bluuebunny/crossref_metadata_2025 huggingface dataset:
Consequences of Microglial Depletion on the Hypercapnic Ventilatory Response of Female Rats
Authors: Kinkead Richard , Jiao Belinda , Fournier Stéphanie , Bretzner Frédéric
Published: June 2021

Panic disorder (PD) is a neurological disorder associated with an abnormally high hypercapnic ventilatory response. In humans and rodents, early life stress is a significant risk factor for PD. Based on recent data indicating that CO2/H+ sensing by microglia is an important mechanism in the translation of hypercapnic stimulation into physiological responses, we tested the hypothesis that depletion of microglia by pharmacological treatment can decrease the hypercapnic ventilatory response. We also proposed that this effect is greater in stressed rats than controls. The prevalence of PD being ~2 times greater in women than men, experiments were performed on female rats. Following birth, rats were either raised under control conditions or subjected to neonatal maternal separation (NMS; 3h/day, postnatal days 3 to 12). At 8 weeks, females were fed a palatable treat containing either vehicle (DMSO) or PLX3397 (40mg/kg). Treatment was performed daily for 10 consecutive days. 1 day after completion of the treatment, rats were placed in a plethysmography chamber to measure ventilatory activity at rest (room air) followed by hypercapnic exposure (FiCO2 = 0.05; 10 min). Iba‐1 immunohistochemistry was used to quantify microglial density; measurements performed in hypothalamic structures containing orexin neurons showed that PLX3397 treatment educed microglial density by 31%; this effect did not differ between the structures quantified. Furthermore, our preliminary results suggest that oestrus cycle influences the impact of microglial depletion on the CO2 response. During the estrus phase, PLX3397 attenuated the hypercapnic ventilatory response of controls but augmented the response of NMS females. These data suggest that microglia contribute to the abnormal effects that ovarian hormones exert on the neural networks regulating CO2/H+ chemoreflex respiratory regulation in NMS rats. These data provide the basis for the exploration of new treatment for respiratory manifestations of PD.

Support or Funding Information

Supported by the Canadian Institutes of Health Research (RK & FB).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Spinal Adenosine 2A Receptor Activation is Necessary for Phrenic Long‐Term Facilitation in Carotid‐Denervated Rats
Authors: Perim Raphael R , Kubilis Paul S , Mitchell Gordon S
Published: June 2021

Moderate acute intermittent hypoxia (AIH) elicits a long‐lasting increase in phrenic nerve activity, known as phrenic long‐term facilitation (pLTF). pLTF was originally demonstrated by intermittent electrical carotid sinus nerve stimulation, highlighting the pivotal role of carotid chemoafferent neurons in this form of respiratory motor plasticity. Surprisingly, there is still some residual pLTF after carotid body denervation (CBX) through unknown mechanisms. Carotid body‐dependent, serotonin 2 receptor‐induced pLTF is not expected after CBX; thus, a distinct mechanism must account for residual pLTF. Greater hypoxia‐induced hypotension after CBX might further reduce spinal tissue PO2 more during each hypoxic episode, potentially inducing pLTF via an alternate adenosine‐dependent mechanism. Thus, we tested the hypothesis that adenosine 2A (A2A) receptor activation underlies residual pLTF after CBX. Phrenic nerve activity and spinal tissue PO2 were measured in vivo during our standard pLTF protocol in urethane anesthetized, male Sprague Dawley rats. The contribution of severe hypoxic hypotension to residual pLTF after CBX was evaluated by preventing the arterial pressure drop during hypoxic episodes via systemic phenylephrine administration. We demonstrate that severe hypoxia‐induced hypotension diminishes spinal tissue oxygenation (at the same arterial PO2) during hypoxic episodes to an extent sufficient to trigger residual pLTF. Preventing hypoxia‐induced hypotension minimizes tissue hypoxia, and residual pLTF is no longer observed. Spinal A2A receptor (MSX‐3; 12 μL, 10 μM), but not a serotonin 2A receptor (Ketanserin, 500 μM, 15 μL), antagonist abolishes residual pLTF after CBX. We conclude that differences in arterial blood pressure regulation impact expression and mechanisms of phrenic motor plasticity, a finding of importance for conditions characterized by hypotension such as anemia or spinal injury, where sympathetic outflow is disrupted by injury.

Support or Funding Information

Supported by: NIH Grants HL69064, SPARC and University of Florida McKnight Brain Institute

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Respiratory Plasticity in Adult Rats after Exposure to Chronic Hyperoxia
Authors: Pratt Ashley E , Bavis Ryan W
Published: June 2021

Neonatal rats reared in moderate hyperoxia (60% O2) from birth hypoventilate when acutely returned to room air (e.g., Bavis et al., Respir. Physiol. Neurobiol. 198: 1–12, 2014); this hypoventilation reflects reductions in both respiratory frequency and tidal volume. Since many forms of respiratory plasticity are specific to development, we questioned whether chronic hyperoxia would have similar effects on normoxic ventilation in adult rats. Adult Sprague‐Dawley rats (3–5 months old) were randomly assigned to Control (chronic 21% O2; n=11) or Hyperoxia (chronic 60% O2; n=10) treatment groups. Normoxic ventilation was measured by whole‐body plethysmography prior to exposure, after 4 and 14 days of exposure, and after 4 days of recovery in room air. Chronic hyperoxia altered minute ventilation in adult rats (Treatment × Day, P=0.002), but surprisingly this effect was not apparent during the hyperoxic exposure itself. Instead, Hyperoxia rats exhibited a modest increase in normoxic ventilation when measured during the recovery period (39±2 vs. 33±1 ml min−1 100g−1; P=0.003). Tidal volumes and respiratory frequencies were similar between groups before and during the chronic exposures, but Hyperoxia rats exhibited greater tidal volumes and respiratory frequencies during the recovery period (Treatment × Day, P=0.047 and 0.038, respectively). Neither metabolism nor blood gases were measured during these experiments, so it is unclear whether the increase in ventilation constitutes a true hyperventilation. We conclude that the effects of chronic hyperoxia on normoxic ventilation are age‐specific.

