from baseline, P=0.0009) compared to the LP group (age: 31±6, 5 females). Likewise, peak changes in mean BP (HP: 16±7 vs. LP: 9±7 mmHg, P=0.02) were greater in the HP group. HR responses were similar between the two groups. Interestingly, a greater proportion of the LP group reported a parental history of hypertension (HP: 20% vs. LP: 87.5%, x2: P=0.007). In summary, sympathetic neural and BP responses to an acute painful stimulus correspond to the magnitude of pain perception in healthy humans. Moreover, this data provides additional intrique to better understand the associative model between a family risk of hypertension and hypoalgesia.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Muscle Metaboreflex Control of Left Ventricular Filling Pressure
Authors: Senador Danielle , Gross Matthew , McNitt Megan , Kaur Jasdeep , Coutsos Matthew , Krishnan Abhinav C. , Mannozzi Joseph T. , Aung Kimberly , Alvarez Alberto , Hanna Hanna W. , Lovelace Abe T. , Levanovich Peter , Dombrowski Maryetta , Lessanework Beruk , O'Leary Donal S.
Published: June 2021

When oxygen delivery to active skeletal muscle is limited, afferent signals from the muscle elicit reflex increases in cardiac output (CO) and mean arterial pressure (MAP) in order to increase perfusion to the ischemic muscle ‐ termed the muscle metaboreflex (MMR). Previous studies have shown that in normal subjects, CO is increased predominantly through increases in heart rate (HR) while maintaining stroke volume (SV) essentially constant. However, increases in HR alone have limited ability to raise CO because as HR increases, SV falls due to decreased filling time. Increases in ventricular contractility can limit the falls in SV, however with sustained increases in CO, blood is translocated from the venous to the arterial circulation and ventricular filling pressure falls which limits the ability to maintain elevated CO. To sustain increases in CO, central blood volume mobilization must also occur to maintain ventricular filling pressure. We previously showed that MMR activation does increase central venous pressure (Sheriff, Augustyniak and O'Leary, Am. J. Physiol., 1998), but whether this translates into increases in left ventricular end‐diastolic pressure (LVEDP) is unknown. MMR was activated via reductions in hindlimb blood flow during mild treadmill exercise in chronically instrumented canines before and after induction of heart failure (HF, rapid ventricular pacing, 220–240 bpm, ~30 days). In normal animals, MMR activation induced a rise in LVEDP from 14.4 ± 1.8 to 18.2 ± 1.8 mmHg (p<0.05) despite substantial increases in HR (Δ 26 ± 4 bpm), CO (Δ 1.45 ± 0.16 l/min) and MAP (Δ 42.3 ± 2.6 mmHg). After induction of HF, MMA activation increased LVEDP from 28.6 ± 2.5 to 38.7 ± 2.6 mmHg (p<0.05) which was a significantly larger rise than observed in normal animals. In HF, the attenuated rise in CO (Δ 0.20 ± 0.08 l/min) with MMR activation likely contributes to the exaggerated increase in LVEDP. We conclude that MMR activation elicits significant blood volume mobilization which increases cardiac filling pressure which thereby likely helps sustain SV despite shortened filling time. In HF, the limited ability to raise CO is not due to reduced filling pressures.

Support or Funding Information

NIH RO1 Grants HL055473 and HL126706

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Intrarenal High Salt Administration Causes Tonic Inhibition of Renal Sympathetic Nerve Activity (RSNA)
Authors: Hindermann Martin , Rodionova Kristina , Dietz Amelie , Ditting Tilmann , Ott Christian , Schmieder Roland , Amann Kerstin , Veelken Roland
Published: June 2021

Afferent renal nerve fibers from the kidney likely counterregulate salt sensitive blood pressure increases by decreasing renal sympathetic nerve activity. We recently reported on a long‐lasting tonic sympatho‐inhibition due to intrarenal afferent renal nerve stimulation eliciting a TRPV1 dependent neuro‐humoral pathway. We wanted to test the hypothesis that sodium influences this afferent sympatho‐depressory mechanism.

