bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of progesterone and estradiol on cardiovagal baroreflex sensitivity in young healthy women
Authors: Martini Emily R , Miner Jennifer A , Brunt Vienna E , Smith Michael M , Kaplan Paul F , Halliwill John R , Minson Christopher T 
Published: June 2021

ObjectiveOur goal was to measure cardiovagal baroreflex (CVBR) sensitivity in young healthy women during gonadotropin‐releasing hormone antagonist (GnRHa), progesterone only (GnRHa+P4), estrogen only (GnRha+E2), and combined progesterone plus estrogen (GnRHa+P4+E2) conditions.MethodsWe suppressed endogenous estrogens and P4 in 31 premenopausal women with GnRHa for 10 days. Subjects were randomized into 2 groups and studied as indicated in figure below. CVBR sensitivity was assessed by lowering and raising blood pressure with intravenous administration of sodium nitroprusside and phenylephrine. CVBR sensitivity was determined as the slope relating R‐R interval and systolic blood pressure.ResultsNo differences in slopes were seen on day 4 (trial 1) and day 10 (trial 3) in Groups 1 or 2. Slopes were significantly higher after P4 only (17.18 ± 1.28) compared to GnRHa only (14.07 ± 1.17), P4+E2 (14.12 ± 1.23), and E2 only (12.33 ± 1.21). Estradiol CVBR slopes were significantly lower than GnRHa only and P4+E2. Thus, P4 only > GnRha only = P4 + E2 > E2 only; all p<0.0001.ConclusionsExogenous sex hormones in young healthy women significantly altered the CVBR slope. P4 increases and E2 decreases this slope, and appear to antagonize each other.Supported by NIH Grant HL081671.
Alterations in carotid baroreflex control of arterial blood pressure during the menstrual cycle in young women
Authors: Kim Areum , Deo Shekhar H , Fisher James P , Fadel Paul J 
Published: June 2021

Limited studies have suggested that menstrual cycle variations in sex hormones may influence arterial baroreflex control of heart rate (HR) and sympathetic nerve activity; however, results are equivocal. In addition, the baroreflex control of blood pressure (BP) has not been directly examined as pharmacological perturbations were mainly used to assess baroreflex function. Therefore, 5s pulses of neck suction (NS, −60 Torr) and neck pressure (NP, +40 Torr) were applied to load and unload the carotid baroreflex (CBR), respectively in young women during the early follicular (EF, day 1–5, low estrogen, low progesterone), late follicular (LF, day 10–12, high estrogen, low progesterone), and mid luteal (ML, day 20–24, high estrogen, high progesterone) menstrual cycle phases. Resting HR and BP were not different between the 3 phases. Similarly, HR responses to NP and NS were not significantly different between phases. In contrast, mean BP responses to NP were significantly greater in the ML phase (Δ17±1 vs. Δ13±1 EF; Δ13±2 LF mmHg; P<0.05); however, responses to NS were not significantly different between phases (EF Δ−10±2, LF Δ−10±1, and ML Δ−10±1 mmHg). These preliminary findings suggest a maintained CBR control of HR throughout the menstrual cycle whereas concomitant elevations in estrogen and progesterone selectively augment CBR‐mediated BP responses to hypotension without effect on CBR responses to hypertension.Supported by R01HL093167.
Augmented skeletal muscle metaboreflex function in hypertensive adults
Authors: Delaney Erin Paul , Edwards David G. , Rose William C. , Fadel Paul J. , Farquhar William B. 
Published: June 2021