Support or Funding Information

Supported by NIH grant P20 GM‐103423 (Maine INBRE).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Acute and chronic changes in the control of breathing in a hyperoxia‐induced model of bronchopulmonary dysplasia
Authors: Mouradian Gary C , Argote‐Alvarez Santiago , Gorzek Ryan , Thuku Gabriel , Michalkiewicz Teresa , Wong‐Riley Margaret , Konduri Girija Ganesh , Hodges Matthew R
Published: June 2021

Infants born very prematurely (<28 weeks gestation) have immature lungs and often require supplemental oxygen. However, long‐term hyperoxia exposure can arrest lung development leading to bronchopulmonary dysplasia (BPD), which increases acute and long‐term respiratory morbidity and mortality. The neural mechanisms controlling breathing are highly plastic during development. Whether the ventilatory control system adapts to pulmonary disease associated with hyperoxia exposure in infancy remains unclear. Here, we tested the hypothesis that there would be age‐dependent adaptations in the control of breathing in an established rat model of hyperoxia‐induced BPD. Hyperoxia exposure (FIO2: 0.9 from 0–10 days of life) led to a BPD‐like lung phenotype, including sustained reductions in alveolar surface area and counts, and modest increases in airway resistance. Hyperoxia exposure also led to chronic increases in room air and acute hypoxic minute ventilation (VE) and age‐dependent changes in breath‐to‐breath tidal volume and breathing frequency variability. Hyperoxia‐exposed rats had normal hypoxic ventilatory responses, oxygen saturation (SpO2) in room air, but greater reductions in SpO2 during acute hypoxia (12% O2) indicating reduced hypoxic sensitivity and/or hypoventilation due to diseased lungs. However, VE was increased indicating an increase in respiratory drive. Perinatal hyperoxia led to greater glial fibrillary acidic protein expression and an increase in neuron counts within 6 of 8 and 1 of 8 key brainstem regions controlling breathing, respectively, suggesting astrocytic expansion. In conclusion, perinatal hyperoxia in rats induced a BPD‐like phenotype and age‐dependent adaptations in VE that may be mediated through changes to the neural architecture of the ventilatory control system. Our results suggest chronically altered ventilatory control in BPD.

Support or Funding Information

Children's Research Hospital of Wisconsin Research Institute, NIH R01 HL 122358, & Parker B. Francis Foundation

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Changes in keyboard typing accuracy and spatial perception after cardiovascular fitness exercise
Authors: Moon Myeonggon , Hong Yonggeun
Published: June 2021

This study aimed to identify the association between cardiopulmonary exercise and neurological activation through measuring dictation accuracy and the extent of spatial perception. First of all, body composition of subjects were analyzed to verify their physical intactness. Then the subjects were given treadmill exercise using modified Bruce protocol. Before and after the treadmill exercise, spatial perception test and dictation task with auditory and visual stimulation were carried out to identify the changes in neurological activation. The Scores of spatial perception after treadmill exercise were higher than those before treadmill exercise (p <0.05). The accuracy of post‐treadmill dictation task with auditory stimulation was decreased compared to that of pre‐treadmill dictation task. Likewise, accuracy of post‐treadmill dictation task with visual stimulation was significantly decreased compared to that of pre‐treadmill dictation task (p <0.05). However, speed of post‐treadmill dictation task with visual stimulation was significantly increased compared to that of pre‐treadmill dictation task (p <0.05). In this study, typing accuracy and spatial perception were assessed to identify alteration of neurological activation following treadmill exercise. Unlike improved spatial perception, typing accuracy was reduced due interference of upper body motions with arm stability during treadmill exercise. In this study, spatial perception and speed of visual dictation was increased. Therefore, cardiovascular fitness exercise was proved to increase neurological activation by accelerating typing speed and spatial perception.

Support or Funding Information

NRF‐2017R1A2A2A01067169, KGM4611821, 2016 Creative Research Program of Inje University, Republic of Korea

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Positive Reinforcement as a Method to Encourage Behavioral Modification
Authors: Landry Elizabeth
Published: June 2021

This research was conducted at a mental health institute in Chattanooga, TN to determine the efficacy of positive reinforcement through a hospital‐wide, weekly television broadcast on behavioral outbursts, communication, and patient confidence. A weekly broadcast written, filmed, and hosted by patients is the means of positive reinforcement. This broadcast includes segments such as patient spotlights for exceptional behaviors or acts of kindness, staff spotlights, patient talent segments, and a congratulations for the patients successfully discharging. The hypothesis is when given more responsibility and more praise for good behaviors the behavioral outburst of the patients will decrease, and their ability to effectively communicate and work as a team will increase. According to patient feedback, there is an increase in morale, confidence, and a constant encouragement for good behavior. Additionally, patients from outside of the broadcast team have noted that seeing their peers is encouraging and inspiring for them, and the patient spotlight section is an encouragement for them to strive to go to the extra mile in their daily activities. This research is based on a model from the AIMS Center in Chattanooga, TN, and seeks to better understand how to actively involve patients in their treatment process in an effective and constructive way.

