bluuebunny/crossref_metadata_2025_split huggingface dataset:
Augmented Muscle Mass as a Novel Buffer against Obesity‐Derived Hypertension
Authors: Butcher Joshua T , Larion Sebastian , Mintz James , Fulton David J , Stepp David W 
Published: November 2023

Obesity is well known to significantly compromise cardiovascular and metabolic function and a front line intervention for the management of obesity is exercise, which reduces adverse cardiovascular related outcomes by increasing weight loss and augmenting muscle mass. Myostatin is a potent negative regulator of skeletal muscle shown to be upregulated in human and animal models of obesity, thus making myostatin an intriguing target for therapeutic intervention, particularly in patients who cannot undergo extensive lifestyle modifications due to various comorbidities.The model used was the db/db mouse, a well characterized mimic of the human condition of obesity, in combination with myostatin deletion. The study used four groups of mice, lean control, lean myostatin KO, obese control, obese myostatin KO.The current study found that augmented muscle mass, through myostatin deletion, prevents hypertension in the db/db mouse. Blood pressure (measured using radiotelemetry in conscious freely moving animals) between the lean and lean KO mice was similar (108 ± 1.5 vs. 105 ± 2.1 mmHg) but obese mice have significantly elevated blood pressure compared to obese KO (117 ± 1.6 vs. 108 ± 2.1 mmHg, p < 0.05). The obese groups have similar mass, fat profiles (NMR), activity (CLAMS) and heart rate, thus the improved cardiovascular outcomes occur despite full presentation of the classic db/db phenotype, indicating that the positive cardiovascular benefits conferred from augmented muscle mass are independent of weight loss. Further studies in lean mice have shown that myostatin deletion significantly delays the onset of hypertension with Angiotensin 2 infusion (800 ug/kg/min). This study also presents the novel finding that deletion of myostatin is accompanied by significant improvement in renal fluid dynamics, both in the lean and obese groups. The lean KO mice have significantly increased urine sodium concentration compared to lean control (197.9 ± 16.4 vs. 155 ± 13.7 mM, p < 0.05) and the obese KO also is significantly increased compared to the obese control (130 ± 7.9 vs. 62 ± 28.58 mM, p < 0.05), Importantly urine micro‐albuminuria, a clinically relevant measure of kidney function assessed by the albumin to creatinine ratio, remains similar in the lean and lean KO (328 ± 85.9 vs. 126 ± 29.3 ug/mg/day) but is rescued in the obese KO compared to obese control (315 ± 77.6 vs. 1037 ± 219.1 ug/mg/day, p < 0.05). Together, these experimental observations suggest that myostatin inhibition could serve as an effective target for conferring the protective cardiovascular benefits of augmented muscle mass (independent of exercise) and prevent/reverse obesity‐derived changes to metabolic, renal and cardiovascular function.Support or Funding InformationStepp and Fulton NHLBI RO1 HL124773
Blood Pressure Responsiveness to Muscle Metaboreflex Activation in Older Adults Following Dietary Nitrate Supplementation
Authors: Schneider Aaron C , Hughes William E , Kruse Nicholas T , Ueda Kenichi , Casey Darren P 
Published: November 2023

There is an increased risk for adverse cardiac events in older individuals that exhibit exaggerated blood pressure (BP) responses to exercise. Evidence suggests that the exaggerated BP responses to exercise in older individuals are due in part to greater muscle metaboreflex activation. The vasoactive molecule nitric oxide (NO) contributes to the regulation of BP and may play a role in the metaboreflex. With aging, NO bioavailability is often reduced but can be improved through nitrate (NO3) supplementation via the nitrate‐nitrite‐NO pathway. Therefore, we sought to test the hypothesis that dietary NO3 supplementation would reduce the BP responses to muscle metaboreflex activation in healthy older adults. To test this hypothesis we utilized a randomized, double‐blind, placebo controlled crossover study design in 8 healthy older adults (67 ± 2 years; 5M/3F). Each subject was studied before and after 4 weeks of NO3 supplementation (beetroot powder) and