bluuebunny/crossref_metadata_2025 huggingface dataset:
Thin Limbs of Henle and Inner Medullary Collecting Ducts are the Major Points of Flow Resistance Along the Renal Tubule
Authors: Gilmer Gabrielle , Deshpande Venkatesh , Schnermann Jurgen , Knepper Mark
Published: June 2021

The driving force for flow along the nephron and collecting ducts is generally thought to derive from the pressure in the glomerular capsule (Bowman's space). In superficial nephrons of rats, the glomerular capsular pressure has been reported to be 12–13 mmHg under euvolemic conditions. To test the adequacy of this driving force, we calculated the theoretical pressure drop along each segment of the rat superficial renal tubule using the Hagen‐Poiseuille laminar flow equation with measured flow rates, tubule diameters, and tubule lengths. We used both a rigid tube model and an elastic tube model based on compliances from the literature. The rigid tube model predicted a net pressure drop from glomerular capsule to renal pelvis of 8.8 mmHg during antidiuresis and 15.5 mmHg during water diuresis. The latter value exceeds the measured value in the glomerular capsule. In contrast, the elastic tube model predicted a 9.5 mmHg pressure drop along the length of the renal tubule during water diuresis. In both models, the greatest flow resistance (pressure drop per unit length) was in the thin descending limb of Henle's loop and the final millimeter of the inner medullary collecting duct. We extended the elastic tube model during water diuresis to long‐looped nephrons (those with loops of Henle extending into the inner medulla). The predicted net tubular pressure drop for these nephrons was 18.3–20.3 mmHg depending on the location of the loop bend. The calculated overall flow resistance was higher in deep nephrons chiefly due to the thin descending and thin ascending limbs of Henle's loop. We do not have reliable glomerular capsular pressure values for deep nephrons. However, the glomerular capsular pressures in deep nephrons are unlikely to be substantially higher than in superficial nephrons because the single‐nephron glomerular filtration rate in deep nephrons is equal to or greater than in superficial nephrons. Thus, the calculated glomerular capsular pressure is 6–8 mmHg higher than the likely actual value with the elastic tube model. This leaves an apparent discrepancy that could be explained either by 1) an underestimate of the compliance of the thin limb segments of the long‐looped nephrons; or 2) an additional driving force for flow such as the peristaltic action of the renal pelvic contractions, which could boost the flow across the restriction points in the thin descending limbs and inner medullary collecting duct.

Support or Funding Information

G.G. was a member of the 2017 NIH Summer Internship Program. V.D. was a member of the 2017 Biomedical Engineering Student Internship Program at the NIH.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Does obesity differentially impact male and female responses to skeletal muscle vasodilation during exercise?
Authors: Carter Katrina J. , Kellawan J Mikhail , Ward Aaron T. , Johansson Rebecca E. , Harrell John W. , Peltonen Garrett L. , Sauder Christina J. , Eldridge Marlowe W. , Schrage William G.
Published: June 2021

Background

Obesity increases risk of cardiovascular disease (CVD), and epidemiologic evidence suggests substantial sex differences in prevalence and burden of CVD. During dynamic exercise in healthy adults, we previously reported a more robust exercise vasodilator response in women compared to men. Therefore, we tested the hypothesis that obesity attenuates sex differences in exercise vasodilation. Obesity can reduce nitric oxide (NO) vascular signaling, thus we tested a second hypothesis that obese subjects exhibit lower NO‐mediated contribution to exercise vasodilation.

Methods

45 healthy lean young (18–40 year) adults (23 females; 22 males; BMI, 22 ± 2) and 26 obese young adults (16 females; 10 males; BMI, 37 ± 6) performed dynamic forearm exercise at 15% of maximal voluntary contraction for 10 minutes (20 contractions/min). Forearm vascular conductance (FVC) was calculated from forearm blood flow (FBF; Doppler ultrasound) and arterial pressure (brachial catheter), as FVC = FBF÷MAP. Lean forearm mass was determined (DEXA), and relative FVC (FVCrel; FBF • 100 mmHg−1 • 100 g−1 lean mass) was calculated. Baseline FVCrel was determined prior to exercise. Steady‐state exercise was reached within 2 minutes, and data were quantified from minute 4.5–5. Intra‐arterial infusion of L‐NMMA occurred from minutes 5–10 of exercise, and steady‐state data were quantified from minute 9.5–10. The change in FVCrel (ΔFVCrel) from baseline to steady‐state quantified the vasodilatory response to exercise, whereas the ΔFVCrel from steady‐state exercise to exercise+L‐NMMA quantified the contribution of NOS to exercise.

Results

Results are mean ± SD. Overall, women exhibited greater vasodilation (main effect for sex; ΔFVCrel, 18 ± 8 vs. 13 ± 6; p = 0.001). Furthermore, lean subjects exhibited greater vasodilation than obese subjects (main effect for group; ΔFVCrel, 17 ± 6 vs. 14 ± 9; p = 0.002). Contrary to the hypothesis, there was no sex‐by‐group interaction (p = 0.67). L‐NMMA infusion decreased steady‐state exercise FVCrel; but this response was not different by sex, obesity, or sex‐obesity interaction (p = 0.66).

Conclusions

These data indicate during dynamic exercise in young adults, exercise vasodilation: 1) is greater in females than males, 2) is reduced in obese compared to lean similarly between sexes, and 3) is mediated by a similar contribution of NO. Therefore, the differences observed in sex and group with steady‐state exercise are likely mediated by NO‐independent signaling.