Support or Funding Information

None

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Neural activity and network during cognitive tasks in heat‐stressed individuals
Authors: Kobayashi Fumino , Nakata Hiroki , Shibasaki Manabu
Published: June 2021

Reductions in cerebral blood flow accompanying heat stress‐induced hypocapnia via hyperventilation are likely to decrease the cognitive function, but the mechanism remains unknown. Using electroencephalographic event‐related potentials (EEG‐ERP) and functional magnetic resonance imaging (fMRI), we evaluated temporal (EEG) and spatial (fMRI) characteristics during cognitive tasks in heat‐stressed humans. Healthy young volunteers performed a visual cognitive task (Go/No‐go task) before (i.e., normothermia) and during heat stress on separate days. The external canal temperature during heat stress was increased by ~ 1.1°C from the normothermic condition. Decreased cerebral blood flow during heat stress was confirmed by reductions in middle cerebral artery blood velocity (MCAV) and internal carotid blood flow in the EEG‐ERP trial. The amplitudes of the Go‐P300 (i.e., execution) and No‐go‐P300 (i.e., inhibition) components were decreased during heat stress. In the fMRI trial, we observed broadly activated brain regions, including the dorsolateral and ventrolateral prefrontal cortices, and motor‐related areas such as the supplementary motor area and premotor area during heat stress rather than during normothermia. These results suggest that heat stress increases the load of neural activity while performing cognitive tasks, relative to normothermia, while heat stress reduced cerebral blood flow and neural activity.

Support or Funding Information

JSPS KAKENHI 18H03166

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cross‐Sensitization to Binge Alcohol Intake Following Binge Intake of Palatable Diets
Authors: Coker Caitlin Rae , Aguilar Elizabeth , Silberman Yuval
Published: June 2021

Obesity and alcoholism, two of the most common chronic conditions in the United States, may be behaviorally linked as binge intake of palatable diets, such as diets high in fat (HFD), and binge alcohol (EtOH) intake may utilize similar neurocircuitry. We hypothesized that binge intake of one modality (i.e. HFD) may sensitize the shared neurocircuitry to further activation by another modality (i.e. EtOH). Therefore, we combined a binge HFD intake model in mice where HFD access is limited to one 24hr session per week (Limited Access HFD: LAH) with a patterned EtOH access schedule that also promotes binge‐like intake in a two‐bottle choice model (Limited Access EtOH: LAE; 4hrs/day, 4days/wk). Control mice were given the same EtOH access schedule but were given continuous ad libitum access to HFD (60% calories from fat) or control Chow diet (10% calories from fat). Six‐week old male C57Bl/6J mice were weight matched, individually housed, and assigned to HFD+LAE, Chow+LAE, or LAH+LAE groups (n=10 per group). All groups of mice were given increasing EtOH concentrations over the course of the study (10% EtOH for three weeks, 15% EtOH for two weeks, and 20% EtOH for two weeks). Body mass was measured daily while EtOH/water intake and EtOH preference were assessed after every drinking session. Over the course of the study, HFD+LAE mice gained significantly more weight than Chow+LAE or LAH+LAE mice (p=0.001; one‐way ANOVA). While weight gain was predominantly linear in HFD+LAE and Chow+LAE mice, LAH+LAE mice showed weight cycling indicating a binge‐like eating pattern. LAH+LAE mice consumed significantly more EtOH than Chow+LAE or HFD+LAE mice (p=0.001, repeated measures two‐way ANOVA), suggesting that binge intake of HFD led to increased binge EtOH intake patterns in LAH mice. LAH+LAE and Chow+LAE mice showed higher preference towards EtOH than HFD+LAE mice (p=0.001, repeated measures two‐way ANOVA). Together, these results suggest limited access to palatable diets induce binge‐like eating patterns that further cross‐sensitize to binge alcohol intake and mitigates the loss of alcohol preference in mice given continuous HFD.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Central Amygdala Angiotensin Type 2 Receptor (AT2R) Activation Reduces Fear‐Related Behavior
Authors: Yu Zhe , Swiercz Adam P. , Krause Eric G. , Marvar Paul J.
Published: June 2021

Background

Previous retrospective clinical studies identify the renin‐angiotensin system (RAS) as a potential therapeutic target in post‐traumatic stress disorder (PTSD), however the mechanisms are unknown. We propose that brain RAS modulates inhibitory and excitatory fear circuits critical to the consolidation and extinction of fear memory in PTSD.

Methods

Using the angiotensin type 2‐receptor (AT2R)‐eGFP‐BAC reporter mouse combined with pharmacological and behavioral approaches, the aim of the study was to examine the role of the brain AT2R in fear memory.

