bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of reflex and mechanical decreases in skin blood flow on exogenous cholinergic‐induced eccrine sweating in humans
Authors: Wilson Thad E. , Fang Milie M. , Dazé Robert P. , Narra Seetharam C. , Metzler‐Wilson Kristen 
Published: June 2021

Human skin blood flow (SkBF) and sweating increase concurrently during increases in skin sympathetic nerve activity and subsequent neurotransmitter release to these cutaneous appendages. Previous studies have blocked sweating without affecting SkBF with the use of the muscarinic agonist atropine, but few have altered SkBF without affecting sweating because standard methods such as introducing an α‐adrenergic agonist decrease SkBF but also can engage eccrine sweat gland receptors. Thus, this study aimed to utilize non‐adrenergic mechanical perturbations to decrease SkBF during intradermal perfusion of a cholinergic agonist. Three intradermal microdialysis fibers were placed in dorsal forearm skin of 4 women and 3 men (age 24±1 yr, height 173±4 cm, weight 80±8 kg) to perfuse 2 doses of pilocarpine nitrate (0.01 and 1.66 mg/ml, corresponding to the ED50 and EMAX from previous dose‐response modeling) or the vehicle (lactated Ringer's). Forearm SkBF (laser‐Doppler flowmetry) was decreased for 3 min by engaging the venoarteriolar response (arm lowered ~30 cm from heart level; CVAR), venoarteriolar response plus decreased perfusion pressure (venous occlusion by proximal cuff inflation; CVAR with ΔPP), and ischemia (arterial occlusion by proximal cuff inflation); sweat rate was measured by perfusing anhydrous medical air through a ventilated capsule (capacitance hygrometry). Drug infusions significantly increased SkBF (+87±18 and +57±16 units) and sweating (+0.37±0.20 and +0.64±0.15 mg/ml/min, for pilocarpine ED50 and EMAX, respectively) compared to vehicle control in which SkBF minimally increased (+8±4 units) and there was no alteration in sweating (−0.02±0.09). Decreased SkBF was observed with CVAR (−26±14, −33±9, and −38±9%), CVAR with ΔPP (−62±7, −42±20 and −61±8%), and ischemia (−99±1, −92±5 and −93±2% for pilocarpine ED50, pilocarpine EMAX, and vehicle control, respectively). Despite these significant decreases in SkBF, changes in eccrine sweat rate were minimal (CVAR = −1±12, +3±3, and −2±5%; CVAR with ΔPP = +3±7, −2±4, and −3±4%; and ischemia = +5±10, +5±5, and +6±5% for pilocarpine ED50, pilocarpine EMAX, and vehicle control, respectively). These data suggest that very acute decreases in SkBF do not proportionally decrease cholinergic‐induced sweating in human forearm skin.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Overexpression of Nrf2 Targeting Glutamatergic Neurons in the RVLM Ameliorates Sympathetic Regulation in Mice With Chronic Heart Failure
Authors: Gao Lie , Lobl Marissa B. , Zucker Irving H. 