placebo (beetroot powder devoid of NO3) for a total of 4 study days. The muscle metaboreflex test consisted of 2 min of isometric handgrip (IHG) at 30% of maximal voluntary contraction followed by 2 minutes and 15 seconds of post exercise forearm ischemia (PEI) to isolate muscle metaboreflex activation. PEI was achieved by inflation of a blood pressure cuff around the upper arm to 240 mmHg 3 seconds before the end of handgrip exercise. Beat‐to‐beat peripheral BP was measured via finger plethysmography) and heart rate via ECG throughout the muscle metaboreflex test. BP responses were analyzed as the change (Δ) from baseline to the end of the IHG and PEI periods. Both IHG and PEI increased systolic (SBP) and mean arterial pressure (MAP) relative to resting (baseline) measurements (P < 0.05 for both). No significant interaction (P = 0.39) was found for changes in ΔSBP when comparing 4‐weeks of NO3 supplementation (14 ± 4 vs. 11 ± 3 mmHg) vs. 4‐weeks of the placebo condition (12 ± 4 vs. 15 ± 3 mmHg). Likewise, the change in ΔMAP after 4 weeks did not differ between NO3 supplementation (10 ± 2 vs. 8 ± 2 mmHg) and the placebo condition (8 ± 1 vs. 8 ± 2 mmHg) during IHG (interaction, P = 0.29). Conversely, the ΔSBP (19 ± 3 vs. 13 ± 4 mmHg, P = 0.03) and ΔMAP (11 ± 2 vs. 7 ± 2 mmHg, P = 0.03) were reduced during PEI following 4‐weeks of NO3 supplementation, whereas placebo had no effect on ΔSBP (13 ± 2 vs. 15 ± 2, P = 0.31) or ΔMAP (7 ± 1 vs. 9 ± 1, P = 0.22) during PEI. The reduced BP during PEI suggests that dietary nitrate supplementation is capable of attenuating the muscle metaboreflex during exercise in older adults. Since the metabolic component of the exercise pressor reflex is augmented in older adults with hypertension, it may be possible that nitrate supplementation could have an even greater impact in this patient population.Support or Funding InformationResearch supported by Neogenis Inc.
Advancing Age Is Associated with Augmented Venoarteriolar Response to Leg Dependency
Authors: Yoo Jeungki , Parker Rosemary , Sun Dan‐Dan , Urey Tony , Roberts‐Reeves Monique , Lawlery Justin , Romero Steven , Crandall Craig , Sarma Satyam , Levine Benjamin , Vongpatanasin Wanpen , Fu Qi 
Published: November 2023

BackgroundThe venoarteriolar response (VAR) is a non‐baroreflex mediated regional vasoconstriction mechanism which has been proposed to contribute to about 45% of the increase in total peripheral resistance during orthostasis. Advancing age is related to elevated total peripheral resistance and it is involved in the pathogenesis of hypertension. However, whether advancing age is associated with an enhanced VAR is not known.ObjectiveTo test the hypothesis that there are sex and age differences in the VAR among healthy individuals.Method18 (10 women) young (mean±SD; 28±4 years) and 22 (11 women) older (72±4 years) healthy normotensive adults participated in the study. Brachial and femoral artery diameter and blood flow velocity were measured using doppler ultrasound. Forearm and calf cutaneous blood flow were measured using laser‐doppler flowmetry. Assessments were performed while the arm and leg were in the horizontal position and repeated following limb dependency (35–40 cm below the heart level) for 5 min. Blood pressure (BP, SunTech) and heart rate (HR, electrocardiogram) were also measured. The percent reduction in vascular conductance (=blood flow/mean BP) during limb dependency was used to assess the VAR.ResultsThe VAR was not different between dominant and non‐dominant limbs. The VAR was more pronounced in the leg compared with the arm (24+/−7% vs. 18+/−5%; P=0.04) while it was not different between men and women. Older subjects had a greater VAR in the leg compared with their younger counterparts (29+/−8% vs. 21+/5%; P=0.04), but the VAR in the arm did not differ between the groups (17+/−6 vs. 19+/−4%, young vs. old; P=0.80). Cutaneous VAR showed similar results as those measured by doppler ultrasound. BP and HR remained unchanged prior to and during limb dependency.ConclusionAging is associated with augmented venoarteriolar response in the leg but not in the arm. The enhanced venoarteriolar response induced vasoconstriction may contribute importantly to hypertension in the older population.