Results

AT2R‐eGFP+ immunoreactive cells co‐localized with the neuronal specific marker NeuN and were expressed in major subnuclei of the amygdala. They were predominately observed in the medial amygdala (203.8 ± 39.4 cells/mm2) and the medial division of central amygdala (CeM) (224.7 ± 9.4 cells/mm2), while the basolateral amygdala (11.7 ± 1.8 cells/mm2) and lateral division of central amygdala (CeL) (3.2 ± 0.8 cells/mm2) contained minimal to no AT2R‐eGFP expression (Fig. 1). Within the CeM, 96% of the AT2R‐eGFP+ neurons expressed the GABAergic marker GAD1, while approximately 17% GABAergic AT2R‐eGFP+ cells expressed interneuron markers, suggesting the remaining may be GABAergic projection neurons. Moreover, these AT2R‐eGFP+ neurons were negative for the CeL marker PKC‐β. In C57Bl/6 mice, we used cue‐dependent and context‐dependent fear conditioning to examine the behavioral role of AT2R in fear memory. Twenty‐four hours after fear conditioning, bilateral intra‐CeA injection of the AT2R agonist C21 (0.06ug/ul) was administered and mice were exposed to the conditioned cue (30 second auditory tones) or context. Fear expression was quantified by percentage of freezing during cue stimuli or the context exposure. Compared to vehicle controls, mice receiving C21 into the CeA displayed a decreased freezing response to both the cue (61.7% ± 5.4 vehicle vs 42.1% ± 5.7 C21 group, p<0.05, n=10–12) and the context (64.6% ± 4.4 vehicle vs 48.3% ± 3.7 C21 group, p<0.05, n=16–17), indicating reduced fear expression (Fig. 2). These behavioral effects were also independent of generalized anxiety‐like behavior as determined by open‐field and EPM testing.

Conclusion

These findings suggest that CeM AT2R‐expressing neurons can modulate CeA outputs that play a role in fear expression and provide evidence for a novel angiotensinergic circuit in the regulation of fear.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cardiac Innervation: Pathophysiology and Therapeutics
Authors: Shivkumar Kalyanam , Ardell Jeffrey L
Published: June 2021

Cardiac neurotransmission via afferents and efferent cardiac nerves modulates key physiological functions of the heart (chronotropy, dromotropy, lusitropy, and inotropy). The processing of cardiac afferent signals at various levels of the neuraxis (intrinsic cardiac nervous system, extracardiac‐intrathoracic ganglia, spinal cord, brain stem, and higher centers), is required for the fine efferent cardiomotor control via the sympathetic and parasympathetic nerves. These reflex feedback loops provide precise regulation of sympathetic–parasympathetic balance in the heart under normal conditions and during periods of increased physiological demands for a higher cardiac output. This system plays a crucial role in the pathophysiology and progression of heart disease (heart failure and arrhythmias that lead to sudden cardiac death). Short term adaptations seen after cardiac injury become maladaptive in the intermediate and long term resulting in adverse outcomes. There is structural and functional remodeling of the neural structures that control the heart following cardiac injury. There are multiple avenues for cardiac neuromodulation and some of these approaches are now being utilized in specialized centers. Several recent advances in scientific methods have improved our understanding the cellular and molecular processes involved in innervation and the functional control of the myocardium in health and disease. This knowledge is strengthening the mechanistic framework to develop targeted neuraxial therapies for preventing cardiac disease progression and sudden cardiac death.

Support or Funding Information

R01HL084261, OT2OD023848

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Neuro‐immune Mechanisms and Pulmonary Fibrosis
Authors: Yu Jerry , Deng Zhong‐bing , Roman Jesse
Published: June 2021

Pulmonary neuroendocrine cells are widely distributed throughout the airway mucosa of mammals. They may exist as solitary cells or aggregate to form neuro‐epithelial bodies (NEBs), which are implicated in lung development and response to tissue injury. Pulmonary fibrosis (PF) is a devastating disease thought to be caused by various pulmonary injuries. Repair after injury is a complex process that involves interactions amongst a network of players including soluble mediators such as cytokines and growth factors produced by inflammatory, endothelial, and epithelial cells. Interestingly, NEBs are connected with the vagus nerve, which in turn is related to each component of this network. We have shown that disrupting the NEB‐Vagal System (NVS) by vagotomy decreases TGF‐β and IL‐4 production, reduces the number of myofibroblasts and M2 macrophages, and ameliorates collagen deposition in lung tissue after bleomycin‐induced lung injury. More recently, we hypothesized that lung injury may activate the NVS and polarize T help (Th) cells and macrophages (M) toward fibrogenic phenotypes (altered balance of Th2/Th1 cells and M2/M1 macrophages), thereby promoting PF. Using the bleomycin‐induced lung injury model (i.v.), we assessed the role of neuro‐immune mechanisms in PF by comparing innervated and denervated lungs in mice subjected to unilateral vagotomy. Using immune‐histochemical staining of whole mount tissues, we found that NEBs in the trachea‐bronchial tree increased significantly after bleomycin, but this was ameliorated in denervated lungs. FACS analysis revealed an increase in CD11b+ and CD4+ three weeks after bleomycin, while the numbers of CD11b+ cells were the same in innervated and denervated lungs. CD4+ cells, on the other hand, were increased in innervated lungs. T regulatory (Treg) cells were increased in the vagotomized lung when compared to the intact lung. Of note, bleomycin increased production of bombesin, which is contained in NEB and is known to promote fibroblast transdifferentiation into myofibroblasts. Further studies performed in vitro suggest that bombesin and 5‐HT increase the M2/M1 ratio. Together, our data suggest that lung injury activates NVS, which stimulates a Th2 response and decreases suppressor Treg cells, thereby promoting PF.

