bluuebunny/crossref_metadata_2025_split huggingface dataset:
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 InformationR01HL084261, OT2OD023848This 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 InformationPulmonary Fibrosis Foundation and VA Merit Review Award PULM‐024‐17SThis 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 InformationJSPS GrantThis 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 InformationNIH HL14388, F32HL140880, T32HL007121, AAS‐Lundbeck FellowshipThis 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 InformationSupported 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

IntroductionIn 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 MethodsCHF 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.ResultsMore 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.ConclusionIn 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 InformationDFG, German Research Foundation Interdisciplinary Center for Clinical Research ‐ University of Erlangen, Erlangen, GermanyThis 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 InformationThis 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.ConclusionThe 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 InformationNIGMS 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.