Published: June 2021

Nrf2 is a key transcription factor that regulates redox status by up‐regulating a broad array of antioxidant genes. Previous data from our laboratory demonstrated that enhanced oxidative stress in the RVLM contributed to the sympatho‐excitation in rabbits with chronic heart failure (HF). Accordingly, we hypothesized that overexpression of Nrf2 in the RVLM will suppress sympathetic tone via enhancing antioxidant defense. Thirty C57BL/6 mice were randomized into four groups: Sham‐lentiviral GFP (7); Sham‐lentiviral GFP Nrf2 (7); HF‐lenti GFP (8); and HF‐lenti GFP Nrf2 (8). HF was induced by coronary artery ligation while sham surgery was used as the control. Nrf2 was upregulated selectively in glutamatergic neurons of RVLM by microinjection of Ca2+/calmodulin‐dependent protein kinase‐II (CaMKII) promoter‐driven Nrf2 lentivirus and a corresponding GFP vector was used as the control. We found that (1) Nrf2 protein was significantly downregulated in the RVLM of HF mice, which was restored by Nrf2 gene transfer. (2) The increased urinary NE excretion in HF was attenuated by Nrf2 overexpression (Sham‐GFP: 575.2 ± 265.0, HF‐GFP, 1119.6 ± 270.5, HF‐Nrf2: 812.1 ± 133.0 ng/24hr. *p < 0.05, n = 7–8/group). (3) Radio telemetry experiments (in the conscious state) showed that Nrf2 overexpression enhanced spontaneous baroreflex gain and increased PE induced bradycardia in HF (Decline of HR: Sham‐GFP: −53.7 ± 4.8; HF−GFP: −4.7 ± 5.1; HF‐Nrf2: −25.1 ± 2.3 % of Max. *P < 0.05 HF‐GFP vs Sham‐GFP and HF‐Nrf2 vs HF‐GFP, n = 7–8/group), and attenuated stress‐induced pressor responses in both Sham (surgical‐stress: 101.5 ± 5.9 vs 129.7 ± 7.2 mmHg, restraint‐stress: 118.8 ± 6.8 vs 151.5 ± 8.2 mmHg. *P < 0.05, n = 7/group) and HF mice (surgery‐stress: 111.06 ± 5.87 vs 135.83 ± 7.24 mmHg, restrain‐stress: 102.8 ± 8.2 vs 119.2 ± 6.3 mmHg. *P < 0.05, n = 8/group). No difference in baseline blood pressure and heart rate were observed among these groups. (4) Acute experiments (in the anesthetized state) revealed a decrease in basal renal sympathetic nerve activity (Sham‐GFP: 28.6 ± 5.2, HF‐GFP: 64.7 ± 8.3, HF‐Nrf2: 44.0 ± 6.5 % of Max. *P < 0.05 HF‐GFP vs Sham‐GFP and HF‐Nrf2 vs HF‐GFP, n = 7–8/group) and improvement of baroreflex sensitivity (Maximal Gain: Sham‐GFP: 2.9 ± 0.1, HF‐GFP: 1.1 ± 0.2, HF‐Nrf2: 1.8 ± 0.3 % of mmHg. **p < 0.01 HF‐GFP vs Sham‐GFP; *P < 0.05 HF‐Nrf2 vs HF‐GFP, n = 7–8/group) in HF mice by Nrf2 overexpression. Based on the above data, we conclude that upregulating Nrf2 expression in glutamatergic neurons of the RVLM ameliorates sympathetic regulation in mice with HF and attenuates stress‐induced pressor responses in both sham and HF mice.Support or Funding InformationSupported by NIH grant P01‐HL62222This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sex Differences in the Sympathetic Restraint of Skeletal Muscle Blood Flow in the Human Leg Vasculature
Authors: Bunsawat Kanokwan , Ratchford Stephen M. , Clifton Heather L. , Theisen Jeremy K. , Barrett‐O'Keefe Zachary , Broxterman Ryan M. , Gifford Jayson R. , Hydren Jay , Rossman Matthew J. , Ives Stephen J. , Trinity Joel D. , Witman Melissa A.H. , Garten Ryan S. , Morgan David E. , Nelson Ashley D. , Richardson Russell S. , Wray D. Walter 
Published: June 2021

BackgroundThe sympathetic nervous system plays an important role in regulating skeletal muscle blood flow at rest and during exercise. Previous studies have identified sex differences in resting muscle sympathetic nerve activity1 and forearm alpha‐adrenergic receptor sensitivity.2 However, whether sympathetic restraint of limb blood flow differs between sexes, and the degree to which this restraint persists during dynamic exercise, is not well understood.MethodsIn four young men (28±2 yrs; 26±2 kg/m2) and six young women (24±2 yrs; 23±1 kg/m2), we evaluated changes in leg blood flow (LBF, Doppler ultrasound), mean arterial blood pressure (MAP, indwelling femoral artery catheter), and leg vascular conductance (LVC) before and after intra‐arterial infusion of phentolamine (PHEN, non‐selective alpha‐adrenergic antagonist, 5 μg/dL/min) at rest and during small muscle mass knee‐extensor (KE) exercise (15W). Influences from beta‐adrenergic receptors were blocked by intravenous administration of propranolol (0.07 mg/kg bolus).ResultsNo sex differences in LBF, MAP, or LVC were observed at rest. Following PHEN administration, sex differences