Support or Funding Information

Pulmonary Fibrosis Foundation and VA Merit Review Award PULM‐024‐17S

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Simultaneous Measurement of Hypothalamic Paraventricular Nucleus Neuronal and Sympathetic Nerve Activity in Freely Moving Rats
Authors: Ikegame Shizuka , Yoshimoto Misa , Miki Kenju
Published: June 2021

The hypothalamic paraventricular nucleus (PVN) plays important role in regulation of sympathetic nerve activity (SNA). Studies have reported that the PVN projects directly to the sympathetic preganglionic neurons of the spinal cord and pre‐sympathetic motor neurons of the rostral ventrolateral medulla. However, to our knowledge, simultaneous measurement of PVN neuronal activity (PVNNA) and SNA in freely moving animals has not been reported. Thus, the functional relationship between PVNNA and SNA remains unclear. The aim of the present study was to establish a method for simultaneous and continuous measurement of PVNNA and SNA in freely moving rats. Male Wistar rats were chronically instrumented with multiple electrodes (100‐μm stainless steel wire) for measurement of PVNNA, renal SNA (RSNA), electroencephalogram, electromyogram, and electrocardiogram, and with a catheter for measurement of arterial pressure (AP). PVNNA and RSNA were measured continuously in rats during daily activity and in response to air jet stress. We found that PVNNA changed in a behavioral‐dependent manner. Rapid eye movement sleep increased PVNNA, LSNA, and mean AP, but decreased RSNA and heart rate. In addition, PVN, RSNA, mean AP, and heart rate increased in response to air jet stress. These data suggest that the functional relationship between PVNNA, RSNA, and LSNA is altered depending on changes in physiological conditions.

Support or Funding Information

JSPS Grant

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sensitization of the Cardiac Sympathetic Afferent Reflex Contributes to Increased Sympathetic Tone in a Mouse Model of Hypertrophic Cardiomyopathy
Authors: Larson Robert A , Lu Yongjun , Benson Christopher J , Chapleau Mark W
Published: June 2021

Familial hypertrophic cardiomyopathy (HCM), the most common genetic heart disease, results in cardiac hypertrophy, myocyte disarray, fibrosis, and increased risk of arrhythmias and sudden death. Humans with HCM exhibit increased cardiac sympathetic tone in the absence of heart failure, but the mechanism is poorly understood. We previously reported a selective increase in sympathetic tone to the heart in mice with cardiac‐specific expression of mutated alpha‐tropomyosin (Glu180Gly), an established model of HCM. In this study, using the same mouse model, we tested the hypothesis that cardiac spinal (‘sympathetic’) afferents are sensitized by metabolites produced in the HCM heart, resulting in an enhanced cardiac sympathetic afferent reflex (CSAR). The CSAR was assessed by measuring heart rate (HR) and mean arterial pressure (MAP) responses to epicardial application of the TRPV1 agonist capsaicin (2.5mM, 2μL) to the left ventricle (LV) in anesthetized, ventilated HCM (n=5) and wild‐type (WT) littermate control (n=5) mice. HR (HCM +33±10 bpm vs. WT +8±2 bpm) and MAP (HCM +19±2 mmHg vs. WT +9±3 mmHg) responses to capsaicin were markedly enhanced in HCM mice (p<0.05). Pretreatment with the ganglionic blocker hexamethonium (30μg/g, IV) abolished HR (+3±1 bpm) and MAP (+3±2 mmHg) responses to capsaicin in HCM mice (n=3) indicating that the responses were reflex mediated. Inhibiting the activity of endogenously‐active cardiac afferents by application of the local anesthetic lidocaine (2%) to LV epicardium decreased HR markedly in HCM mice (−42±5 bpm, n=5, p<0.05), with no effect in WT (+2±1 bpm, n=5). We considered the possibility that increases in cardiac and vascular responsiveness to sympathetic activation may have contributed to the enhanced reflex HR and MAP responses to epicardial capsaicin in HCM mice. Tachycardic responses to the β‐receptor agonist isoproterenol (500pg/g, IV) and pressor responses to the α‐receptor agonist phenylephrine (60ng/g, IV) were attenuated (p<0.01), not enhanced in HCM mice (n=4 per group). Thus, capsaicin‐induced reflex increases in HR and MAP were enhanced in HCM mice despite decreases in end‐organ responsiveness. To explore the mechanism of the enhanced CSAR in HCM mice, we measured mRNA expression (qPCR) of acid‐sensing ion channel 3 (ASIC3) in dorsal root ganglia (T1–T9), and found that expression increased by 2‐fold in HCM vs. WT mice (n=6 each, P<0.05). We conclude that the CSAR is enhanced in HCM mice, and speculate that acid‐induced sensitization of cardiac ‘sympathetic’ afferents contributes to increased efferent sympathetic activity, arrhythmias and disease progression in HCM.