Recent animal studies have reported that exercise pressor reflex mediated increases in blood pressure are exaggerated in hypertensive (HTN) rodents. Whether these findings can be extended to human hypertension remains unclear.PURPOSEWe sought to investigate the metabolic component of the exercise pressor reflex (muscle metaboreflex) in HTN humans.METHODSMean arterial pressure (MAP), muscle sympathetic nerve activity (MSNA), and metabolites were measured at baseline, during static handgrip (HG) exercise at 30% and 40% maximal voluntary contraction, and during post‐exercise ischemia (PEI) to isolate the muscle metaboreflex in normotensive (NTN; n=23; 60±1 years) and HTN (n=15; 63±1 years) subjects. MAP and MSNA responses were also quantified during a non‐exercise sympatho‐excitatory stimulus (cold pressor test).RESULTSThe changes in MAP and MSNA from baseline to PEI were greater in HTN subjects after the 30% HG trial (MAP: NTN, Δ 13±1 vs. HTN, Δ 16±2 mmHg, p=0.05; MSNA: NTN, Δ 54±10 vs. HTN, Δ 101±11 AIU/min, p=0.009) and after the 40% HG trial (MAP: NTN, Δ 15±1 vs. HTN, Δ 22±2 mmHg, p=0.007; MSNA: NTN, Δ 57±10 vs. HTN, Δ 136±11 AIU/min, p≤0.001). There were no group differences in metabolite concentration. MAP and MSNA responses to the cold pressor test were not different between groups.CONCLUSIONThese data suggest that muscle metaboreflex function is augmented in HTN humans.Supported by HL07485
Effects of HIF‐1α gene deletion in respiratory centers on ventilatory acclimatization to hypoxia (VAH)
Authors: Go Ariel , Fu Zhenxing , Johnson Randall S. , Powell Frank L. 
Published: June 2021

HIF‐1α controls the expression of several genes that increase O2 supply. VAH is the time‐dependant increase in ventilation and O2‐ sensitivity with chronic hypoxia (CH). Previously, we found that normal VAH in mice depends on HIF‐1α expression in the CNS. To better localize and define the timing of this effect, we used the Cre‐LoxP strategy to delete HIF‐1α, in the nucleus tractus solitarius (NTS), which receives input from carotid body chemoreceptors and exhibits intrinsic CO2‐senstivity. We made stereotaxic microinjections of AAV‐Cre into the NTS of HIF‐1α floxed mice and exposed them to CH (10% O2, 2 wks). AAV‐LacZ microinjections were used for controls and localization. We measured ventilation with barometric pressure plethysmography:Ventilation increased in normoxia but not hypoxia or hypercapnia with HIF‐1α deletion in the NTS during CH, primarily through increased fR. This suggests HIF‐1α in the NTS suppresses normoxic ventilatory drive during CH but does not affect the ventilatory chemoreflexes. Further studies are needed to quantify HIF‐1α deletion and determine its effect in unacclimatized mice, at other sites in the brain and at different times relative to CH. Supported by RO1 NIH‐HL‐081823.
The role of β‐carotene and its cleavage enzyme β‐carotene‐ 15,15′‐oxygenase (CMO1) during mammalian embryonic development
Authors: Kim Youn‐Kyung , Wassef Lesley , Chung Stacey , Wyss Adrian , Blaner William S. 
Published: June 2021

The mammalian developing fetus relies on maternal circulating retinoids (vitamin A and its derivatives) to support its elevated vitamin A requirements. Β‐carotene is the major precursor of vitamin A in the human diet, and the central cleavage enzyme, β‐ carotene‐15,15′‐oxygenase (CMO1) has been suggested as the main enzyme involved in the production of vitamin A from β‐ carotene in vivo. To study the role of β‐carotene as vitamin A precursor during development we performed loss of CMO1 function studies in mice lacking retinol‐binding protein (RBP), an established model of embryonic vitamin A deficiency. Embryos from dams lacking both CMO1 and RBP (CMO1−/−RBP−/−) bred on a vitamin A‐deficient diet were malformed, but their defects were more severe than those of RBP−/ − mice. Since no differences were observed in serum retinoids levels between CMO1−/ −RBP−/ − and RBP−/ − dams, the embryonic malformations were likely due to the lack of CMO1 in the developing tissues. Upon maternal administration of β‐carotene, defects were almost fully rescued in CMO1+/−RBP−/ − embryos, while only partially improved in CMO1−/ −RBP−/ − embryos. These data suggest that CMO1 is a key enzyme in the conversion of β‐carotene to vitamin A in the developing tissues. However, they do not rule out a contribution of the β‐carotene asymmetric cleavage enzyme, β‐carotene‐9,10′‐ oxygenase (CMO2), to this process.Grant Funding Source: NIH 5R01HD57493
Identification of glucocorticoid response elements in the rat angiotensin II receptor (AT2R) promoter
Authors: Dasgupta Chiranjib , Xue Qin , Zhang Lubo 
Published: June 2021