Support or Funding Information

HL105820, HL007936

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
NO/NOS‐Dependent Modulation of Inflammation in Acrolein‐Induced Vascular Toxicity
Authors: Brown Theresa , Joseph Mathew , Ranganna Kasturi , Xiao Daniel , Newaz Mohammad A. , Yousefipour Zivar
Published: June 2021

Modulation of inflammatory signaling has been elucidated in different disease models including vascular biology. No/NOS system plays an important role in the process of inflammation. Balance between nitric oxide (NO) and superoxide is critical in inflammatory process. Peroxisome proliferator‐activated receptor gamma (PPARγ) has been implicated in pathology of diseases involving inflammation and in our previous studies we reported reduction in PPARγ protein expression and activity in animals exposed to acrolein. Since PPARγ influences both NO and superoxide generation, in this study we are proposing involvement of impairment of this regulation in acrolein‐mediated inflammatory response. Male iNOS knockout (inducible nitric oxide synthase, KO) mice were treated with acrolein (0.5 μg/kg; i.p.; 7 days) with/without rosiglitazone (Roz: PPARγ ligand, 10 mg/kg; orally; 10 days). Age/weight matched wild type (WT) were used as control. Urine and kidney tissue was processed for western blot and biochemical analysis. KO mice had higher (87%) 8‐Isoprostane in response to acrolein but lower NO (23%) compared to WT. Roz reduced 8‐isoprostane in KO mice by 47% and increased NO production by 35%. Total Antioxidant Status (TAS) was reduced in WT (31%) and KO (53%) mice treated with acrolein. Roz improved TAS in both KO (33%) and WT (21%) mice. Acrolein did not affect expression of eNOS (endothelial nitric oxide synthase) in WT and KO mice. Roz increased eNOS expression in WT (23%) and KO (33%) and iNOS expression in WT (28%). Expression of PPARγ was increased in WT (30%) and KO (28%) mice treated with acrolein and was further increased with addition of Roz (89% & 102% respectively). Based on these data, we are concluding that acrolein‐mediated reduction in PPARγ affects eNOS/iNOS/NO pathway and activation of PPARγ minimizes acrolein effect by improving PPARγ‐dependent NO/NOS interaction.

Support or Funding Information

NIH, SC3GM103746

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Racial Differences in Forearm Vascular Conductance Response during Dynamic Handgrip Exercise
Authors: Barbosa Thales C. , Kaur Jasdeep , Stephens Brandi Y. , Akins John D. , Brothers R. Matthew , Fadel Paul J.
Published: June 2021

Healthy young African‐Americans (AA) present impaired vasodilator function compared to Caucasian‐Americans (CA), as indicated by reduced flow‐mediated dilation, and lower vasodilation during mental stress. Whether such impairments affect vascular responses to dynamic exercise is unclear. Previous studies used relatively low‐intensity dynamic handgrip exercise, which resulted in a tendency towards lower forearm vascular conductance (FVC) and brachial artery blood flow (BABF) responses in AA as exercise intensity increased from 10% to 20% maximal voluntary contraction (MVC). Therefore, we hypothesized that with higher intensities, AA would present an attenuated increase in FVC to dynamic exercise. To investigate this, healthy young CA men [N = 6; 23 ± 2 years (mean ± SEM)] and AA men (N = 6; 20 ± 2 years) performed 6 trials of dynamic handgrip exercise at absolute workloads of 4, 8, 12, 16, 20, and 24 kg, while BABF (duplex Doppler ultrasound) and mean arterial pressure (MAP; finger photopletysmography) were continuously measured. FVC was calculated as: BABF/MAP. Each exercise trial lasted for 3 min with a duty cycle of 1‐s contraction/2‐s relaxation, with a minimum of 5‐min rest period between trials. Cadence was provided via metronome, with real‐time visual feedback of handgrip force. The groups had similar MVCs (CA: 56 ± 3 vs. AA: 53 ± 1 kg; P = 0.480), and the workloads used in the exercise trials represented an average of 7.4 ± 0.2%, 14.9 ± 0.4%, 22.3 ± 0.6%, 29.7 ± 0.8%, 37.1 ± 1.0%, and 44.6 ± 1.2% MVC. Both groups presented an intensity‐dependent increase in FVC. However, this FVC response was attenuated in the AA group (ANOVA interaction P = 0.046), with lower changes from BL at 8 kg (CA: +113 ± 10 vs. AA: +66 ± 10 mL min−1 100 mmHg−1; P = 0.025), 12 kg (CA: +152 ± 11 vs. AA: +89 ± 11 mL min−1 100 mmHg−1; P = 0.004), 16 kg (CA: +182 ± 14 vs. AA: +133 ± 14 mL min−1 100 mmHg−1; P = 0.020), and 24 kg (CA: +239 ± 21 vs. AA: +185 ± 21 mL min−1 100 mmHg−1; P = 0.011). Similarly, there was an intensity‐dependent increase in BABF in both groups, with a tendency of a lower response in the AA group (ANOVA group main‐effect P = 0.073). These preliminary findings suggest that, compared to CA, AA have an impaired vasodilator response to dynamic handgrip exercise.

Support or Funding Information

Supported by UTA College of Nursing and Health Innovation

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Vascular Function after Sauna Bathing in Healthy Older Adults
Authors: Gravel Hugo , Barry Hadiatou , Behzadi Parya Yousefi , Gagnon Daniel
Published: June 2021

Repeated heat exposure by immersion in warm water improves vascular function in healthy young adults. This observation could explain the health benefits of sauna bathing reported in population‐based studies, in which regular sauna sessions lasting more than 19 minutes were shown to significantly decrease the risk of cardiovascular mortality. However, it is unknown if such sauna durations improve vascular function in older adults. The purpose of this study was to determine if 20 min of sauna bathing acutely improves vascular function in healthy older adults.