Support or Funding Information

NIH HL14388, F32HL140880, T32HL007121, AAS‐Lundbeck Fellowship

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Baroreflex Control of Heart Rate is Impaired in Patients with Peripheral Arterial Disease
Authors: Cui Jian , Kuroki Marcos T. , Leiter Timothy , Gao Zhaohui , Kim Danielle Jin‐Kwang , Blaha Cheryl , Pai Sam , Sinoway Lawrence I.
Published: June 2021

Prior reports suggest that exercise pressor reflex is heightened in peripheral arterial disease (PAD). It is unclear if PAD alters the baroreflex. We hypothesized that the sensitivity of baroreflex (BRS) control of heart rate (HR) in PAD patients would be lower than that in healthy control subjects. We studied 12 PAD patients (8 M, 4 F, 66 ± 2 yrs), and 10 healthy control subjects (7 M, 3 F, 65 ± 2 yrs). The ankle‐brachial pressure index in the most affected leg in the patients was 0.64 ± 0.03. ECG and beat‐by‐beat blood pressure (BP, Finometer) were recorded for 10 min under resting condition. Thereafter, the subjects performed rhythmic plantar flexion with incremental loading (2–12 kg, +1 kg/min) until the subject reached fatigue or exercised for a maximum of 14 min. The PAD patients performed the exercise with the most affected leg. The cardiac BRS was estimated with the sequence technique. The HR variability (HRV) indices were also calculated. Under resting conditions, cardiac BRS in PAD patents was significantly lower than that in the control subjects (5.5 ± 0.7 vs. 12.0 ± 2.3 ms/mmHg, P=0.008). The resting time domain HRV in PAD patents was also lower than in healthy subjects. Plantar flexion exercise induced BP response was greater at end exercise in PAD patients than that in healthy control subjects. Interestingly, plantar flexion exercise tended to decrease cardiac BRS in healthy subjects, whereas it tended to increase cardiac BRS in PAD patients. The plantar flexion exercise decreased the time domain HRV index (last 5 min) in the both groups. We speculate that the decreased cardiac BRS as well as the attenuated vagal tone (i.e. lower HRV) indicate that autonomic function is impaired in PAD. Further studies are needed to examine if exercise training in PAD alters the baroreflex function.

Support or Funding Information

Supported by National Institutes of Health Grants P01 HL134609 (Sinoway), UL1 TR002014 (Sinoway), and Pennsylvania Department of Health Tobacco CURE Funds SAP#4100079742 (Cui).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Different forms of afferent nerve input in cardiac and renal disease in rats?
Authors: Rodionova Kristina , Hindermann Martin , Ditting Tilmann , Pickny Lisa , Loosen Sonja , Ott Christian , Schmieder Roland , Amann Kerstin , Veelken Roland
Published: June 2021

Introduction

In a renal disease model (anti‐Thy 1.1 nephropathy) the responsiveness of afferent renal nerve units was shifted from units with highly active primary neurons (tonic response pattern) to units with neurons of very low activity upon stimulation (phasic response pattern). Afferent renal nerve activity was likely decreased. Likewise, afferent vagal nerve activity in congestive heart failure had a lower frequency at saturation than controls. Hence we wanted to test the hypothesis that in congestive heart failure (CHF) the vagal afferent nerve pathway consists of a decreased number of highly active tonic sensory neurons in the nodose ganglion as compared to controls.

Material and Methods

CHF was induced by coronary artery ligature, nephropathy by injections of an anti Thy1.1 antibody (OX7, 1.2mg/kg). After a respective time (CHF 21 days, nephropathy 7 days after induction) nodose ganglion neurons with cardiac vagal afferents from CHF rats or neurons form dorsal root ganglia with renal afferents from rats with nephropathy (as well as controls) were cultured. Current clamp was used to characterize neurons as “tonic”, i.e. sustained action potential (AP) firing or “phasic”, i.e. <5 APs upon current injection. Electrophysiological parameters and AP properties were determined in neurons from animals with CHF or nephropathy and compared to controls.

Results

More than 100 neurons were investigated. In CHF rats, the number of neurons with a tonic, more active response pattern from CHF animals did not differ from controls (64% vs. 70 %, ns). However, tonic cardiac neurons from CHF rats exhibited an increased production of action potentials compared to controls (24.4+/−5.0 vs. 14.7+/−1.8 APs/10s; p<0.05; mean+/− SEM). In nephropathic rats, the number of neurons with a tonic, more active response pattern decreased significantly (43% vs. 64 %, p<0.05) as compared to controls, but there was no difference in action potential production between nephropathic rats and controls.

Conclusion

In contrast to our hypothesis, in congestive heart failure the number of afferent neurons with a tonic response pattern was not significantly altered. However, the action potential production of these neurons even significantly increased upon stimulation. Hence, in congestive heart failure vagal afferent neurons increase their sensitivity in the presence of impaired intracardiac receptors whereas in renal disease the responsiveness of the first part of the afferent pathway is impaired as a whole.