ObjectiveIdentification of molecular mechanism responsible for glucocorticoid induced down‐regulation of angiotensin II receptor (AT2R) gene expression.MethodsTranscription of AT2R is repressed by glucocorticoids. To understand the molecular basis of glucocorticoid effect on AT2R, we amplified a 2130 base pair promoter region of rat AT2R, and cloned it in‐frame to pGL3‐Luciferase repoter (wild‐type AT2R‐pGL3‐Luc) into KpnI/XhoI sites. In silico analyses of this region of AT2R promoter identified several putative glucocorticoid response elements (GRE). Several constructs were created out of the wild‐type AT2R‐pGL3‐Luc, by deleting one putative GRE at a time.ResultsReporter gene assay in H9C2 rat cardiomyocytes using above mentioned constructs identified that deletion of eight, (but not all of the presumptive GREs) augmented Luciferase activity. Authenticity of these GREs was confirmed by Electrophoretic Mobility Shift Assay (EMSA), and by competition experiments with a rat consensus and AT1a‐R GRE oligos. Immunological identity of the protein causing gel‐retardation was shown to be glucocorticoid receptor (GR) in supershift analysis using anti‐GR antibody.ConclusionsOur study confirmed presence of eight GRE on AT2R promoter. Further studies are underway to identify physiological processes that use these GREs for regulation of AT2R expression.
Progesterone administration antagonizes the effect of estradiol on endothelium‐dependent vasodilation in young healthy women
Authors: Miner Jennifer Ann , Smith Michael M , Martini Emily R , Brunt Vienna E , Kaplan Paul F , Halliwill John R , Minson Christopher T 
Published: June 2021

PurposeTo examine the acute effects of progesterone and estrogen on endothelium‐dependent vasodilation in healthy reproductive‐aged women.MethodsWe suppressed endogenous estrogens and progesterone in 16 premenopausal women for 10 days using a gonadotropin‐releasing hormone antagonist (GnRHa). On day 4, subjects were tested and then supplemented either 0.1 mg estradiol (GnRHA+E2; N=8) transdermally or 200 mg progesterone (GnRHa+P4; N=8) orally per day. On day 7 subjects were tested and began supplementation with both hormones (GnRHa+P4+E2), and were tested again on day 10. Flow‐mediated vasodilation (FMD) of the brachial artery was assessed using B‐mode arterial ultrasound, combined with synchronized Doppler analysis.ResultsSignificant differences were observed when comparing FMD in GnRHa (7.85 ± 2.77%) and GnRHa+E2 conditions (10.14 ± 1.40%; p<0.05). The E2 increase was abolished when progesterone was also supplemented (6.27 ± 2.41%). In contrast, GnRHa+P4 (6.66 ± 2.56%) did not significantly alter FMD from GnRHa (7.80 ± 2.76%) and GnRHa+P4+E2 (7.40 ± 3.02%). However, a multi‐level prediction model demonstrates progesterone (p<0.02) and estradiol (p<0.01) predict FMD within subjects.ConclusionThese data suggest that acute progesterone administration antagonizes the effect of estrogen on endothelium‐dependent vasodilation.Supported by NIH Grant HL081671.
Laboratory evaluation of the accuracy of a triaxial accelerometer embedded into a cell phone platform for measuring physical activity
Authors: MANOHAR CHINMAY , CRADY SHELLY MC , Fujiki Yuichi , Pavlidis Ioannis , Levine James 
Published: June 2021

BackgroundPhysical activity is important in obesity, metabolic and cardiovascular diseases and cancer prevention. Several cell phone platforms integrate an accelerometer onto the motherboard. We wrote a software application to access the on board accelerometer from the iPhone (Apple Computer, Cupertino, CA) to measure and quantify physical activity. Here we tested the validity of the cell phone accelerometer to assess physical activity in a controlled laboratory setting.Methods31 subjects wore the cell phone along with the validated Physical Activity Monitoring System (PAMS) with different body postures and during graded walking at 7 velocities. Energy expenditure was measured using indirect calorimetry. Data were also collected from 7346 users who downloaded the “Walk n’ Play” application from the internet.ResultsIn all the 31 subjects, the cell phone accelerometer distinguished sedentary and walking activity reliably even with ½ mph increments in walking and was accurate and precise compared to the PAMS, with an intra‐class correlation coefficient (r2> 0.98). The cell phone accelerometer showed excellent sequential increases with increased in walking velocity and energy expenditure (r2>0.9). The data from the 7346 free‐living people demonstrated that most daily activity detected with the cell phone accelerometer occurs in the low intensity.ConclusionsAn accelerometer embedded into a cell phone was shown to be accurate and reliable in measuring and quantifying physical activity in the laboratory setting. Before a comprehensive integrated physical activity promoting and weight loss platform can be deployed, free‐living evaluation is necessary.
Dominant anabolic effects of low‐dose corticosteroid in C2C12 cells
Authors: Zhu Ercheng , Fang Liwei , Caiozzo Vincent J , Sassoon Catherine S.H. 
Published: June 2021