Six older adults (4 women) without cardiovascular disease and risk factors (age range: 57–71 yrs) underwent a sauna bathing session consisting of 2 bouts of 10 min in a dry Finnish sauna (80°C) separated by 10 min of seated rest outside the sauna. Prior to and following sauna bathing, flow‐mediated dilation (FMD) of the brachial artery in response to reactive hyperemia induced by 5 min of forearm ischemia was assessed by Doppler ultrasound after a minimum of 30 min rest in the supine position in a quiet and thermoneutral environment. The percent change in artery diameter from baseline to peak was used as an index of macrovascular function, whereas post‐occlusive reactive hyperemia (PORH), estimated by the brachial artery flow area‐under‐the‐curve above baseline during the 3 min following ischemia, was used to evaluate microvascular function. Heart rate (HR), mean arterial pressure (MAP), oral temperature (Toral) and mean skin temperature (Tsk) were monitored throughout the study.

Sauna caused an increase in HR (55 ± 8 to 86 ± 10 bpm, P<0.01), mean Tsk (33.0 ± 0.5 to 40.7 ± 0.7°C, P<0.01) and Toral (36.7 ± 0.3 to 37.4 ± 0.2°C, P=0.025) while changes in MAP were not statistically different (100 ± 8 to 90 ± 4 mmHg, p=0.137). At the time of FMD assessment, HR (53 ± 5 and 52 ± 5 bpm, P=0.56), MAP (92 ± 6 and 90 ± 5 mmHg, P=0.59) and Toral (36.8 ± 0.3 and 36.9 ± 0.1 °C, P=0.27) were similar before and after sauna bathing, whereas mean Tsk was elevated prior to the post‐sauna FMD assessment (34.3 ± 0.4 vs. 32.9 ± 0.5°C, P<0.01). FMD was similar before and after sauna bathing (4.79 ± 2.21% vs. 4.86 ± 2.73%, P=0.93). PORH was also similar before and after sauna bathing (286 ± 198 vs. 380 ± 168 ml, P=0.18).

These preliminary results indicate that macro‐ and microvascular functions are unaffected by two 10 min bouts of sauna bathing at 80°C in healthy older adults.

Support or Funding Information

Funded by Fondation de l'Institut de cardiologie de Montréal and by Fonds de Recherche du Québec – Santé.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Short‐Term Ingestion of Virgin Coconut Oil Improves Endothelial‐Dependent Dilation but not Exercise‐Mediated Hyperemia in Healthy Young Adults
Authors: Robinson Susan , O'Brien Myles William , Kimmerly Derek
Published: June 2021

Virgin coconut oil (VCO) is high in antioxidants (e.g., polyphenols) that may reduce reactive oxygen species‐induced conversion of vascular endothelial‐derived nitric oxide (NO) to toxic peroxynitrite. As such, flow‐mediated dilation (FMD, a surrogate marker of NO bioavailability) and exercise‐mediated hyperemia may be enhanced following short‐term VCO supplementation. However, these potential beneficial effects have never been assessed in humans. We tested the hypotheses that a 4 week VCO supplement (30 ml·day−1) would improve resting popliteal artery (PA) FMD and the hyperemic response to aerobic exercise. Thirty‐four young, healthy participants were divided into VCO (n=19, 10♂, 22±2 years, 24±3 kg·m−2), and Control (n=15, 10♂, 24±2 years, 24±3 kg·m−2) groups. PA‐FMD and PA blood flow were assessed via high‐resolution duplex ultrasonography (Vivid i, GE Healthcare) and analyzed using commercial software (Cardiovascular Suite, Quipu). After resting measurements, a 10‐minute bout of moderate‐intensity (60% heart rate reserve) cycling exercise was completed. PA blood flow was measured for 5‐minutes post‐exercise and total PA blood volume was calculated from the area under the curve. After 4 weeks, PA‐FMD increased (p < 0.05) following VCO supplementation (4.9±0.9% to 5.5±1.2%) with no change (p > 0.9) in the Control group (5.7±2.1% to 5.8±1.9%). There were no differences (both, p > 0.28) in post‐exercise total PA blood volumes in either group (VCO: 495±355 ml to 598±384 ml; Control: 562±362 ml to 488±229 ml). The increased FMD response observed in our young healthy adults suggests that short‐term VCO supplementation has potential as a dietary treatment for populations with elevated ROS levels and reduced vascular endothelial (e.g., older adults, smokers, etc.). However, additional research is required to test this hypothesis.

Support or Funding Information

Support provided by: Canadian Foundation for Innovation: Leaders Opportunity Fund, and a Faculty of Health Professions Research Development grant. SAR and MWO were recipients of a NS Graduate Scholarship. MWO was awarded a NSHRF Scotia Scholar Award and a Heart & Stroke BrightRed 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.
Type 2 Diabetic Rats Develop Exercise Pressor Reflex Dysfunction Over Time: New Insight Into Aging With Diabetes
Authors: Grotle Ann‐Katrin , Huo Yu , Harrison Michelle L. , Graham James , Stanhope Kimber L. , Havel Peter J. , Fadel Paul J. , Stone Audrey J.
Published: June 2021