Support or Funding Information

DFG, German Research Foundation Interdisciplinary Center for Clinical Research ‐ University of Erlangen, Erlangen, Germany

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Impact of shifting epithelial Na+ transport on renal medullary oxygen tension: Modeling and analysis
Authors: Akhter Tahmina , Layton Anita
Published: June 2021

The mammalian kidney is particularly vulnerable to hypoperfusion, because O2 supply to the renal medulla barely exceeds its O2 requirements. Renal O2 consumption is mainly driven by the metabolic work of tubular Na+ reabsorption. In this study, we examined the impact of shifting the Na+ transport site on medullary oxygen tension (PO2) of the rat kidney. To accomplish that goal, we extended our published model of renal epithelial transport to include renal vasculature and to simulate the crosstalk among nephron segments and vasculature. The model represents the complex structural organization of the medulla, which is believed to have a significant impact on medullary O2 distribution. The transport of red blood cells, hemoglobin, and O2 was explicitly represented. We considered basal cellular O2 consumption and O2 consumption for Na+/K+‐ATPase‐mediated transport. Our model predicts that the structural organization of the outer medulla results in significant Po2 gradients in the axial and radial directions. The segregation of descending vasa recta, the main supply of O2, at the center and immediate periphery of the vascular bundles gives rise to large radial differences in Po2, limits O2 reabsorption from long descending vasa recta, and helps preserve O2 delivery to the inner medulla. When Na+ delivery to the S3 and thick ascending limb segments is elevated (e.g., by pharmacological manipulation), local interstitial PO2 may decrease significantly, a result that indicates elevated risk of hypoxia.

Support or Funding Information

This research was supported by the Canada 150 Research Chair program and by the National Institutes of Health: National Institute of Diabetes and Digestive and Kidney Diseases, grant R01DK106102.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Renal vasodilation induced by Glucagon‐like peptide‐1 is mediated only by the known receptor
Authors: Sorensen Charlotte Mehlin , Jensen Elisa Pouline , Hviid Aleksander Vauvert , Moller Sophie
Published: June 2021

Glucagon‐like peptide‐1 (GLP‐1) stimulates insulin release after a meal. The GLP‐1 receptor is found in many tissues including the renal vasculature. GLP‐1 increases renal blood flow (RBF) and glomerular filtration rate by inducing a renal vasodilation. The GLP‐1 receptor knock‐out (KO) mouse has increased glomerular filtration rate (GFR) suggesting a dilation of the afferent arteriole. Moreover, GLP‐1 elicits a vasodilation in mesenteric arteries from the GLP‐1 receptor KO mouse suggesting that GLP‐1 can induce vasodilation through other mechanisms that by the known receptor. Also, the metabolite of GLP‐1 (GLP‐1(9–36)) has been suggested to have vasodilatory effects.

Using wire‐myography and isolated segmental arteries from GLP‐1 receptor KO and wild‐type (WT) mice we show that GLP‐1 only elicits renal vasodilation via the known receptor and not by any indirect pathways. In preconstricted segmental arteries GLP‐1 induces a vasodilation that can be inhibited by exendin(9–39) (a GLP‐1 receptor antagonist). Also, GLP‐1(9–36) has no vasodilatory effect on isolated renal vessels from WT and KO showing that in the renal vasculature the metabolite has no effect either directly on the GLP‐1 receptor or through any other pathway.

In the isolated juxtamedullary nephron preparation the autoregulatory response in afferent arterioles measured during acute pressure increases in isolated kidneys from WT and GLP‐1 receptor KO mice is normal. This indicates that the pre‐glomerular vasculature in the kidney is not affected functionally by the loss of the GLP‐1 receptor. GLP‐1 only attenuates the autoregulatory response in afferent arterioles from WT mice showing that also in afferent arterioles there is no alternative signaling pathway. GLP‐1 primarily attenuates the myogenic response and not the tubuloglomerular feedback (TGF).

Using pressure myography we show that GLP‐1 reduces the myogenic response in WT segmental arteries but has no effect in the GLP‐1 receptor KO vessels. GLP‐1 increases the diameter of WT segmental arteries but a further diameter increase is still found during passive conditions (Ca2+ free media) suggesting that GLP‐1 dose not completely remove all vascular tension.

Conclusion

The renal vascular effects of GLP‐1 are elicited only via the known GLP‐1 receptor. The metabolite GLP‐1(9–36) has no effect on the renal GLP‐1 receptor or through alternative pathways. Afferent arterioles and segmental arteries from GLP‐1 receptor KO mice respond normally to acute pressure increases.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Radiofrequency Renal Denervation Prevents Further Progression of Hypertension and Decreases Renal Medullary Fibrosis in One‐year‐old Spontaneously Hypertensive Rats (SHR)
Authors: Gao Juan , Denys Ian , Sutphen Jane , Del Valle Luis , Kapusta Daniel R
Published: June 2021

We have reported that radiofrequency renal denervation (RF‐RDN) in SHR at 20‐weeks of age, decreased blood pressure (BP) and fibrosis in kidney cortex and medulla when rats were sacrificed at 6 months. However, whether RF‐RDN can have similar benefits in older rats remains unknown. This study examined whether performing RF‐RDN in older rats also has a beneficial effect on BP and renal fibrosis. Baseline systolic and diastolic BP (SBP/DPB) was measured (telemetry) in nine‐month‐old SHR and Wistar Kyoto rats (WKY). Groups of rats then received bilateral RF‐RDN or Sham‐RDN (SHR‐RDN, n=9; SHR‐Sham, n=10; WKY‐RDN, n=5; WKY‐Sham, n=8). Rats were then sacrificed at 12‐months of age. Kidneys were harvested, sectioned, and assessed for fibrosis by Masson's trichrome stain. A pathologist, who was blinded to treatment groups, evaluated each kidney section for fibrosis. Compared to SHR with Sham‐RDN, RF‐RDN prevented a further increase in systolic and diastolic BP from baseline (9‐month) in SHR as they aged to 12‐months (SHR‐Sham mmHg: 9‐month 193±4/127±4; 12‐month 207±3/142±5; SHR‐RDN mmHg: 9‐month 197±3/132±2; 12‐month 197±4/132±3). RF‐RDN did not alter SBP or DBP in aged WKY. One‐year‐old SHR with prior Sham‐RDN showed extensive renal fibrosis in kidney cortex and medulla. In contrast, RF‐RDN significantly decreased renal fibrosis in the medulla, but not cortex. There was no fibrosis in kidneys of age matched WKY. These findings suggest that RF‐RDN may be a potential therapy for halting progression of hypertension and decreasing medullary fibrosis in the aged population.