High‐dose corticosteroid induces diaphragm muscle dysfunction, whereas low‐dose corticosteroid preserves function. To elucidate the mechanisms of the protective effects of low‐dose corticosteroid, in C2C12 cell cultures we tested the hypothesis that low‐dose methylprednisolone (MP) increases protein synthesis via IGF/PI3K/Akt/mTOR, and decreases proteolysis via IGF/PI3K/Akt/Foxo pathways.MethodsMyotubes of normal control (NC) and dominant negative MAF‐box (shRNA MAF‐box‐targeted interference) were treated with 0, 10 (low‐dose), and 100 (high‐dose) μMol MP (MP0, MP10, and MP100, respectively) for 3 days in the presence of rhIGF‐1 (50 ng/ml), the former with or without of rapamycin (RP) (25 ng/ml). We measured total, cytoplasmic, and nuclear protein pools, MAF‐box protein expressions, and MAF‐box mRNA.ResultsBoth mTOR‐mediated protein synthesis increased and MAF‐box‐mediated proteolysis decreased following MP10 administration (Figure). MP10 treatment did not increase MAF‐box protein despite enhanced MAF‐box mRNA levels. MP100 overexpressed both MAF‐box protein and mRNA levels.ConclusionLow‐dose methylprednisolone promotes protein synthesis and reduces proteolysis via Akt/mTOR and Akt/Foxo pathways, respectively. The reduced proteolysis is likely related to MAF‐box RNA stabilization.Funded By: VA Medical Research, NIH AR‐46856
Reversible Modification of Thick‐ and Thin‐filament Proteins in Oxidant‐induced Changes to Skeletal Muscle Function
Authors: Gross Sean M , Lehman Steven L 
Published: June 2021

Exposure of skeletal muscle to reactive oxygen species (ROS) has been shown to modify the calcium sensitivity of force production.Calcium sensitivity changes were largely reversed by the reducing agent DTT, indicating modification of protein thiol groups. To determine which proteins are modified we used permeabilized rabbit psoas in which the intracellular and redox conditions can be tightly controlled. Oxidants hydrogen peroxide and dithiodypridine (DTDP) and reductants DTT and glutathione were used to modify thiols. We identified myofilament proteins with modified thiols using 3 gel electrophoresis techniques: 1d SDS page, 2d IEF/SDS page, and diagonal SDS page electrophoresis. To relate modifications of myofilament protein thiols to altered muscle mechanics, force‐pCa curves were measured. Exposure to oxidants caused increased actin and myosin oxidation. Treatment with glutathione produced gluathionylation of myofilament proteins including myosin. 2d diagonal gels showed that several myofilament proteins formed intermolecular disulfide bonds and that the regulatory myosin light chain could form an intramolecular disulfide bond. Force‐pCa curves confirmed that treatments that modified free thiol groups also modified calcium sensitivity. Results indicate that the reversible modification of both thick and thin filament proteins play a role in the oxidant‐induced changes to muscle function.
Diet‐induced obesity differentially affects baroreflex‐mediated sympathetic and parasympathetic outflow
Authors: McCully Belinda Houghton , Brooks Virginia L , Andresen Michael C 
Published: June 2021