Type 2 diabetes Mellitus (T2DM) patients have an augmented sympathetic activity and cardiovascular response to exercise. The exercise pressor reflex, which is evoked by mechanical and metabolic stimuli arising from contracting muscle, and results in an increase in mean arterial pressure and heart rate, may contribute to this augmented response. Studies have shown that the exercise pressor reflex is augmented in several cardiovascular related diseases including T2DM; however, it is not known how the exercise pressor reflex is expressed in aging T2DM rats. Therefore, the purpose of this study was to determine the expression of the exercise pressor reflex with aging in T2DM rats. We measured the exercise pressor reflex in unanaesthetized, decerebrated UC Davis T2DM rats and healthy (CTL) Sprague Dawley rats by statically contracting the hindlimb for 30 s while mean arterial pressure (MAP) and heart rate (HR) were continuously measured. Young (4 mo old) adult T2DM rats (BW: 594±15 g, glucose: 337±73 mg/dl, HbA1c: 7.4±0.3%) and older (12 mo old) adult T2DM rats (BW: 546±26 g, glucose: 549±28 mg/dl, HbA1c: 12.82±0.18%), were compared to adult CTL rats (BW:465±18 g, glucose: 200±14 mg/dl, HbA1c: 4.73±0.1%). We found that the pressor (younger T2DM: ΔMAP=21±5 mmHg, n=4; older T2DM: ΔMAP=39±5 mmHg, n=5; CTL: ΔMAP=17±2 mmHg, n=8; p<0.05) but not cardioaccelerator (younger T2DM: ΔHR=16±4 bpm, n=4; older T2DM: ΔHR=19±7 bpm, n=5; CTL: ΔHR=14±1 bpm, n=8; p>0.05) responses to static contraction were significantly greater in the older adult T2DM, but not in the younger T2DM rats compared to the CTL rats. Developed tension was similar for all group comparisons, p>0.05. We conclude that older T2DM rats develop an augmented exercise pressor reflex to static contraction of the hindlimb, but this hyper‐reactivity is not present in younger T2DM rats. In a population where exercise is typically prescribed as a treatment modality, an augmented exercise pressor reflex can put these individuals at a higher risk for experiencing cardiovascular events while exercising.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Blocking Interleukin‐6 Signal Pathway Attenuates Exaggerated Exercise Pressor Reflex in Rats with Femoral Artery Occlusion
Authors: Lu Jian , Xing Jihong , Li Jianhua
Published: June 2021

A rat model of femoral artery occlusion was employed to study the exercise pressor reflex in peripheral artery disease. Prior studies have shown that pro‐inflammatory interleukin‐6 (IL‐6) is engaged in the amplified blood pressure response to static muscle contraction in occluded rats. IL‐6 complexes with soluble IL‐6 receptor (IL‐6R) to activate cells expressing the signal transducer glycoprotein (gp130). Thus, the current study was to determine the role played by IL‐6 activated signal complex (IL‐6‐gp130) in regulating the exercise pressor reflex in rats with femoral occlusion. Following 72 hours of femoral artery occlusion, the levels of protein expression of IL‐6R and gp130 were increased in dorsal root ganglion (DRG). In addition, we examined the pressor response to static muscle contraction after 62.5 ng/kg and 125 ng/kg of SC144 (a gp130 inhibitor) were injected into the arterial blood supply of the hindlimb muscle of control rats and occluded rats. We found that SC144 significantly attenuated the pressor response to contraction in occluded rats, but the effect of SC144 was not observed in control rats. In control rats, peak response of mean arterial pressure (MAP) was 15±2 mmHg after saline and 12±3 mmHg after 125 ng/kg of SC144 (n=6; P > 0.05 vs. saline). In occluded rats, peak MAP response was 25±5 mmHg after saline and 14±5 mmHg after 125 ng/kg of SC144 (n=6; P < 0.05 vs. saline). There was no difference in developed muscle tension between saline group and group injected with SC144 (528±28 g in saline control vs. 545±29 g with SC144 injection, P > 0.05). Overall, our data suggest that IL‐6 signal mechanisms in muscle sensory nerves contribute to the exaggerated sympathetic and pressor responsiveness observed during exercise in experimental rats with peripheral artery disease.

Support or Funding Information

This study was supported by NIH P01 HL134609

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Three days of chronic intermittent hypoxia is sufficient to induce β1‐adrenoceptor dependent increases in left ventricular contractility
Authors: Lucking Eric F. , Dhaliwal Pardeep , O'Halloran Ken D.
Published: June 2021

Chronic intermittent Hypoxia (CIH) is the primary pathological feature of obstructive sleep apnea, manifesting sympathetic nervous system hyperactivity and hypertension. Modest durations of CIH exposure have been shown to increase cardiac output that may contribute to the hypertensive state. Prolonged CIH exposures induce heart failure. We sought to determine if increases in cardiac work develop before the CIH‐induced hypertensive phenotype is established.

Male Wistar rats were exposed to repetitive cycles of hypoxia (FiO2=0.05 nadir; 90 seconds) and normoxia (FiO2=0.21; 210 seconds) for eight hours per day for three days (CIH; n=6). Sham animals (n=7) were constantly exposed to room air and the same environmental cues. Assessment of cardiovascular parameters was performed under urethane anesthesia (1.5 g/kg i.p.). Data are presented as mean±SD (sham vs CIH) and were analysed using unpaired Student's t‐tests. P<0.05 was taken as significant.