Groups of anesthetized SD rats (n=8) were equipped with femoral catheters (blood pressure (BP) & heart rate (HR) recording, drug application), a renal arterial catheter for intrarenal administration (IRA) of high salt (10 % NaCl, 10 μl) or Capsaicin (CAP 3.3, 6.6, 10, 33*10–7 M, 10 μl) and a bipolar electrode for RSNA recordings; eventually an intravenous (iv) bolus of the NK1‐receptor blocker RP67580 (10*10–3M, 15 μl) was given. Cultured dorsal root ganglion neurons (Th11‐L2) of rats with renal afferents were investigated in current clamp mode to assess action potential generation or in voltage clamp mode to investigate inward currents during 10 sec exposure to 4.5 % NaCl or equi‐osmotic 20% mannitol. Results are given in mean±SEM.

IRA high salt and IRA CAP decreased RSNA from baseline 4.1±0.6 μV*sec to 2.2±0.8 μV*sec (10% NaCl, p<0.05) and 3.9±0.5 μV*sec to 0.9±0.2 μV*sec (CAP, p<0.01). Suppressed RSNA in high salt groups and CAP could be unmasked by systemic (i.v.) administration of the NK1‐blocker (2.7±1.8 μV*sec to 5.8±2.2 μV*sec; p<0.05 (10% NaCl); 1.0±0.2 μV*sec to 6.1±1.5 μV*sec; p<0.01 (CAP)). Cultured renal neurons exhibited production of action potentials (3.5±0.8*, from baseline, p<0.05) and increased sustained inward currents from baseline during exposure to NaCl 4.5 % (−10708.8±3546.5 pA*, from baseline, p<0.05). No responses to mannitol 20%.

Increased intrarenal sodium concentrations might induce long‐lasting sympatho‐depression via a neuro‐humoral TRPV1 dependent and tachykinin mediated afferent nerve pathway from the kidney. Impairment of this sympatho‐depressory mechanism could be involved in salt sensitive hypertension.

Support or Funding Information

DFG Deutsche Forschungsgemeinschaft VE 104/4‐1

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hypertonic saline infusion affects glycemic responses following glucose load in healthy men
Authors: Jansen Lisa Tjorven , Suh Hyun‐Gyu , Sprong Cameron , Adams J.D. , Butts Cory , Seal Adam , Scott Dylan , Melander Olle , Lemetais Guillaime , Dolci Alberto , Vanhaecke Tiphaine , Perrier Erica , Kirkland Tracie , Kavouras Stavros
Published: June 2021

Low water intake and plasma hypertonicity have been independently associated with hyperglycemia and incidence of diabetes mellitus in epidemiological studies. Recent data also suggest that reducing water intake deteriorates glucose regulation in patients with type 2 diabetes. To date, it is unclear whether plasma hypertonicity would also impact glycemic control in subjects with normal glycemic and insulinemic function.

OBJECTIVE

To assess the effect of hypertonic saline infusion on glycemic responses to an oral glucose tolerance test (OGTT) in healthy adult men.

METHODS

30 healthy, non‐smoking adult men (36.6±7.0 y, 83.9±12.8 kg, body mass index 27.0±3.4 kg·m−2, HbA1c 5.2±0.3%, HOMA‐IR 1.59±0.97) were recruited for this study. Each subject underwent two experimental trials, consisting of a 2‐h intravenous infusion of saline (ISO: 0.9% NaCl and HYPER: 3.0% NaCl) at an infusion rate of 0.1 ml·kg·min−1, followed by a 4‐h oral OGTT. Blood samples were taken at 30 min intervals throughout the infusion period and during the OGTT. Plasma osmolality (POsm), glucose (Glu), angiotensin II (AngII), renin, and aldosterone (Ald) were measured and plasma volume (PV) was calculated using hematocrit and hemoglobin based on the Dill & Costill equation.