Diet‐induced obesity (DIO) impairs the baroreflex control of heart rate (HR), which may arise from differential influences of the sympathetic (SNS) and parasympathetic (PNS) nervous systems. To test this hypothesis, Δ mean arterial pressure (MAP) and Δ HR to 30‐sec maximal stimulation of the aortic baroreceptors (aortic depressor nerve; 20V, 100Hz) were recorded before and after muscarinic receptor blockade (MB; methscopolamine, iv bolus 500ug/kg) in inactin‐anesthetized male SD rats. Rats were fed a normal (N, 13.5% kcal fat) or high fat diet (HFD, 33% kcal fat) for 4–5 weeks. Rats fed the HFD were separated into obesity prone (OP) or resistant (OR) groups, based on the top and bottom tertile of weight gain, respectively. Baseline values did not differ between groups.As shown in the table above, Δ HR and Δ MAP were blunted in OP rats compared to N and OR rats (†p<0.05 vs OP). Removal of PNS influence with MB attenuated Δ HR and Δ MAP in N and OR rats (*p<0.05 control vs MB), which were similar to the OP rat control responses. MB had no effect on the OP group. These findings suggest that DIO impairs aortic baroreceptor activation of the PNS, but may minimally impact the SNS. Funded by AHA (Brooks) and NIH (McCully NS045553, Brooks HL088552, Andresen HL41119).

Δ HR (bpm)
Δ MAP (mmHg)

Control
MB
Control
MB

N (n=6)
−53±7†
−28±4*
−57±6†
−47±4*

OR (n=6)
−45±6†
−31±3*
−60±5†
−48±4*

OP (n=6)
−30±6
−28±6
−41±8
−47±4
Role of exercise in the regulation of NF‐kappaB‐dependent gene expression in Alzheimer's Disease‐affected brain
Authors: Lloyd Jesse William , Beaman‐Hall Carol , Heckstall Ebony Monique , Vallano Mary‐Lou , Keslacy Stefan 
Published: June 2021

IntroductionA defining feature of Alzheimer's disease (AD) is plaque deposition induced by accumulation of Amyloid beta peptides (Aβ) that trigger chronic inflammation in the brain. Aβ‐related neurodegenerative changes are improved by chronic exercise. NF‐κB pathway is a “master controller” of the inflammatory process. Hypothesis: We hypothesize that exercise will diminish the AD‐associated NF‐κB activation in the brain. Aβ‐related model of AD APP/PS1 and wild‐type (WT) mice were exposed to voluntary running for 1 month (EX) and compared to sedentary (SED).ResultsEX demonstrated a decrease in plaque count. Using a qRT‐PCR array, we observed that exercise induced a downregulation of inflammatory genes, (IL‐1α, IL‐1β, Ltbr Tlr1/8/9/, Trfrs10b, Tnfrsf1a and Traf3) and an upregulation of anti‐inflammatory genes (Ccl2, IFNγ, Cd27, Card10 and IFNγ) associated with NF‐κB in hippocampus (Hip) of SED APP/PS1 mice. AD‐induced expression and phosphorylation of NF‐κB/P65 were diminished in Hip, cerebellum (Cb) and cortex (Cx) of EX. Phospho‐IKKα/β levels were reduced in Hip of EX compare to SED. P65, physically bound to IκB, was sequestrated into the cytoplasm following exercise.ConclusionThe molecular mechanisms underlying the beneficial effect of exercise in AD‐affected brain may rely on i) P65/IκB physical interaction and ii) regulation of the immune system through IFNγ signaling.
Renal Vascular Responses Are Attenuated in Smooth Muscle‐Specific Na+/Ca2+ Exchanger Knockout Mice during Acute Angiotensin II Infusions
Authors: Zhao Di , Blaustein Mordecai P , Navar L. Gabriel 
Published: June 2021