Systolic blood pressure (p=0.439), mean arterial pressure (p=0.267) and heart rate (p=0.149) were all unaffected by three days of CIH exposure. In addition, plasma adrenaline (p=0.294) and noradrenaline (p=0.155) concentrations were not elevated in CIH exposed animals compared with sham controls. However, at baseline, left ventricular contractility (dP/dtMAX) was significantly increased in CIH exposed animals compared with sham animals (12320 ± 2725 vs 15300 ± 2002 mmHg/s; p=0.025). Interestingly, β1‐adrenoceptor inhibition with atenolol (5 mg/kg; i.v.) provided greater inhibition of left ventricular contractility in CIH animals compared with sham animals (−4747 ± 2080 vs −7604 ± 1298 mmHg/s; p=0.014), reducing dP/dtMAX to equivalent levels. Systolic blood pressure (p=0.735) and heart rate (p=0.25) responses to atenolol were similar in sham and CIH animals. Sympathetic ganglion blockade with hexamethonium (25 mg/kg; i.v.) produced equivalent responses in CIH and sham animals for measured cardiovascular parameters (p>0.05).

This study suggests that global sympathetic hyperactivity has not yet developed in this three‐day model of CIH, as evidenced by catecholamine concentrations, blood pressure and heart rate, which are equivalent with sham animals. Nevertheless, three days of CIH exposure is sufficient to increase cardiac work. We hypothesize that through this mechanism the heart drives development of the hypertensive phenotype in the early stages of CIH, as opposed to sympathetically‐mediated peripheral vasoconstriction.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Diet Associated with Exercise Training Improves Heart Rate Recovery and Autonomic Control in Metabolic Syndrome Subjects
Authors: Cepeda Felipe Xerez , Rodrigues Sara , Dutra‐Marques Akothirene C.B. , Toschi‐Dias Edgar , Carvalho Jefferson C. , Carvalho Glauce L. , Rondon Maria Urbana P.B. , Alves Maria Janieire N.N. , Trombetta Ivani C.
Published: June 2021

Purpose

Previous study showed that metabolic syndrome (SMet) subjects have impaired attenuation of heart rate recovery (ΔHRR) after maximal exercise. Autonomic dysfunction is the possible mechanism involved in this alteration. We tested the hypothesis that hypocaloric diet and exercise training (D+ET) improves DHRR, heart rate reserve and autonomic control in MetS subjects.

Methods

Never treated patients with MetS (ATP‐III) were assigned into intervention group (MetS/D+ET, n=33) submitted to D (−500 kcal/day) and ET (40 min, 3 times/week of cycle exercise) and control group (MetS/C, n=23) for 4 months. We evaluated pre and post‐intervention or control period, cardiac autonomic control (LF = low frequency, HF = high frequency, LF/HF = sympathovagal balance) by heart rate variability (ECG), muscle sympathetic nervous activity (MSNA ‐ microneurography) and we calculated the ΔHRR (maximal HR minus HR in the 1st, 2nd and 4th min of recovery) and the heart rate reserve (maximal HR minus resting HR) after cardiopulmonary exercise test.

Results

SMet/D+ET improved metabolic profile, functional capacity and reduce body weight. Compared with pre‐intervention, MetS/D+ET increased HF n.u. (33±3 vs. 39±3 bpm, P=0.01) and decreased MSNA (30±1 vs. 25±2 bpm, P<0.001), LF n.u. (67±3 vs. 61±3 bpm, P=0.02) and LF/HF (3.0±0.3 vs. 2.2±0.4 bpm, P=0.02). Furthermore, MetS/D+ET increased ΔHRR at 1st min (16±1 vs. 21±2 bpm, P=0.02), ΔHRR at 2nd min (28±1 vs. 36±2 bpm, P<0.001), ΔHRR at 4th min (46±2 vs. 56±2 bpm, P<0.001) and heart rate reserve (76±3 vs. 86±3 bpm, P <0.001). No significant change was observed in SMet/C.

Conclusion

The intervention by hypocaloric diet and exercise training improves the autonomic control, heart rate reserve and heart rate recovery after maximal exercise in subjects with MetS.

Support or Funding Information

Grant #2011/17533‐6, #2015/17533‐6 and #2016/16831‐7, São Paulo Research Foundation (FAPESP) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Functional Interaction Between NMDA Receptors and SK Channels in Hypothalamic Magnocellular Neurons: Role in Heart Failure
Authors: Ferreira‐Neto Hildebrando Candido , Stern Javier Eduardo
Published: June 2021

Neurohumoral activation, which includes elevated plasma levels of vasopressin, is a hallmark of heart failure (HF). However, the precise mechanisms that regulate hypothalamic magnocellular neurosecretory cells (MNCs) neuronal excitability during HF remains incompletely understood. Here, we evaluated whether an increase in intracellular Ca2+ induced by NMDA receptor activation would evoke a compensatory feedback inhibitory mechanism via activation of Ca2+‐dependent K+ channels, and whether this mechanism would contribute to the regulation of MNCs excitability in HF rats. Whole‐cell patch clamp recordings obtained from MNCs (holding potential: −50 mV) in slices from Sham and HF rats showed that focal application of NMDA (50 mM, 300 ms) evoked an inward NMDAR‐mediated current (INMDAR) whose magnitude was similar in Sham and HF rats (amplitude: Sham 0.16±0.02 vs HF 0.20±0.02 nA, p>0.05; area: Sham 94±24 vs HF 77±15 nA.ms, p>0.05). INMDAR was immediately followed by an outward current, whose magnitude was larger in MNCs from HF than Sham rats (amplitude: Sham 0.9±0.1 vs HF 1.6±0.3 nA, p<0.05; area: Sham 215±19 vs HF 410±76 nA.ms, p<0.01). Blockade of K+ currents with Cs+ revealed that the INMDAR was in fact significantly larger in MNCs from HF than Sham rats (amplitude: Sham 0.18±0.04 vs HF 0.86±0.02 nA, p<0.05; area: Sham 111±24 vs HF 263±54 nA.ms, p<0.05). Intracellular dialysis of MNCs with the Ca2+ chelator BAPTA significantly reduced the outward current triggered by NMDAR activation in both groups to the same extent (amplitude: Sham 0.17±0.05 vs HF 0.22±0.07 nA, p>0.05; area: Sham 18±9 vs HF 42±19 nA.ms, p>0.05). Bath application of the SK channel blocker apamin significantly decreased the outward current triggered by INMDAR in MNCs from HF rats (p<0.05), but this effect was minimal in Sham rats (p>0.05). Finally, current clamp recording showed that focal application of NMDA after SK channel blockade increased the number of evoked spikes both in Sham and HF rats compared to control conditions (Sham 168±25%, p<0.001 vs control; HF 311±71%, p<0.01 vs control), but this effect was exacerbated in HF rats (p=0.06 vs Sham). Taken together, our data supports the presence of a functional coupling between excitatory NMDAR and inhibitory SK channels in MNCs. This interaction is enhanced in HF rats contributing to dampening the NMDAR‐mediated hyperexcitability observed in MNCs during this condition.