were evident for both the drug‐induced increase in resting LBF (+337±79 vs. +172±43 mL/min, p<0.05, men vs. women) and LVC (+3.69±1.04 vs. +1.97±0.45 mL/min/mmHg, men vs. women, p=0.06). During KE exercise, no sex differences were evident for LBF, MAP, or LVC prior to PHEN infusion, and drug administration provoked similar increases in LBF (+630±128 vs. +560±85 mL/min, men vs. women) and LVC (+7.2±1.5 vs. +6.9±1.6 mL/min/mmHg, men vs. women) between groups.ConclusionAt rest, men demonstrate a larger increase in LBF and LVC in response to local alpha adrenergic receptor blockade via PHEN infusion, suggesting a greater degree of basal sympathetic vasoconstriction than their female counterparts. However, during exercise, similar increases in leg hemodynamics were observed between men and women following PHEN administration. Together, these data support the presence of a sex difference in the sympathetic restraint of resting limb blood flow that does not persist during moderate intensity exercise.Support or Funding InformationThis project is funded in part by the National Institutes of Health (HL118313) and the U.S. Department of Veterans Affairs (RX001697, RX001418, E6910R).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sympathetic Baroreflex Sensitivity During Mental Stress in Humans With Chronic Anxiety
Authors: Holwerda Seth W. , Gremaud Allene L. , Luehrs Rachel E. , Fiedorowicz Jess G. , Abboud Francois M. , Pierce Gary L. 
Published: June 2021

Elevated muscle sympathetic nerve activity (MSNA) is associated with the pathogenesis of hypertension and cardiac arrhythmias, and may be related to greater cardiovascular disease (CVD) risk among individuals with chronic anxiety. Augmented sympathetic responsiveness in chronic anxiety may potentially be attributed to alteration in sympathetic baroreflex control. We hypothesized that MSNA and its responsiveness to stress would be augmented in chronic anxiety, and that augmented MSNA responsiveness would be related to impaired sympathetic baroreflex sensitivity. Sympathetic baroreflex sensitivity was assessed by relating spontaneous changes in multi‐unit MSNA to beat‐to‐beat changes in diastolic blood pressure (DBP) using a weighted linear regression at rest (10 min) and during mental stress (MS, 4‐min mental arithmetic) in 18 individuals with moderate/high chronic anxiety (ANX, 6 men/12 women; 32±2 yrs; 27±2 kg/m2) who were nonsmokers and free of CVD, and in 18 healthy controls with low/no anxiety (CON, 8 men/10 women; 39±3 yrs; 30±1 kg/m2). Resting MSNA was not elevated among ANX compared to CON (MSNA burst incidence: ANX 29 ± 5 vs. CON 40 ± 4 bursts/100hb; Avg. relative MSNA burst amplitude: ANX 48 ± 1 vs. CON 47 ± 1 AU). Avg. relative MSNA burst amplitude in response to MS was significantly augmented among ANX compared to CON (ANX: 61 ± 2 vs. CON: 54 ± 2 AU, P=0.02), while % change in MSNA burst incidence was not significantly different between ANX and CON (ANX: 4 ± 7 vs. CON: 6 ± 7 bursts/100hb, P=0.86). Increases in avg. relative MSNA burst amplitude during MS were significantly correlated with trait anxiety score among all participants after adjusting for age, sex, and BMI (R=0.48, P=0.01). The slope between MSNA burst incidence and DBP was not different between ANX and CON at rest (ANX: −2.8 ± 0.6 vs. CON: −3.5 ± 0.5 bursts/100hb/mmHg−1, P=0.35), and was significantly reduced during MS (P=0.03) with no difference between ANX and CON (ANX: −2.2 ± 0.4 vs. CON: −2.3 ± 0.5 bursts/100hb/mmHg−1, P=0.42). The slope between total MSNA and diastolic BP was similar between ANX and CON at rest (ANX: −1.5 ± 0.3 vs. CON: −1.9 ± 0.3 AU/beat/mmHg−1, P=0.3) and unchanged (P=0.49) during MS (ANX: −1.5 ± 0.3 vs. CON: −1.5 vs. 0.3 AU/beat/mmHg−1, P=0.99). These preliminary findings demonstrate that individuals with chronic anxiety exhibit augmented increases in MSNA burst amplitude but not burst incidence to mental stress, and this alteration in the MSNA response to mental stress in chronic anxiety is not a result of impairment in sympathetic baroreflex sensitivity.Support or Funding InformationAHA 17POST33440101, T32 HL07121 NHLBI (P01HL014388), U54 TR001356 and AHA (13DG143400012)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Epidural Spinal Cord Stimulation Acutely Reduces Efferent Postganglionic Sympathetic Nerve Activity in Humans
Authors: Holwerda Seth W. , Holland Marshall T. , Reddy Chandan G. , Pierce Gary L. 