Studies in smooth muscle‐specific Na+/Ca2+ exchanger knockout (NCX1sm−/−) mice reveal reduced arterial pressure and impaired myogenic responses compared to heterozygous littermates. In this study, we determined renal function in male anesthetized NCX1sm−/− mice (n=6) and global NCX1 heterozygous (NCX1+/−, n=8) littermates before and during acute Ang II infusions (5 ng/g Body Weight/min). Systolic blood pressure in awake mice was lower in NCX1sm−/− mice compared to NCX1+/− mice (119±4 versus 131±3 mm Hg, P<0.05). Acute Ang II infusions increased mean arterial pressure in NCX1sm−/− (98±8 to 123±8 mm Hg, P<0.001) and NCX1+/− mice (109±2 to 134±3 mm Hg, P<0.001). Acute Ang II infusions did not change renal plasma flow (RPF; Δ0.06±0.09 ml/min, P>0.05) or glomerular filtration rate (GFR; Δ0.003±0.04 ml/min, P>0.05) in NCX1sm−/−mice, whereas acute Ang II infusions significantly decreased RPF (Δ−0.2±0.09 ml/min, P<0.05) and GFR (Δ−0.08±0.03 ml/min, P<0.05) in NCX1+/− mice. The urine flow responses to acute Ang II infusions were significantly greater in NCX1sm−/−mice as compared with NCX1+/− mice (Δ1.88±0.83 versus Δ‐0.33±0.42 μl/min, P<0.05). Urine flow and urinary sodium excretion were higher in NCX1sm−/− mice as compared with NCX1+/− mice during acute Ang II infusions. These data suggest that renal vascular responses to Ang II are attenuated in NCX1sm−/− mice as compared with NCX1+/− mice and that NCX1 contributes to the renal vasoconstriction response to acute Ang II infusions.Supported by NIH/NHLBI.Disclosure: no conflict of interest
Renal Function of Rats with Isoproternol‐induced Cardiac Hypertrophy
Authors: Thieme Karina , Oliveira‐Souza Maria 
Published: June 2021

AimAvaliate the effect of Isoproterenol‐induced cardiac hypertrophy on renal function and proteic expression in rats.MethodsMale Wistar rats were submitted to subcutaneous injection of isoproterenol (ISO) (0.3 mg.kg(‐1).day(‐1) sc) or vehicle for 7 days. Renal plasmatic flow (RPF) and glomerular filtration rate (GFR) were determined by para aminohypurate and inulin clearance. The excretion of ions was also analyzed. Cardiac hypertrophy and organs congestion were evaluated by respective organs weights. The proteic expression of many renal transporters and Angiotensin II receptors will be analysed by Western Blot technique.Results and DiscussionChronic β‐adrenergic stimulation does not affect hemodynamic parameters, despite cardiac hypertrophy. Our results showed that ISO‐treatment does not affect RPF (control: 4,19 ± 0,45; n = 12 versus ISO: 4,17 ± 0,36; n = 11), which is consistent with a normal cardiac output found in this model. However, there was a significant decrease of GFR (control: 2,24 ± 0,22; n = 12 versus ISO: 1,49 ± 0,13; n = 11 * p< 0.01), which could be related to inflammatory process, leading to alteration in ultratiltration coefficient (Kf). Urinary Na+ and K+ were significantly reduced and enhanced, respectively. These changes in excretion of ions could be related to alterations in expression of renal transporters and are under investigation.Research Support: Fapesp
Increases in Cardiac Output Recruit Intrapulmonary Shunt Pathways in the Rat
Authors: Bates Melissa , Pegelow David , Fulmer Brendan , Drezdon Alyssa , Farrell Emily , Eldridge Marlowe 
Published: June 2021

Using an intact, spontaneously breathing, instrumented rat model, we investigated the effects of progressive embolization and pulmonary blood flow on intrapulmonary shunt pathway (IPAVs) recruitment. We hypothesized that progressive embolization and increased regional flow would recruit IPAVs in a dose‐dependent manner. We injected six boluses of 5×105 15μm spheres (3×106 total) in 0.4 or 0.8 mL aliquots via the inferior vena cava and harvested the kidney to assess transpulmonary passage of spheres. Spheres bypassed the lungs in 1/3 rats and 3/3 rats injected with 0.4 and 0.8 mL, respectively. The shunt fraction increased in a dose‐dependent manner with progressive embolization. Interestingly, right ventricular systolic pressure (RVSP) rose in the rats receiving 0.4mL injections (28±4 to 36±15 mmHg), but not in animals receiving 0.8 mL (24±3 mmHg vs 24±1mmHg). The transiently higher cardiac output associated with the larger volume injections may recruit and distend the pulmonary vasculature, including IPAVs, resulting in lower RVSP and greater sphere passage. These data suggest that increased pulmonary blood flow is important for IPAV recruitment. Further studies are needed to better define the mechanical and mediator‐based mechanisms regulating IPAVs and their importance in determining pulmonary vasculature pressure.This research was supported by a grant from the NIH (5R01HL086897‐02).