Support or Funding Information

R01HL090948

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Blockade of central angiotensin II AT1 receptors attenuates acute intermittent hypoxia‐induced sympathetic long‐term facilitation (S‐LTF)
Authors: Shimoura Caroline Gusson , Andrade Mary Ann , Toney Glenn M.
Published: June 2021

After exposure to acute intermittent hypoxia (AIH) and while undergoing continuous normoxic ventilation, a progressive increase of sympathetic nerve discharge (SND) is observed in the anesthetized rat. This phenomenon, referred to as post‐AIH sympathetic long‐term facilitation (S‐LTF), involves neuroplasticity resulting, at least in part, from repetitive arterial chemoreceptor activation, but the underlying mechanisms remain to be determined. Evidence indicates that post‐AIH S‐LTF is largely unaffected by intravenous injection of the angiotensin II (AngII) AT1 receptor antagonist losartan. Because AIH repetitively increases renal SNA in associated with large amplitude reductions of arterial pressure and thus renal perfusion pressure, both of which potently stimulate the renin‐AngII system, we hypothesized that central AngII actions contribute to post‐AIH S‐LTF. Anesthetized male rats received an injection (2 μl) of losartan (40 pmol) or vehicle (aCSF) into a lateral cerebral ventricle 20 minutes before exposure to a 1 hour AIH protocol, which consisted of 10 cycles of changing FiO2 from 100% to 15% every 3 minutes. Losartan significantly attenuated (p<0.001) the increase of splanchnic SND caused by AIH (vehicle: 112±34%, n=4 vs losartan: 27±7%, n=7). These data indicate that AngII acting at central AT1 receptors contributes to post‐AIH S‐LTF. When considered together with literature evidence, we conclude that the AngII signal of AIH is generated centrally, not peripherally.

Support or Funding Information

NIH HL088052 & AHA 25710176 (GMT)

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Central Fractalkine Induces Systemic Inflammation Independently of Hypothalamic Prostaglandin E2
Authors: Mota Clarissa Maria Dias , da Rocha Maria José Alves , Antunes‐Rodrigues José , de Siqueira Branco Luiz Guilherme
Published: June 2021

Fractalkine (FKN; CX3CL1) belongs to the gamma‐chemokine family and binds to CX3CR1 receptors. Currently, the mechanisms involving FKN‐induced inflammatory mediators are research targets in an attempt to study immune diseases mechanisms. Besides, FKN seems to modulate inflammation in the nervous system by inducing the secretion of pro‐inflammatory mediators such as prostaglandin E2 (PGE2). PGE2 is a classic and important mediator of fever that activates warm‐responsive neurons in the anteroventral preoptic region of the hypothalamus (AVPO). Here, we tested the hypothesis that central FKN modulates febrigenic signaling both centrally and peripherally. Thus, male Wistar rats (280–350 g, n=5/group) were obtained from the Central Animal Facility at the University of São Paulo in Ribeirão Preto and all the experiments were performed according to the Brazilian society of laboratory animals science and in conformance with the FASEB Statement of Principles for the use of animals in research and education. We performed intracerebroventricular (icv) microinjections of saline (1 μL) and FKN (doses of 5, 50, 500 pg/μL) and measured body temperature (Tb), besides assessing tail skin temperature (Tsk) as a thermoeffector indicator. We also measured AVPO PGE2, plasma corticosterone (CORT) and interleukin‐6 (IL‐6) levels. FKN induced a long lasting febrile response in which the highest dose (500 pg/μL) induced a marked rise on Tb that was accompanied by a reduced Tsk. FKN had no effect on AVPO PGE2 production, whereas caused increases in plasma CORT and IL‐6 levels. Our data consistently indicate that FKN induces fever (reducing Tsk) in a PGE2 independent way probably by increasing plasma IL‐6 levels.