RESULTS

POsm at baseline was similar between conditions (287±3 and 286±3 mmol·kg−1 in HYPER and ISO, respectively). Following the 2‐h infusion, POsm was significantly higher in the HYPER condition than the ISO condition (305‐±3 vs. 288±3 mmol·kg−1; P < 0.0001), with greater PV expansion (20.1±6.9 vs. 10.9±3.2%, P < 0.0001). In the HYPER condition, POsm remained above baseline throughout the OGTT (296±3 mmol·kg−1 at OGTT4‐h; P < 0.0001). During the OGTT, Glu in the HYPER trial was higher than in the ISO trial at 60 min (HYPER: 157±24; ISO: 145±29 mg·dL−1; P < 0.018) and 90 min (HYPER: 139±33; ISO 128±29 mg·dL−1; P < 0.038). The renin‐angiotensin‐aldosterone system was suppressed as indicated by decreased plasma values of AngII, renin, and Ald, probably due to PV expansion in both trials.

CONCLUSION

Plasma hypertonicity induced by hypertonic saline infusion unfavorably affected glycemic response to an OGTT in healthy adult men.

Support or Funding Information

This research was supported by Danone Research

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Neurons in the Organum Vasculosum of the Lamina Terminalis Sense Both Angiotensin II and NaCl to Regulate Thirst
Authors: Kinsman Brian J. , Browning Kirsteen N. , Stocker Sean D.
Published: June 2021

Angiotensin II (AngII) and NaCl are sensed by hypothalamic circumventricular organs to subsequently regulate body fluid homeostasis and blood pressure. AngII predominantly acts within the subfornical organ (SFO), whereas NaCl is sensed by neurons in the organum vasculosum of the lamina terminalis (OVLT). However, OVLT neurons also abundantly express AngII‐type I receptors. Therefore, we performed a series of in vitro and in vivo experiments in adult male Sprague‐Dawley rats to determine whether OVLT neurons sense both AngII and NaCl to impact body fluid homeostasis. First, in vitro whole‐cell recordings were performed on OVLT neurons in the presence of kynurenic acid (1mM) and bicuculline (20μM) to assess discharge responses to +7.5 mM NaCl (3 min) versus 100pM AngII (90s) in a randomized order. The majority of OVLT neurons (66%, 23/35) demonstrated an increase in discharge frequency to both AngII (1.31±0.25Hz to 2.19±0.31Hz; p<0.001) and hypertonic NaCl (1.11±0.18Hz to 2.16±0.27 Hz; p<0.001). Smaller proportions of OVLT neurons were either excited by NaCl alone (3/35), AngII alone (4/35), neither stimulus (3/35), or were inhibited by NaCl (2/35). In a second set of experiments, in vivo single‐unit recordings of OVLT neurons were performed to assess discharge responses to intracarotid injection (50uL over 15 s) of hypertonic NaCl (0.5M NaCl) or AngII (200ng). Half of OVLT neurons (50%, 6/12) displayed an increase in discharge to intracarotid injection of AngII (3.2±0.7 to 9.2±1.9 Hz, P<0.01) and 0.5M NaCl (3.6±0.6 to 9.0±1.6 Hz, P<0.01). The remainder of OVLT neurons showed an increase in discharge to hypertonic NaCl only (n=1) or AngII only (5/12). In a final set of experiments, we employed an optogenetic approach to determine the extent by which inhibition of OVLT neurons would attenuate thirst stimulated by NaCl versus AngII. rAAV2‐CamKII‐eNPHR3.0‐mCherry (5×1012 particles/mL, 50nL) was injected into the OVLT, and an optical ferrule (200um OD) was implanted 300um dorsal to the injection site. Approximately 4 weeks later, optogenetic inhibition of OVLT neurons (561nm, 10mW) significantly reduced water intake in response to intravenous infusion (1.25 mL per 30 min) of 2M NaCl (control: 5.1±0.9 mL vs laser: 1.6±0.9 mL; n=4, P<0.01). In addition, optogenetic inhibition of OVLT neurons also attenuated hypotension‐induced thirst produced by intravenous injection of 25 mg/kg diazoxide (control: 4.5±0.8 mL vs laser: 1.3±0.7 mL; n=4, P<0.01). These findings suggest that individual OVLT neurons can sense both NaCl and AngII to functionally regulate thirst to both stimuli.

