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Zhang J, Zhao X, Zhang L, Lu J, Bai J, An S, Zhu Y, Zhang H, Hao Y, Tian Y. Microbiota-derived acetate suppresses sympathetic outflow via olfactory receptor 59 in the rostral ventrolateral medulla. Pharmacol Res 2025; 216:107766. [PMID: 40345351 DOI: 10.1016/j.phrs.2025.107766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 05/04/2025] [Accepted: 05/06/2025] [Indexed: 05/11/2025]
Abstract
BACKGROUND Dysbiosis of gut microbiota is closely associated with the development of hypertension, yet the underlying mechanism remains unclear. In this study, we aimed to elucidate the molecular mechanisms through which microbiota-derived acetate regulates sympathetic activity and arterial blood pressure (ABP). Bulk RNA sequencing was used to determine the expression of short-chain fatty acids receptors in the rostral ventrolateral medulla (RVLM). We examined the influence of olfactory receptor 59 (Olr59) on renal sympathetic nerve activity (RSNA) and ABP in anesthetized rats. The effect of Olr59 on the excitability of RVLM neurons was assessed through calcium imaging. Moreover, the 24-hour ambulatory blood pressure of conscious rats was recorded using radiotelemetry. The RNA sequencing results indicated that Olr59 was the most highly expressed short-chain fatty acids receptor in the rat RVLM and was upregulated in spontaneously hypertensive rats (SHR). Injection of the Olr59 agonist acetate or β-ionone into the RVLM reduced ABP and RSNA. However, administration of Olr59 antagonist or the knockdown of Olr59 in RVLM neurons did not significantly alter ABP, but it counteracted the hypotensive effect of acetate within the RVLM. Application of acetate or β-ionone to isolated brain slices mainly inhibited calcium signal in spinally-projecting RVLM neurons. Furthermore, overexpression of Olr59 in RVLM neurons via adeno-associated virus reduced ABP in SHR. Microbiota-derived acetate inhibits sympathetic activity and decreases blood pressure via Olr59 in the RVLM. Thus, Olr59 represents a promising new target for the treatment of hypertension.
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Affiliation(s)
- Jinye Zhang
- Department of Neurobiology, Hebei Medical University, Shijiazhuang 050017, China
| | - Xue Zhao
- Department of Neurobiology, Hebei Medical University, Shijiazhuang 050017, China
| | - Lin Zhang
- Department of Neurobiology, Hebei Medical University, Shijiazhuang 050017, China
| | - Jinmeng Lu
- Department of Neurobiology, Hebei Medical University, Shijiazhuang 050017, China
| | - Jinlu Bai
- Department of Neurobiology, Hebei Medical University, Shijiazhuang 050017, China
| | - Shuo An
- Department of Neurobiology, Hebei Medical University, Shijiazhuang 050017, China
| | - Yufang Zhu
- College of Nursing, Hebei Medical University, Shijiazhuang 050017, China
| | - Huaxing Zhang
- Core Facilities and Centers, Hebei Medical University, Shijiazhuang 050017, China
| | - Yinchao Hao
- Functional Laboratory, Experimental Center for Teaching, Hebei Medical University, Shijiazhuang 050017, China.
| | - Yanming Tian
- Department of Neurobiology, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key Laboratory of Neurophysiology, Shijiazhuang 050017, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China.
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Estrada JA, Hori A, Fukazawa A, Ishizawa R, Hotta N, Kim HK, Smith SA, Mizuno M. Abnormal cardiovascular control during exercise: Role of insulin resistance in the brain. Auton Neurosci 2025; 258:103239. [PMID: 39874739 DOI: 10.1016/j.autneu.2025.103239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 12/19/2024] [Accepted: 01/13/2025] [Indexed: 01/30/2025]
Abstract
During exercise circulatory adjustments to meet oxygen demands are mediated by multiple autonomic mechanisms, the skeletal muscle exercise pressor reflex (EPR), the baroreflex (BR), and by feedforward signals from central command neurons in higher brain centers. Insulin resistance in peripheral tissues includes sensitization of skeletal muscle afferents by hyperinsulinemia which is in part responsible for the abnormally heightened EPR function observed in diabetic animal models and patients. However, the role of insulin signaling within the central nervous system (CNS) is receiving increased attention as a potential therapeutic intervention in diseases with underlying insulin resistance. This review will highlight recent advances in our understanding of how insulin resistance induces changes in central signaling. The alterations in central insulin signaling produce aberrant cardiovascular responses to exercise. In particular, we will discuss the role of insulin signaling within the medullary cardiovascular control nuclei. The nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM) are key nuclei where insulin has been demonstrated to modulate cardiovascular reflexes. The first locus of integration for the EPR, BR and central command is the NTS which is high in neurons expressing insulin receptors (IRs). The IRs on these neurons are well positioned to modulate cardiovascular responses to exercise. Additionally, the differences in IR density and presence of receptor isoforms enable specificity and diversity of insulin actions within the CNS. Therefore, non-invasive delivery of insulin into the CNS may be an effective means of normalizing cardiovascular responses to exercise in patients with insulin resistance.