Support or Funding Information

NIGMS of NIH U54 GM104940 LA CaTS Roadmap Scholar to JG. NIH P30GM106392 to DRK and JG.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
AVP‐ANP Signaling Axis in Salt‐Sensitive Hypertension
Authors: Polina Iuliia , Kurashkina Elizaveta , Sultanova Regina , Domondon Mark , Bankir Lise , Staruschenko Alexander , Ilatovskaya Daria
Published: June 2021

High salt (HS) diet in salt‐sensitive (SS) individuals leads to development of hypertension and associated renal complications. Atrial natriuretic peptide (ANP) is proposed to attenuate SS hypertension by improving sodium and water excretion, thus lowering blood pressure (BP). Intriguingly, both the ANP receptor and the vasopressin‐dependent urea transporter UT‐A1 are abundantly expressed in the terminal collecting duct (CD). This segment is a major site of urea reabsorption and accumulation, and a key player in the urine concentrating mechanism. We hypothesized that ANP and vasopressin (AVP) may exert coordinated effects on salt, urea and water transport in the terminal inner medullary CD. To test this hypothesis, we compared wild type (WT) Dahl Salt Sensitive (SSWT) rats to SS rats lacking the Nppa gene which encodes for ANP (SSNppa−/−). The rats were fed either a high salt (HS, 4% NaCl) or a low salt (LS, 0.4% NaCl) diet for 21 days (Dyets, Inc). BP was monitored throughout the study using telemetry, and 24 hour urine samples were collected in metabolic cages on days 0 and 21 of the salt challenge. At the end of the protocol, rats were euthanized, kidneys and plasma samples were harvested.

SSNppa−/− rats fed a HS diet exhibited severely elevated BP and attenuated diuresis (11.3 ± 0.7 vs 3.9 ± 0.9 mL per day) compared to SSWT controls. Urinary osmoles excretion was reduced SSNppa−/− rats on a HS diet. ELISA assay revealed that 24h urea excretion was significantly lower in SSNppa−/− rats on HS diet (87 ± 12 vs 139 ± 8 mg per 100 g of body weight in SSWT; p=0.003). These data suggest that SSNppa−/− rats have lower urine concentrating ability on HS diet compared to SSWT. Expression of AVP receptors (AVP2R) in the renal tissue was significantly reduced in SSNppa−/− on both diets compared to SSWT controls as shown by Western blot analysis, and further confirmed in immunohistochemical staining for both cortical and medullary CDs. However, we did not find statistically significant difference in urinary copeptin level (used as a surrogate marker for AVP) between SSWT and SSNppa−/− rats on LS diet (10.0 ± 2.8 pg/mL; vs 8.9 ± 0.8 pg/mL, respectively). CDs of SSNppa−/− rats fed a HS diet demonstrated a dramatically increased expression of AQP2 channels compared to SSWT, which did not differ in LS‐diet fed groups. Understanding ANP/AVP signaling axis and interaction with respect to water and sodium transport in the CDs can help us find new targets for medications to best compromise between efficient natriuresis and urine concentrating ability.

Support or Funding Information

Supported by NIH.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Salt Loading Effects on ENaC and Blood Pressure in Aged 129Sv Mice
Authors: Schramm Whitney C. , Malik Zeeshan S. , Liu Lauren P. , Chacko Kevin M. , Alli Abdel A.
Published: June 2021

Essential hypertension in the elderly population is a major public health problem because these patients usually do not respond well to antihypertensive drugs. More than half the cases of essential hypertension are thought to be associated with salt sensitivity from excessive dietary salt intake. We hypothesized that salt loading augments renal epithelial sodium channel expression and blood pressure in aged 129Sv mice. The renal epithelial sodium channel regulates total body salt balance and blood pressure, but mechanisms for its regulation by dietary salt intake in the aged kidney are not completely known. Twelve month old 129Sv mice were subject to salt loading for 4 weeks. Water intake, urine production, blood pressure, and electrolytes in the urine were measured before and after salt loading. Both the total and cleaved forms of ENaC subunits were assessed by Western blotting and densitometric analysis. ENaC alpha protein was augmented in the kidneys of salt‐loaded hypertensive 129Sv mice compared to non‐salt loaded mice. Water intake, urine output, and systolic blood pressure significantly increased in the 129Sv mice after salt‐loading. Salt loading resulted in an increase in urinary sodium levels and a decrease in urinary potassium levels. These findings may provide new links between salt‐sensitivity, ENaC expression, and blood pressure regulation in the aged kidney.

Support or Funding Information

This project was funded by the U.S. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (Grant K01 DK099617; to A.A.A.) and the University of Florida College of Medicine.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.