Published: June 2021

Evidence in clinical and animal studies demonstrates that epidural spinal cord stimulation (SCS) mimics the effects of sympathetic block or sympathectomy and increases peripheral blood flow. However, the extent to which SCS lowers sympathetic nerve activity in humans remains unclear because no studies have directly assessed muscle sympathetic nerve activity (MSNA) responses to SCS. We tested the hypothesis that acute SCS (60 min) at the lower thoracic spine would 1) lead to reduced MSNA in the peroneal nerve, and 2) increase blood flow in the legs, but not the arms. Twelve patients (54 ± 3 yrs, 5 men/7 women) that previously underwent surgical implantation of a SCS device for management of neuropathic pain were studied. Following 48 hours of no SCS, femoral and brachial artery blood flow was assessed using Doppler ultrasound at baseline and at 15, 30, 45, 60 min of SCS, and 15 min post SCS. MSNA was assessed using microneurography under the same conditions during a second visit (n=5). Femoral artery blood flow was significantly increased throughout SCS and 15 min post SCS (15 min: 26 ± 1%, 30 min: 32 ± 14%, 45 min: 30 ± 13%, 60 min: 26 ± 13%, 15 min post SCS: 40 ± 14% ml/min, P=0.02), but no change in brachial artery blood flow was observed (15 min: 4 ± 6%, 30 min: 5 ± 8%, 45 min: 5 ± 7%, 60 min: 7 ± 7% ml/min, 15 min post SCS: 6 ± 11% ml/min, P=0.86). MSNA was progressively reduced during SCS, reaching significance at 45 and 60 min, and returned toward baseline following SCS (15 min: −1 ± 6%, 30 min: −13 ± 4%, 45 min: −17 ± 6%, 60 min: −21 ± 7%, 15 min post SCS: −4 ± 5% bursts/100heartbeats, P=0.01). Similar results were observed for MSNA total activity (AU/min) (P<0.042). During measures of MSNA, self‐reported neuropathic pain was low at baseline and not significantly changed by SCS (scale 0–10; BL: 2.8 ± 0.8, 15 min: 1.7 ± 0.9, 30 min: 1.5 ± 1, 45 min: 1.7 ± 1, 60 min: 1.5 ± 1, P=0.07), suggesting that reductions in MSNA were SCS‐mediated and not primarily a result of pain relief. These preliminary results demonstrate proof of principle that acute lower thoracic SCS significantly reduces peroneal MSNA in humans.Support or Funding InformationAHA 17POST33440101, T32 HL07121, NHLBI (P01HL014388), U54 TR001356 and AHA (13DG143400012)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Chronic chemogenetic activation of OVLT neurons alters body fluid homeostasis and sympathetically‐mediated hypertension
Authors: Stocker Sean D. , Farquhar William B. , Wenner Megan M. 