The Influence of Acute Hypernatremia on Pressor and Sympathetic Responses during Exercise Pressor Reflex Activation
Authors: Brian Michael S , Matthews Evan L , Wenner Megan M , Rose William R , Stocker Sean D , Farquhar William B 
Published: November 2023

Acute hypernatremia has been shown to increase sympathetic nerve activity in animals and humans, however the impact on exercise blood pressure (BP) responses is unknown. The purpose of this study was to test the hypothesis that acute hypernatremia would increase BP and muscle sympathetic nerve activity (MSNA) responses to exercise pressor reflex activation (EPR). EPR activation was achieved during 2 minutes of handgrip (HG) exercise followed by post exercise ischemia (PEI). BP and MSNA responses were measured pre‐ and post‐a 23 min intravenous infusion of 3% hypertonic saline (HSI) to acutely increase serum sodium (SNa+) and plasma osmolality (pOsm). Eighteen participants (age 23±1 yrs; BMI 24±1 kg/m2) completed the protocol; SNa+ and pOsm significantly increased from pre‐ to post‐HSI (138.2±0.3 to 141.3±0.4 mmol/L; 285±1 to 291±1 mOsm/kg H2O; p<0.05 for both). Resting MSNA increased pre‐ to post‐HSI (n=13, 11±2 to 15±2 bursts·min−1; p<0.05), while resting BP remained stable (p=0.98). HG exercise and PEI led to robust increases in MSNA and BP pre‐ and post‐infusion. MSNA responses during HG were greater following HSI (Δ9±2 vs. Δ14±3 bursts·min−1, p<0.05), but not during PEI (Δ8±2 vs. Δ9±3 bursts·min−1, p>0.05). Mean BP responses were similar pre‐ to post‐HSI during HG and PEI (HG: Δ16±2 vs. Δ18±2 mmHg; PEI: Δ13±2 vs. Δ15±3 mmHg, p>0.05). A second set of participants (n=7, age 23±1 yrs; BMI 25±1 kg/m2) completed a time control protocol, consisting of quiet rest instead of an infusion. The time control condition yielded no change in resting SNa+, pOsm, mean BP, or MSNA (all p>0.05); HG exercise and PEI led to robust increases in BP and MSNA (p<0.05) but responses were not different pre‐ to post‐quiet rest. In summary, acute hypernatremia increases resting MSNA and MSNA response during HG exercise.Support or Funding InformationSupported by R01 HL128388‐01A1
Renal Denervation Prevents Progression of Hypertension by Reversing Baroreflex Resetting in a Rabbit Model of Chronic Kidney Disease
Authors: Sata Yusuke , Burke Sandra L , Lim Kyungjoon , Esler Murray D , Schlaich Markus P , Head Geoffrey A 
Published: November 2023

BackgroundHypertension progresses rapidly when associated with chronic kidney disease (CKD) to become treatment‐resistant. Renal denervation (RDN) is reportedly effective in lowering blood pressure in this disease but the pathophysiological mechanisms are not fully investigated. A rabbit model of moderate CKD, induced by 11/12th nephrectomy and characterised by rapid and sustained elevation of plasma creatinine and blood pressure allows for determination of the effects of RDN and whether its efficacy improves with time.AimsTo determine the short‐ and long‐term effects of RDN on CKD‐induced changes to mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), baroreflex function and renal function.MethodsCKD was induced by lesioning of the left kidney and right nephrectomy. In 2 weeks, rabbits underwent bilateral RDN or sham‐RDN. RSNA, recorded from the left renal nerve, and MAP were measured weekly, and baroreflexes were examined 2 and 4 weeks after RDN or sham‐RDN.ResultsTwo weeks after induction of CKD, creatinine increased by 59% and remained elevated by 41% over the following 4 weeks. MAP had increased by 14% to 77±1 mmHg after CKD and continued to rise from this level by +8% and +13% after 2 and 4 weeks in sham‐RDN rabbits. However, in rabbits which underwent RDN, there was no further increase in MAP over the 4 weeks. RSNA was 23% lower 2–3 weeks following RDN than after sham‐RDN (P<0.05). CKD shifted the RSNA baroreflex towards the higher MAP and this was reversed after 2 weeks of RDN with marked reductions in gain (38%) and range (42%). There was no further change to the baroreflex after 4 weeks RDN (Fig). Neither GFR (14±2 ml/min in controls), which was 45% lower in CKD rabbits, nor creatinine levels were altered by 4 weeks of RDN.ConclusionRDN is effective for 4 weeks in ameliorating the hypertension in this model of CKD. Sympathetic activation and the baroreflex resetting were also reversed without altering renal function. These are the pathophysiological rationale to target renal nerves in the treatment of hypertension with moderate CKD.