Support or Funding Information

NIH R01 HL113270 and AHA Established Investigator Award

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of the Superior Cervical Ganglion in Response to Hypoxia in Juvenile Rats
Authors: Coffee Gregory A. , Getsy Paulina M. , Lewis Stephen J.
Published: June 2021

The superior cervical ganglion (SCG) sends sympathetic input to the carotid body (CB) via the ganglioglomerular nerve (GGN) in order to modulate carotid sinus nerve (CSN) chemosensory afferent discharge via controlling vascular tone. This chemoafferent discharge is then relayed to the nucleus tractus solitarius (NTS) where the information is processed resulting in a compensatory increase in respiration. Hypoxic gas challenge stimulates the GGN. However, little is known as to the effects of superior cervical ganglionecomy (SCGx) on carotid body chemosensory afferent response to hypoxia (HX).

Our objective was to determine the effect of unilateral SCGx on the ventilatory responses elicited by HX (10% O2, 90% N2) gas challenge (5 episodes of 5 min in duration separated by 15 min) in freely‐moving juvenile (P25) Sprague‐Dawley rats.

Male rats postnatal (P) 21 were subjected to sham or unilateral (right) SCGx and were allowed 4 days to recover. On the day of the experiment, P25 rats were placed in whole‐body plethysmography chambers and subjected to the hypoxic gas exposure. Ventilatory parameters included frequency of breathing, tidal volume, minute ventilation (= frequency x tidal volume), inspiratory and expiatory times, end inspiratory and expiratory pauses, peak inspiratory and expiratory flows, EF50 (expiratory flow at 50% expired tidal volume) and central inspiratory drive (tidal volume/inspiratory time).

The HX challenge elicited robust ventilatory responses in sham‐operated rats compared to unilateral (right) SCGx. Frequency (breathes/min), minute ventilation (ml/min), peak inspiratory flow (msec), and peak expiratory flow (msec) were diminished in unilateral (right) SCGx rats compared to sham. End expiratory pause (msec) showed a faster return to baseline following hypoxic challenge in unilateral (right) SCGx compared to sham. These findings demonstrate a role for CB sympathetic input from the SCG in modulating the ventilatory response to hypoxia.

Support or Funding Information

NIH‐SPARC 1OT2OD023860‐02 SJLewis

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Superior Cervical Ganglionectomy alters Glomus Cell Potassium‐Channel Properties in Response to Hypoxia
Authors: Getsy Paulina M. , Coffee Gregory A. , Lewis Stephen J.
Published: June 2021

The carotid body (CB) chemosensory glomus (type I) cells respond to changes in blood PO2, PCO2, and pH by releasing neurotransmitters that increase action potential discharge of chemosensory afferent fibers within the carotid sinus nerve (CSN). The CSN then signals to the nucleus tractus solitarius (NTS) within the dorsal brainstem, which leads to a compensatory increase in ventilation in order to restore blood gas levels and pH. Along with the CSN, the ganglioglomerular nerve (GGN) also innervates the carotid body. The GGN consists of post‐ganglionic sympathetic fibers, which originate from the superior cervical ganglion (SCG). Stimulation of the GGN causes an increase in CB chemosensory afferent discharge. However, it is unknown whether loss of sympathetic input to the CB directly alters the chemosensitivity of glomus cells. Our objective was to characterize electrophysiological properties of CB glomus cell potassium (K+) channels in response to acute hypoxia following superior cervical ganglionectomy (SCGx). Sprague Dawley (SD) male rats postnatal (P) 21 were subjected to unilateral (right) SCGx. The left SCG was identified, but not removed. Four days post surgery at P25 the right and left carotid bodies were removed, and primary glomus cells were isolated and plated on coverslips. Glomus cell K+ channel properties were then recorded using the whole‐cell perforated patch‐clamp technique. Our preliminary results reveal that following unilateral (right) SCGx, glomus cells respond to hypoxia with significant reductions (P<0.05 to P<0.01) in outward K+ current amplitudes over the test potential range +10 to +60 mV. The mean maximal effect, a reduction in K+ amplitude of 64.9 ± 18.5% (mean ± SD, n = 3 cells), occurred at a Vtest of +30 mV. In contrast, wild‐type control CB glomus cells respond to hypoxia with a significant reduction (P<0.05) in outward K+ current amplitude at only a Vtest of +60 mV (n = 4 cells). In addition, glomus cells from SCGx rats appear to respond to hypoxia via a different population of K+ channels that do not appear to be presently active in wild‐type glomus cells when exposed to hypoxia. These findings demonstrate that loss of sympathetic input from the SCG increases CB glomus cell sensitivity to hypoxia, and modulates the O2‐sensing capabilities of glomus cell K+ channels.