Published: June 2021

The organum vascuolsum of the lamina terminalis (OVLT) contains a specialized group of neurons that can sense changes in extracellular NaCl concentrations to alter body fluid homeostasis and arterial blood pressure (ABP). Acute excitation of these neurons with hypertonic NaCl produces a sympathetically‐mediated increase in ABP. The purpose of the present study was to determine whether chronic activation of OVLT neurons produces hypertension. Rats were instrumented with telemetry devices and received an OVLT‐targeted injection of rAAV2‐hSyn‐HM4D(Gi)‐mCherry (3×1012 particles/mL, 50nL). Animals were returned to home cages to recover for 4 weeks with access to 0.1% NaCl chow and 0.9% NaCl drinking solution. After a 3‐day recording of baseline ABP and heart rate, clozapine‐N‐oxide was added to the 0.9% drinking solution for 7 days to produce a daily dose of ~3 mg/kg body weight. The concentration of the clozapine‐N‐oxide was adjusted daily to account for changes in fluid intake. Administration of clozapine‐N‐oxide to OVLT‐HM4D(Gi)‐expressing rats significantly increased 24‐h fluid intake from baseline to Day 7 (60±10 vs 178±29mL; n=4, P<0.01). Chronic activation of OVLT neurons significantly increased 24‐h mean ABP from baseline values versus Day 7 (97±2 vs 106±1 mmHg; n=4, P<0.05). Heart rate decreased from baseline values versus Day 7 (385±14 vs 330±26 bpm; n=4, P<0.05). Ganglionic blockade with hexamethonium (30 mg/kg, ip) produced a greater fall in mean ABP at Day 7 versus baseline values (baseline: −38±6 mmHg vs −53±5 mmHg; n=4, P<0.05). In addition, chronic activation of OVLT neurons increased 24‐h systolic blood pressure variability, calculated by the SD of systolic blood pressure, from baseline values versus Day 7 (9.1±0.4 vs 11.2±0.3 mmHg, P<0.05). Collectively, these observations suggest the chronic activation of OVLT neurons produces profound changes in body fluid homeostasis and cardiovascular regulation as reflected by 3x‐increase in fluid intake, a sympathetically‐mediated hypertension, and an increase in systolic blood pressure variability.Support or Funding InformationNIH R01 113270 and 128388This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
AT1A Receptors on Vasopressin‐Producing Cells are Important for Vasopressin Secretion but not Blood Pressure Responses to Chronic Intracerebroventricular Angiotensin in Mice
Authors: Zhang Shao Y. , Sandgren Jeremy A. , Linggonegoro Danny W. , Usachev Andrew M. , Pearson Nicole A. , Grobe Justin L. 
Published: June 2021

Vasopressin (AVP) plays an important role in cardiometabolic physiology by elevating blood pressure and water reabsorption. This hormone is produced in the magnocellular neurosecretory cells (MNCs) within the supraoptic nucleus (SON) and periventricular nucleus (PVN) of the hypothalamus. Angiotensin II (ANG) has been shown to act at AT1A receptors in the brain and cause AVP‐dependent elevations in blood pressure. Critically, the contribution of AT1A receptors specifically on AVP‐producing cells to blood pressure remains unclear. We hypothesized that AT1A receptor knockout only from AVP‐expressing cells would prevent blood pressure elevations in response to chronic intracerebroventricular (ICV) ANG infusion. Mice with AT1A knockout from AVP‐producing cells (AT1AAVP‐KO) were generated by breeding AVP‐Cre mice with AT1Aflox mice. Subcutaneous osmotic mini‐pumps were used to infuse artificial cerebrospinal fluid (aCSF) or ANG (50 ng/hr) into the lateral cerebral ventricle. Blood pressure was measured daily by tail‐cuff plethysmography for three weeks before and two weeks following implantation surgery. Water intake and urine output were measured using metabolic cages. Baseline systolic blood pressure (SBP) was indistinguishable among groups (Control aCSF 113±2, Control ANG 112±2, AT1AAVP‐KO aCSF 114±3, AT1AAVP‐KO ANG 113±2 mmHg; p=ns). ANG increased SBP similarly in control and KO mice (Control aCSF 107±3, Control ANG 121±2, AT1AAVP‐KO aCSF 111±2, AT1AAVP‐KO ANG 119±4 