Support or Funding Information

The São Paulo Research Foundation (FAPESP) grant numbers #16/17681‐9 and #17/01633‐8 and the National Council for Scientific and Technological Development (CNPq), Brazil.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Glucoprivic sensitivity of hindbrain catecholamine neurons is astrocyte‐dependent
Authors: Rogers Richard C. , McDougal David , Ritter Sue , Qualls‐Creekmore Emily , Hermann Gerlinda E.
Published: June 2021

Hypoglycemia poses a threat to survival. Endocrine, metabolic, and behavioral counter‐regulatory responses (CRRs) act to correct blood glucose deficit. These responses require sensor, integrator, and effector elements to restore glucose homeostasis. Groups of hindbrain catecholamine (CA) neurons are essential for implementation of different CRRs which include activation of descending sympathetic pathways controlling epinephrine and glucagon release and ascending pathways controlling feeding behavior and glucocorticoids (3, 4). Hindbrain astrocytes respond to low glucose (1, 2, 5). Therefore, we postulated that CA neurons are activated by astrocytes during glucose deficit. To directly test the proposition that CA neuron responses to glucoprivic challenges are astrocyte dependent, we utilized male and female transgenic mice in which the calcium reporter construct (GCaMP5) was expressed selectively in tyrosine hydroxylase neurons (TH‐GCaMP5; TH+). We conducted live‐cell calcium imaging studies on tissue slices containing the nucleus of the solitary tract (NST) and the ventrolateral medulla (VLM); loci of glucoregulatory circuitry (4). Results show that hindbrain TH+ neurons are robustly activated by a glucoprivic challenge and that this response is dependent on functional astrocytes. Pretreatment of hindbrain slices with fluorocitrate (an astrocytic metabolic suppressor) abolished TH+ neuronal responses to glucoprivation, but not to glutamate stimulation. Pharmacologic results suggest that the astrocytic connection with TH+ neurons is purinergic via P2 receptors. Parallel imaging studies on hindbrain slices of NST from wild type C57BL/6J mice (astrocytes and neurons were prelabeled with a calcium reporter dye and an astrocytic vital dye) show that both cell types are activated by glucoprivation but astrocytes responded nearly a minute sooner than neurons. Pretreatment of these hindbrain slices with fluorocitrate eliminated both astrocytic and neuronal responses to glucoprivation; pretreatment with P2 antagonists only abolished neuronal responses to glucoprivation without interruption of astrocyte responses. These results support earlier work suggesting that the primary detection of glucoprivic signals by the hindbrain is mediated by astrocytes which utilize purinergic gliotransmission to activate critical effector neurons.

Support or Funding Information

NIH NIDDK 108765, U54 GM 104940, ADA‐1‐15‐JF‐37,

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 GABA Receptor Antagonists on the Biphasic Hypoxic Ventilatory Response of Newborn Rats
Authors: Cottingham Peter L. , March Ryan J. , Bavis Ryan W.
Published: June 2021

Newborn mammals exhibit a characteristically biphasic hypoxic ventilatory response (HVR) in which an initial increase in ventilation is followed by a progressive decline toward (or below) baseline values. Studies in anesthetized, newborn piglets suggest that the secondary hypoxic depression is partially attributable to γ‐aminobutyric acid (GABA) signaling through GABAA and GABAB receptors (Huang et al. J Appl Physiol 77:1006–1010, 1994). To determine whether GABAA and GABAB receptors similarly contribute to the biphasic HVR of newborn rats, we measured normoxic (21% O2) and hypoxic (12% O2) ventilation of newborn (P3–5) rats by head‐body plethysmography 30 minutes after intraperitoneal injection with vehicle or a GABA receptor antagonist. Two different GABAB receptor antagonists, CGP‐35348 (200 mg kg−1) and CGP‐46381 (50 or 100 mg kg−1), were found to have no effect on normoxic ventilation or the HVR (all P>0.05). Similar results were obtained for the GABAA receptor antagonist (+)‐bicuculline (2 or 3 mg kg−1). Collectively, these data do not support a role for GABAergic signaling in the biphasic HVR of newborn rats.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Aging Effects on Diaphragm Muscle Sarcopenia
Authors: Vang Pangdra , Zhan Wen Zhi , Gransee Heather , Sieck Gary , Mantilla Carlos
Published: June 2021

The population at very old age is increasing dramatically throughout the world. Aging adults experience increased health and medical needs associated with debility and sarcopenia (i.e., muscle atrophy and force loss). Respiratory complications and diseases are common causes of morbidity and mortality in the elderly. Sarcopenia of respiratory muscles such as the diaphragm muscle (DIAm) may contribute to respiratory complications since the DIAm, the main inspiratory muscle in mammals, plays an important role in ventilation and generating the forces necessary to maintain airway clearance. Presently, there is limited information about aging effects into very old age. Specifically, whether DIAm sarcopenia is exacerbated in old age and if it will effect ventilation into very old age are presently unknown. We hypothesized that DIAm sarcopenia in very old mice (>30 mo; ~30% survival) will result in reduced DIAm force generation across motor behaviors, exhibit impaired ventilation, decreased isometric force, and reduced fiber cross‐sectional area compared to old (24 mo; ~80% survival), and young (6 mo, 100% survival). C57BL/6 × 129 female and male mice (n = 30) at 6 mo, 24 mo, and >30 mo were used to examine transdiaphragmatic pressure (Pdi) generation during eupnea, exposure to hypoxia‐hypercapnia, as well as higher force behaviors in airway occlusion, and/or bilateral phrenic stimulation. Ventilation was assessed using whole body plethysmography and venous blood gases. Isometric force was examined via physiological muscle force testing, and fiber cross‐sectional area was determined in immunohistochemically labeled sections across fiber types. There was a significant reduction in Pdi between young and old mice for higher force behaviors – tracheal occlusion and bilateral phrenic nerve stimulation, (p < 0.001); however, there was no further decline in Pdi for all behaviors between old and very old mice. There was no evidence of impaired ventilation (ventilatory parameters – respiratory rate, minute ventilation, or tidal volume) across age groups, and no evidence of differences between sex in any of the measurements. A loss of ability to generate higher levels of force necessary to maintain airway clearance may predispose older individuals to recurrent infection. Understanding the mechanisms of sarcopenia in old age will be important in mitigating the effects of aging on quality of life and maintaining the health span.