Support or Funding Information

NIH‐SPARC 1OT2OD023860‐02 SJLewis

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Exploring the Developmental Thermal Biology of an Abundant Native Amphibian in Southern California, the Baja California Chorus Frog
Authors: Korito Lindsey , Manzanares Samantha , Bucsky Julie , Mueller Casey A.
Published: June 2021

The Baja California chorus frog (Pseudacris hypochondriaca), a member of the Pacific chorus frog complex, is probably the most abundant native amphibian in southern California. The persistence of this species when many other amphibians are in decline provides a unique opportunity to examine the developmental and physiological attributes of a successful species. Developing stages are often particularly susceptible to environmental influences, and understanding physiological function during this time can provide insight into the drivers of species abundance and distributions. The focus of our research is to examine how the developmental physiology of the Baja California chorus frog is influenced by, and responds to, temperature. We collected egg clutches from local ponds within 24 h of fertilization. The clutches were separated and incubated at 10°C, 15°C and 20°C. Oxygen consumption rate (Vo2) was measured throughout development at each temperature. Embryos and tadpoles were fixed throughout development in 4% paraformaldehyde in phosphate buffered saline, then transferred to 70% EtOH, removed from their egg (if not already hatched) and photographed under a dissecting microscope. The yolk and embryo/tadpole were separated, weighed, dried at 65°C for 24 h, and reweighed. The stage and length of each embryo/tadpole was determined from photographs. Average time to 50% hatch and hatch window duration was determined across clutches. Development rate was strongly affected by temperature, with warmer temperatures reducing time to hatch. Temperature also influenced the duration of hatching, with the hatch window ranging from a few days at warmer temperatures to over a week at 10°C. Preliminary results indicate Vo2 was higher and more variable in embryos incubated at 20°C, but there was a limited temperature effect on growth, with length, dry mass and yolk dry mass similar between temperatures throughout development. These results indicate the conversion of yolk into tissue occurred at the same rate across temperatures, and the energy allocated to growth was not altered. However, because more oxygen was consumed at 20°C, the cost of development was higher than at 15°C. Individuals incubated in warmer temperatures may be “wasting some oxygen”, but this does not appear to confer negative physiological consequences. We will further explore morphological and physiological responses to temperature in embryos and tadpoles of this species to understand if robust thermal biology contributes to the success of the species.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Variation in atmospheric oxygen levels affects adult insect wing morphology and flight performance
Authors: Lyn Sheena L. , Christensen Jacob , VandenBrooks John , Schaefer Charles , Parker Greg
Published: June 2021

Objective and Hypotheses

Changes in atmospheric oxygen over geologic time have been hypothesized to drive several evolutionary events in the history of insects. However, the insect fossil record is composed of mostly isolated wings, which presents challenges in interpreting the data and testing these hypotheses. Therefore, our objective was to understand how insect wing morphology varies with atmospheric oxygen as a critical first step in addressing these hypotheses. Given that wing veins contain tracheae which have been shown to vary with rearing oxygen elsewhere in the body, we hypothesized that wing vein diameters should be inversely correlated with rearing oxygen and that these changes would affect flight performance of these insects.