Effects of Hydrogen Sulfide on Mesenteric Blood Flow
Authors: Barrera Adelaeda , Naik Jay , Gonzalez Bosc Laura V. , Mendiola Perenkita , Kanagy Nancy L. 
Published: November 2023

In sleep apnea, recurrent obstruction of the upper airway leads to sleep fragmentation and intermittent hypoxia (IH). In animal studies, IH causes wake‐time hypertension by elevating vascular resistance due in part to decreased production of the vasodilator, hydrogen sulfide (H2S). Inhibiting cystathionine γ‐lyase (CSE) to prevent H2S synthesis augments constriction in isolated mesenteric arteries, but H2S regulation of resistance in this vascular bed in vivo is unknown. The goal of this study was to evaluate CSE regulation of blood flow and resistance in the mesenteric circulation of control rats and in rats made hypertensive by exposure to IH for 14 days. We hypothesized that inhibiting CSE would increase vascular resistance and mean arterial pressure (MAP) more in control than in IH exposed rats. Rats were anesthetized with inhaled isofluorane (2%) and instrumented with femoral artery and vein catheters as well as Doppler flow probes on the main mesenteric artery. Under anesthesia, CSE inhibition (β‐cyanoalanine, BCA, 30mg/kg bolus + 5 mg/kg/min for 20 minute) increased MAP in both control and IH rats compared to saline infusion (control: 7.2±1.2 vs. −2.8±1.1; IH: 9.3±1.1 vs. 3.3±0.7, % change from baseline, p<0.05, n=6–8 rats per group) but did not alter mesenteric resistance. To determine if anesthesia masked acute changes in vascular resistance in response to CSE inhibition, the study was repeated in conscious animals. In conscious control rats, BCA infusion significantly increased MAP (saline −0.8±1.18 vs BCA 7.9±2.55, % change from baseline, p<0.05, n=7) and mesenteric resistance (saline 0.9±3.1 vs BCA 15.6±6.5, % change from baseline, p<0.05, n=12). We then tested our hypothesis that chronic CSE inhibition would increase vascular resistance and MAP in control but not in IH rats. The irreversible CSE inhibitor DL‐propargylglycine (PAG) was used to permit a once daily i.v injection (50 mg/kg/day for 5 days). CSE inhibition significantly increased both, MAP and mesenteric resistance in control but not in IH rats (MAP: control: 110.3±2.9 vs. 122.4±4.0 post PAG; IH: 118.8±2.1 vs. 111.3±3.7 post PAG, mmHg, p<0.05 n=3–5 rats per group; Relative mesenteric resistance normalized to starting values: Sham: 1±0 vs. 1.5±0.07.1; IH: 1±0 vs. 0.85±0.19, p<0.05, n=3–5 rats per group). Our results suggest that endogenous H2S is an important regulator of blood pressure and mesenteric vascular resistance and that this control is lost after IH exposure.Support or Funding InformationThis work was supported by the NIH, NHLBI, and AHA [Grants HL123301, HL007736‐21, and 15GRNT25090039 (LGB)] and institutional funding from the University of New Mexico.