Support or Funding Information

This work was supported by grants R25‐GM075148, R01‐AG044615, and R01‐AG057052 from the National Institutes of Health.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Phrenic‐to‐Intercostal Reflex Activity in Response to High Frequency Spinal Cord Stimulation (HF‐SCS)
Authors: Kowalski Krzysztof E. , DiMarco Anthony F.
Published: June 2021

Objective

HF‐SCS is a novel technique of inspiratory muscle activation which results in coincident activation of the diaphragm and inspiratory intercostal muscles via spinal cord pathways and has the potential to provide respiratory support in ventilator dependent persons with spinal cord injury. The purpose of the present study was to examine the phrenic to intercostal reflex during HF‐SCS.

Methods

In 3 anesthetized and C2 spinalized dogs, electrical stimulation was applied via a stimulating electrode located on the ventral surface of the upper thoracic spinal cord at the T2 level before and after cervical phrenicotomy. Fine wire recording electrodes were used to assess single motor unit (SMU) activity of the external intercostal muscles before and after phrenicotomy.

Results

Following unilateral phrenic nerve section, mean peak SMU firing frequency of EI ipsilateral to the section was significantly greater when compared to control (15.9±0.7 vs. 12.1±0.5 Hz, p<0.05). However, mean peak SMU firing frequency of the contralateral EI was unchanged (11.1±0.4 vs. 12±0.4 Hz, NS). Section of the contralateral phrenic nerve results in significantly higher mean peak SMU firing frequency of the contralateral EI (15.9±0.7 Hz, p<0.05) when compared to before section.

Conclusion

This study demonstrates that during HF‐SCS after C2 spinalization: 1) diaphragmatic afferents reflexly inhibit motor activity to the ipsilateral external intercostal muscles, and 2) the neural circuitry mediating the phrenic‐to‐intercostal reflex is preserved at a spinal level. Consequently, HF‐SCS applied to support ventilation in high tetraplegics with unilateral phrenic nerve injury may elicit increased activity of ipsilateral inspiratory intercostal muscles.

Support or Funding Information

Support: NIH‐NINDS (R01NS064157) and MetroHeath Foundation

Disclosure: Dr. DiMarco is a Founder of and has a significant financial interest in Synapse BioMedical, Inc, a manufacturer of diaphragm pacing systems.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Slc26a3 (DRA) Deficient Mice Display an Acidic Colonic pH‐microclimate, Develop a Strongly Altered Microbiome and Colonic Inflammation
Authors: Kini Archana , Basic Marijana , Singh Anurag Kumar , Riederer Brigette , Römermann Dorothee , Suerbaum Sebastian , Bleich André , Strowig Till , Seidler Ursula
Published: June 2021

Background

The anion transporter Slc26a3 (DRA‐Down Regulated in Adenoma) is localized on the apical membrane of the colonic mucosa and is functionally involved in the absorption of luminal chloride (Cl−) in exchange for bicarbonate ions (HCO3−). Mutations in the dra gene result in congenital chloride diarrhoea (CLD) which is characterized by secretory diarrhoea, loss of Cl− in the stool, dehydration and metabolic alkalosis. These patients also have a higher risk of incidence of acute as well chronic intestinal inflammation (Wedenoja et al. Hum. Mut 2011). We previously reported low colonic HCO3− output rates and an increased susceptibility to Dextran Sodium Sulfate (DSS) damage in slc26a3−/− mice (Xiao, F. et al. Acta Phys. 2015).

Aim

The present study was undertaken to explore whether the slc26a3−/− mice develop spontaneous intestinal inflammation, and whether an altered microbiome composition may be the underlying molecular mechanism for inflammation.

Methods

Colonic surface pH was measured in vivo by two photon microscopy, the inflammatory state of the mucosa by Quantitative PCR (qPCR) and immunohistochemistry, the intestinal microbiome by 16S rRNA sequencing, and the effect of the microbiome of the slc26a3−/− colon on the development of inflammation in germ‐free mice by fecal crossing experiments.

Results

The slc26a3−/− mice developed distal colonic inflammation evidenced by an increase in proinflammatory cytokine expression and the number of inflammatory cells in the colonic mucosa/submucosa at the time of sacrifice. The slc26a3−/− microbiome was significantly different from that of cohoused wild type (WT) littermates, with a strongly decreased diversity, and an increased percentage of several proinflammatory species. Transmission of this dysbiotic microbiome into germ free mice did not lead to a development of inflammation in the recipient mice. Instead, the species richness in the germ free mice gavaged with slc26a3−/− microbiome had increased, and the percentage of proinflammatory species decreased, in comparison to its donor microbiome.

Conclusions

Slc26a3−/− mice display a very low colonic pH microclimate and develop spontaneous intestinal inflammation. The microbiome of slc26a3−/− colon is “dysbiotic” with strongly reduced diversity. However, transmission of this microbiome into germ‐free mice does not result in inflammation, but does result in microbiome normalization, suggesting that the reduced pH microclimate and reduced colonic transit time is necessary for the development of intestinal dysbiosis.

Support or Funding Information

Volkswagen Foundation VW Vorab, DFG project SE460/17‐1 and 19‐1 and SFB621/C9

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