Methods

Drosophila melanogaster and Blatella germanica were reared from hatching to adults under three different oxygen concentrations: 12% (hypoxia), 21% (normoxia) and 31% (hyperoxia). The wings were then dissected and imaged using a mechanical stage mounted on an inverted microscope. Wing area, wing vein diameters, wing vein lengths, and tracheal diameters were all measured using ImageJ. In a second experiment, flies were again reared in three different oxygen concentrations and then flown in all three oxygen levels to test the effect of these changes in wing morphology on flight performance.

Results

In both Drosophila and Blatella, mass specific wing area, wing vein diameters, and tracheal diameters were all inversely correlated with rearing oxygen. In terms of flight performance, flies reared in 31% oxygen flew the best. However, overall flies flew the best in the oxygen level they were reared under.

Conclusions

These results demonstrate that rearing oxygen impacts wing morphology in several groups of insects and that these changes in morphology directly impact flight performance. These changes suggest that wing morphology in the fossil record can be used to interpret evolutionary changes. Additionally, this suggests that wing vein diameter may be a potential proxy for atmospheric oxygen over geologic time.
Early Neuronal Inflammation May Be a Contributing Factor to Changes in Epidermal Innervation Associated with Neuropathy in Prediabetic Mice
Authors: Reller Abigail M. , Umbaugh David S. , Schaller Megan L. , Maciejewski J. Claire , Wooten Joshua S. , Guilford Brianne L.
Published: June 2021

Neuropathy, a crippling diabetic complication, was initially purported to result from lack of glycemic control. However, recent research has linked neuropathy to obesity in individuals without diabetes. Furthermore, evidence indicates mice show signs of neuropathy after high fat feeding. However, the pathogenesis of neuropathy induced by a high fat diet is still unknown.

PURPOSE

The purpose of this study was to determine if early neuronal inflammation is a contributing factor to changes in epidermal innervation and mechanical hypersensitivity associated with neuropathy in prediabetic mice fed a high fat diet.

METHODS

Male C57Bl/6 mice were randomized to a standard diet (Std, 15% kcal from fat) or high fat diet (HF, 54% kcal from fat) for 2, 4, or 8 weeks (n = 11–12 mice per group). Inflammatory mediators (IL‐1α, IL‐1β, IL‐2, IL‐3, IL‐4, IL‐5, IL‐6, IL‐10, IL‐12p70, IL‐17, MCP‐1, IFN‐γ, TNF‐α, MIP‐1α, GMCSF, RANTES) were quantified in the lumbar dorsal root ganglia (DRG) using Multiplex ELISA. Additionally, qRT‐PCR was performed to measure mRNA expression of genes associated with inflammation (IL‐1β, IL‐6, IL‐10, MCP‐1, TNF‐α, RANTES) in epididymal adipose. Mechanical sensitivity associated with neuropathy was determined using the von Frey test and measured every other week, beginning the week before the dietary intervention. In order to quantify intraepidermal nerve fiber (IENF) density and a specific population of peptidergic nociceptive nerve fibers (TrkA) in the hindpaw footpad skin, fluorescence immunohistochemistry was performed.

RESULTS

Compared to Std, HF had greater bodyweight, fasting blood glucose, and insulin after 8 wks. After 2 wks, IL‐1α was higher in HF compared to Std. After 4 wks, IL‐5, IENF, and TrkA nerve fiber density were higher in HF compared to Std. There were no significant differences in hindpaw sensitivity or adipose mRNA expression of IL‐1β, IL‐10, IL‐6, TNF‐α, RANTES, or MCP‐1 after 2, 4, or 8 wks.

CONCLUSION

In mice fed a high fat diet for 4 wks, increased IENF and TrkA nerve fiber density was accompanied by an increase in the inflammatory mediators IL‐1α and IL‐5 in the lumbar DRG despite lack of increased inflammatory gene expression in the adipose. This suggests a high fat diet causes an early increase in neuronal inflammation and increased nociceptive nerve fiber density that may be responsible for mechanical hypersensitivity, a sign associated with “painful” neuropathy in prediabetic mice

Support or Funding Information

Supported by Southern Illinois University Edwardsville Seed Grants for Transitional and Exploratory Projects

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.