Blood Pressure Response to Isometric Exercise During Short‐term Water Restriction
Authors: Watso Joseph , Babcock Matthew C , Stocker Sean D , Wenner Megan M , Farquhar William B 
Published: November 2023

Water restriction causes an acute decline in plasma volume and elevation in plasma osmolality, both of which can increase sympathetic outflow. Greater sympathetic outflow is associated with alterations in blood pressure (BP) variability and BP reactivity.PURPOSETo test the hypothesis that water restriction increases BP variability and BP reactivity.METHODSEleven healthy participants (5M/6W, age: 24±1 yrs; BMI: 24.3±1.0 kg/m2; BP 110±4/64±2 mmHg) completed two hydration protocols in a randomized order, separated by a month. Daily water intake for the euhydration (EU) condition was 23 mL H2O/kg/day for 3 days prior to testing on day 4. Water intake for the hypohydration (HYPO) condition included a stepwise reduction in water intake for 3 days, followed by a 16‐hour water restriction period prior to testing. Participants wore an ambulatory BP monitor and collected urine for 24 hours preceding each study visit. Subjects completed a 2‐minute bout of isometric handgrip exercise at 40% of their maximal voluntary contraction (HG) followed by 3 minutes of post‐exercise ischemia (PEI). Beat‐by‐beat BP was measured continuously with finger photoplethysmography.RESULTSPlasma volume declined 4.9±0.7% during the HYPO condition and plasma osmolality was significantly elevated in the HYPO compared to the EU condition (288.0±1.2 vs. 284.6±1.3 mOsm/kg H2O, p<0.05). Several other variables suggested mild dehydration during the HYPO condition, including higher urine osmolality (634±48 vs. 432±52 mOsm/kg H2O, p<0.05), urine specific gravity (1.018±0.002 vs. 1.011±0.001, p<0.05) and thirst rating on a 0–10 scale (6.1±0.2 vs. 1.9±1.0, p<0.05). Despite this, preliminary data suggest no change in beat‐by‐beat BP variability (SD mean BP 1.3±0.0 vs. 1.4±0.1, p>0.05) or ambulatory BP variability (SD mean BP 11.7±0.4 vs. 11.4±1.2, p>0.05) during the HYPO compared to the EU condition. BP reactivity during HG (Delta mean BP 10±3 vs. 13±2 mmHg, p>0.05) or PEI (Delta mean BP 13±3 vs. 13±2 mmHg, p>0.05) was not different between conditions. Heart rate change from baseline to HG and PEI was also not different between conditions (p>0.05).CONCLUSIONThese preliminary findings suggest that short‐term water restriction in young healthy adults does not increase BP variability or BP reactivity.Support or Funding InformationSupported by NIH Grant 1R01HL128388‐01A1
Ablation of MMP9 upregulates autophagic flux in the diabetic heart
Authors: Nandi Shyam Sundar , Mishra Paras Kumar 
Published: November 2023

Autophagy is a lysosome‐mediated catabolic process for recycling of defective cytoplasmic components. Matrix metalloproteinase‐9 (MMP9) is a collagenase, and ablation of MMP9 is cardioprotective for diabetic hearts. However, whether the cardioprotective role of MMP9 ablation is mediated by autophagic adaptation is unclear. We hypothesized that ablation of MMP9 protects the diabetic heart by upregulating cardiac autophagic flux. To test the hypothesis, we used 12–14 week male WT (C57 BL/6J), Ins2+⁄− Akita (Type1 diabetic), MMP9 knockout (MMP9−⁄−), and Ins2+⁄−/MMP9−⁄− (DKO) mice. DKO mice were generated by cross‐breeding male Ins2+⁄− Akita with female MMP9−⁄− mice. We measured the levels of LC3B‐II protein accumulation (autophagic flux marker) in these mice using bafilomycin A1 (inhibitor of autophagic degradation). To evaluate the cardiac function, we performed M‐mode echocardiography. For in vitro studies, we generated stable MMP9−⁄− HL1 cardiomyocyte cell line using CRISPR‐cas9 technique (MMP9−⁄− HL1). Autophagic flux was measured in control and MMP9−⁄− HL1 cardiomyocytes treated with low (LG‐5mM) or high (HG‐25mM) dose of D‐glucose. Our results revealed that autophagic flux is upregulated in MMP9−⁄− hearts (1.44±0.07 fold) as compared to WT hearts. Autophagic flux was also upregulated in Ins2+⁄− Akita hearts (1.3±0.12 fold) as compared to WT