mmHg; ANG p<0.05, genotype p=ns, interaction p=ns). Water intake (Control aCSF 2.8±0.3, Control ANG 13.3±3.3, AT1AAVP‐KO aCSF 2.2±0.3, AT1AAVP‐KO ANG 11.3±2.9 mL/day; ANG p<0.05, genotype p=ns, interaction p=ns) and urine output (Control aCSF 0.7±0.2, Control ANG 7.7±2.6, AT1AAVP‐KO aCSF 0.4±0.1, AT1AAVP‐KO ANG 6.4±1.9 mg/day; ANG p<0.05, genotype p=ns, interaction p=ns) were also increased by ANG but not different between genotypes. Interestingly, urine copeptin was elevated by ANG in controls but not AT1AAVP‐KO mice (Control aCSF 27.6±6.1, Control ANG 137.9±35.6, AT1AAVP‐KO aCSF 78.3±15.7, AT1AAVP‐KO ANG 60.0±15.7 mL/day; ANG p<0.05, genotype p=ns, interaction p<0.05). For all studies, Control aCSF n=14, Control ANG n=7, AT1AAVP‐KO aCSF n=14, AT1AAVP‐KO ANG n=10. These data support the conclusion that AT1A receptors on AVP‐expressing cells are important for the control of AVP secretion in response to ICV ANG, but that this specific sub‐population of receptors are of minor importance for SBP responses to ICV ANG.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Identifying ‘angiotensin sensitive’ neurons in the lamina terminalis that coordinate endocrine, cardiovascular and behavioral responses mediating body fluid homeostasis
Authors: Krause Eric G. , Alleyne Amy R. , Cahill Karlena M. , Smeltzer Michael D. , Bruce Erin B. , Tan Yalun , Harden Scott W. , Frazier Charles J. , de Kloet Annette D. 
Published: June 2021

Body fluid homeostasis is controlled by endocrine, cardiovascular and behavioral responses that maintain blood osmolality and perfusion pressure at optimal levels. Angiotensin type 1a receptors (AT1a) in the brain are known to coordinate these responses but the underlying neuronal circuits remain unclear. This study investigates the structure and function of AT1a neurons in the median preoptic nucleus (MnPO) and the organum vasculosum of the lamina terminalis (OVLT) to better understand their role in body fluid homeostasis. Using male mice that express Cre‐recombinase prior to the STOP codon of the AT1a gene (i.e., AT1a‐Cre mice), initial studies combined genetic reporting with in situ hybridization to reveal that neurons in the MnPO and OVLT that express AT1a are largely glutamatergic. Subsequently, AT1a‐Cre mice were delivered a Cre‐inducible adeno‐associated virus to induce expression of channelrhodopsin‐2 (ChR2) and enhanced yellow fluorescent protein (eYFP) specifically within AT1a neurons of the MnPO/OVLT. Neuroanatomical and in vitro electrophysiological studies revealed that AT1a neurons in the MnPO/OVLT send dense glutamatergic projections into the paraventricular nucleus of the hypothalamus that synapse onto vasopressin (AVP)‐synthesizing neurons. To evaluate the functionality of this connection, we optogenetically stimulated AT1a‐expressing neurons in the MnPO/OVLT and recorded cardiovascular parameters in anesthetized mice. Relative to control mice given virus that only expressed eYFP, 10 min of optogenetic stimulation robustly elevated systolic blood pressure in mice expressing ChR2. This effect was rapid in its onset (34 ± 9 vs. −2 ± 4 mmHg at 5 min, p < 0.05) but persisted for the entire 50 min of cardiovascular recording (45 ± 11 vs. −3 ± 7 mmHg at 50 min, p < 0.05). Intriguingly, optogenetic stimulation elicited a significant increase in Fos induction in AVP neurons within the PVN relative to controls. To evaluate behavioral responses, AT1a neurons in the MnPO/OVLT were optogenetically stimulated while conscious freely moving mice had access to both water and 0.3M NaCl. Relative to controls, mice delivered ChR2 showed a significant increase in both water and sodium consumption. Collectively, the results suggest that AT1a neurons in the MnPO/OVLT comprise a neuronal circuit that mediates endocrine, cardiovascular and behavioral responses that maintain body fluid homeostasis.Support or Funding InformationNIH: HL122494 (EGK), MH104641(CJF), HL125805 and AHA GRNT33660969 (AdK)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.