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Affiliation(s)
- Juan A Estrada
- Departments of Applied Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Amane Hori
- Departments of Applied Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Japan Society for the Promotion of Science, Tokyo 102-0083, Japan; College of Life and Health Sciences, Chubu University, Kasugai 487-8501, Japan
| | - Ayumi Fukazawa
- Departments of Applied Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Japan Society for the Promotion of Science, Tokyo 102-0083, Japan
| | - Rie Ishizawa
- Faculty of Sports and Life Science, National Institute of Fitness and Sports in KANOYA, Kagoshima 891-2393, Japan
| | - Norio Hotta
- College of Life and Health Sciences, Chubu University, Kasugai 487-8501, Japan
| | - Han-Kyul Kim
- Departments of Applied Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Scott A Smith
- Departments of Applied Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Masaki Mizuno
- Departments of Applied Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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Kobayashi T, Pham LT, Kobayashi M, Yamanaka K, Itakura A, Waki H. Inhibitory effect of exercise on elevated blood pressure and fetal growth restriction during pregnancy in Dahl salt-sensitive rats. Physiol Rep 2025; 13:e70298. [PMID: 40205775 PMCID: PMC11982524 DOI: 10.14814/phy2.70298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 03/17/2025] [Accepted: 03/19/2025] [Indexed: 04/11/2025] Open
Abstract
Exercise is effective in preventing gestational hypertension, but its mechanism remains unclear. This study investigates the effects of exercise on Dahl salt-sensitive (DSS) rats, which develop elevated blood pressure and fetal growth restriction during pregnancy. DSS rats were divided into exercise and non-exercise groups, with Sprague-Dawley rats as controls. Exercise consisted of voluntary running, starting 4 weeks prior to pregnancy until the last trimester. Cardiovascular parameters, molecular characteristics of the brain and placenta, and fetal conditions were evaluated. Exercise significantly improved elevated blood pressure at early pregnancy and was associated with improved baroreceptor reflex gain. Gene expression analysis in the rostral ventrolateral medulla (RVLM) showed exercise-induced downregulation of nitric oxide synthase and upregulation of superoxide dismutase. These genetic changes suggest that exercise impacts circulatory regulation mechanisms, contributing to blood pressure improvement. In addition, placental analysis revealed a marked increase in placental growth factor expression due to exercise. In conclusion, exercise alleviates elevated blood pressure at early gestation and fetal growth restriction in DSS rats. Genetic modifications in the RVLM may play a critical role in exercise-induced cardiovascular improvements. This study highlights the potential of exercise as a therapeutic approach for managing gestational elevated blood pressure and fetal growth restriction and provides insights into its underlying mechanisms.
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Affiliation(s)
- Toru Kobayashi
- Department of Obstetrics and GynecologyJuntendo UniversityTokyoJapan
- Department of Obstetrics and Gynecology, Graduate School of MedicineJuntendo UniversityTokyoJapan
- Department of Physiology, Graduate School of Health and Sports ScienceJuntendo UniversityChibaJapan
| | - Linh Thuy Pham
- Institute of Health and Sports Science & MedicineJuntendo UniversityChibaJapan
| | - Mutsumi Kobayashi
- Department of Obstetrics and GynecologyJuntendo UniversityTokyoJapan
| | - Ko Yamanaka
- Department of Physiology, Graduate School of Health and Sports ScienceJuntendo UniversityChibaJapan
| | - Atsuo Itakura
- Department of Obstetrics and GynecologyJuntendo UniversityTokyoJapan
| | - Hidefumi Waki
- Department of Physiology, Graduate School of Health and Sports ScienceJuntendo UniversityChibaJapan
- Institute of Health and Sports Science & MedicineJuntendo UniversityChibaJapan
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Brown CR, Shetty M, Foster JD. Palmitoylation regulates norepinephrine transporter uptake, surface localization, and total expression with pathogenic implications in postural orthostatic tachycardia syndrome. J Neurochem 2025; 169:e16241. [PMID: 39395208 PMCID: PMC11808474 DOI: 10.1111/jnc.16241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 09/21/2024] [Accepted: 09/24/2024] [Indexed: 10/14/2024]
Abstract