hearts. However, ablation of MMP9 in Ins2+⁄− Akita further increases cardiac autophagic flux (1.75±0.25 fold of Akita). The in vitro studies demonstrated that ablation of MMP9 in HL1 cardiomyocytes upregulates autophagic flux (2.6±1.4 fold) as compared to control HL1 cardiomyocytes. Moreover, HG treatment increased autophagic flux (1.4±0.25 fold) in HL1 cardiomyocytes, which was further increased by MMP9 ablation (1.7±0.24 fold) in HL1 cardiomyocytes. M‐mode echocardiography showed that percentage ejection fraction (% EF) was decreased in diabetic Akita as compared to WT (WT: 61.41±2.84 and Akita: 48.40±2.44) mice, but it was restored in DKO (61.28±0.71). There was no significant change in % EF in MMP9−⁄− (61.89±1.46) mice. These findings demonstrate a novel MMP9‐mediated regulation of autophagy in the diabetic heart, where ablation of MMP9 induces cardiac autophagic flux in the diabetic heart that may contribute to ameliorate cardiac dysfunction.Support or Funding InformationAmerican Heart Association Postdoctoral fellowship award 16POST30180003 and NationalInstitute of Health grants HL113281and HL16205
Sympathetic decentralization after spinal cord injury spares Zucker Diabetic Fatty rats from frank diabetes
Authors: Poormasjedi‐Meibod Malihe‐Sadat 
Published: November 2023

IntroductionMetabolic syndrome, characterized by the constellation of visceral obesity, atherogenic dyslipidemia, proinflammatory state, hypertension, and insulin resistance, confers a 5‐fold increase in the risk of type 2 diabetes (T2D). Accumulating data from human and animal studies revealed a strong association between sympathetic nervous system (SNS) activation and different components of metabolic syndrome, such as obesity, hypertension, and insulin resistance. However, it is not clear whether sympathoexcitation is a cause or result of metabolic syndrome and the subsequent T2D. Here we used high thoracic spinal cord injury (SCI) as an effective means for SNS decentralization in order to investigate the potential role of the SNS in the pathogenesis of T2D in an animal model of metabolic syndrome.Method/DesignEighteen male Zucker Diabetic Fatty rats (ZDF‐Leprfa/fa, Metabolic syndrome/T2D animal model) were evenly assigned to two groups: uninjured (Fatty‐Sham), and T3 complete SCI (Fatty‐SCI). Lean Zucker Diabetic Fatty rats (ZDF‐Lepr+, n = 9) acted as controls. T2D development was evaluated using biweekly random blood glucose measurements and oral glucose tolerance test (OGTT) at week 11 post‐injury. Twelve weeks post‐injury, animals were euthanized and blood samples and pancreas tissue were collected for further analyses.ResultsWe found that SCI‐induced SNS decentralization, manifested by a dramatic decline in plasma norepinephrine (P = 0.011), was accompanied by improved glucose tolerance, i.e. decreased glucose area under the curve (AUC, P = 0.001), increased fasting insulin (1.00 ± 0.33 vs. 3.02 ± 1.5 ng/ml, p = 0.011), and augmented insulin response after an OGTT, i.e. increased insulin AUC (P = 0.001) in the Fatty‐SCI group compared to uninjured Fatty‐Sham group. Although Fatty‐Sham and Fatty‐SCI groups exhibited a comparable degree of insulin resistance, Fatty‐SCI had significantly higher β‐cell activity indicated by a significant increase in homeostatic model assessment‐%B (HOMA‐%B) index (P = 0.0064). Pancreatic gene expression analysis revealed that SCI caused a significant reduction in the local expression of inflammatory mediators, i.e. IL‐1β and TNF‐α, which are critical for inhibition of insulin secretion, and induction of β‐cell apoptosis and dysfunction. While SNS decentralization spared the Fatty‐SCI rats from frank diabetes, Fatty‐SCI and Fatty‐Sham rats both exhibited other components of metabolic syndrome, including abdominal obesity and dyslipidemia, as compared to lean rats.Support or Funding InformationThis work has been supported by Michael Smith Foundation for Health Research, Craig H. Neilsen Foundation, Heart and Stroke Foundation of Canada, and the International Collaboration on Repair Discoveries.