Postural orthostatic tachycardia syndrome (POTS) is an adrenergic signaling disorder characterized by excessive plasma norepinephrine, postural tachycardia, and syncope. The norepinephrine transporter (NET) modulates adrenergic homeostasis via the reuptake of extracellular catecholamines and is implicated in the pathogenesis of adrenergic and neurological disorders. In this study, we reveal NET is palmitoylated in male Sprague-Dawley rats and Lilly Laboratory Cell Porcine Kidney (LLC-PK1) cells. S-palmitoylation, or the addition of a 16-carbon saturated fatty acid, is a reversible post-translational modification responsible for the regulation of numerous biological mechanisms. We found that LLC-PK1 NET is dynamically palmitoylated, and that inhibition with the palmitoyl acyltransferase (DHHC) inhibitor, 2-bromopalmitate (2BP) results in decreased NET palmitoylation within 90 min of treatment. This result was followed closely by a reduction in transport capacity, cell surface, and total cellular NET expression after 120 min of treatment. Increasing 2BP concentrations and treatment time revealed a nearly complete loss of total NET protein. Co-expression with individual DHHCs revealed a single DHHC enzyme, DHHC1, promoted wild-type (WT) hNET palmitoylation and elevated NET protein levels. The POTS-associated NET mutant, A457P, exhibits dramatically decreased transport capacity and cell surface levels which we have confirmed in the current study. In an attempt to recover A457P NET expression, we co-expressed the A457P variant with DHHC1 to drive expression as seen with the WT protein but instead saw an increase in NET N-terminal immuno-detectable forms and fragments. Elimination of a potential palmitoylation site at cysteine 44 in the N-terminal tail of hNET resulted in a low expression phenotype mimicking the A457P hNET variant. Further investigation of A457P NET palmitoylation and surface expression is necessary, but our preliminary novel findings reveal palmitoylation as a mechanism of NET regulation and suggest that dysregulation of this process may contribute to the pathogenesis of adrenergic disorders like POTS.
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Affiliation(s)
- Christopher R. Brown
- Department of Biomedical SciencesUniversity of North Dakota School of Medicine and Health SciencesGrand ForksNorth DakotaUSA
| | - Madhur Shetty
- Department of Biomedical SciencesUniversity of North Dakota School of Medicine and Health SciencesGrand ForksNorth DakotaUSA
| | - James D. Foster
- Department of Biomedical SciencesUniversity of North Dakota School of Medicine and Health SciencesGrand ForksNorth DakotaUSA
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5
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Schmidt E, Krauss JK. Treatment of iNPH: novel insights. J Neurosurg Sci 2025; 69:79-91. [PMID: 40045806 DOI: 10.23736/s0390-5616.24.06360-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2025]
Abstract
This review advocates for a shift from traditional symptom-based diagnosis of idiopathic normal pressure hydrocephalus (iNPH) to a deeper investigation into its underlying pathophysiological mechanisms, particularly the role of altered cerebral hydrodynamics as an important pathological hallmark. We explore the heterogeneity of iNPH, emphasizing its frequent overlap and cooccurrence with neurodegenerative conditions like Alzheimer and Parkinson disease, and subcortical vascular encephalopathy, complicating diagnosis and treatment strategies. The lumbar infusion test emerges as a useful diagnostic tool, offering quantitative insights into CSF outflow resistance that should be considered as a useful biomarker related to cerebral hydrodynamics and iNPH pathophysiology. Furthermore, we propose the hypothesis that shunt placement, by regulating brain fluid mechanics, may also serve as a form of neuromodulation, potentially enhancing neuronal function and mitigating clinical symptoms. This review advocates for an interdisciplinary, physics-based and patient-centered approach that emphasizes early detection, accurate diagnostics, and personalized treatment plans to enhance patient outcomes and quality of life, particularly in the aging population.
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Affiliation(s)
- Eric Schmidt
- Department of Neurosurgery, Toulouse University Hospital, Toulouse, France -
| | - Joachim K Krauss
- Department of Neurosurgery, Hannover Medical School, Hannover, Germany
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Dimartino P, Zadorozhna M, Yumiceba V, Basile A, Cani I, Melo US, Henck J, Breur M, Tonon C, Lodi R, Brusco A, Pippucci T, Koufi FD, Boschetti E, Ramazzotti G, Manzoli L, Ratti S, Pinto E Vairo F, Delatycki MB, Vaula G, Cortelli P, Bugiani M, Spielmann M, Giorgio E. Structural Variants at the LMNB1 Locus: Deciphering Pathomechanisms in Autosomal Dominant Adult-Onset Demyelinating Leukodystrophy. Ann Neurol 2024; 96:855-870. [PMID: 39078102 DOI: 10.1002/ana.27038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 07/10/2024] [Accepted: 07/10/2024] [Indexed: 07/31/2024]
Abstract
OBJECTIVE We aimed to elucidate the pathogenic mechanisms underlying autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), and to understand the genotype/phenotype correlation of structural variants (SVs) in the LMNB1 locus. BACKGROUND Since the discovery of 3D genome architectures and topologically associating domains (TADs), new pathomechanisms have been postulated for SVs, regardless of gene dosage changes. ADLD is a rare genetic disease associated with duplications (classical ADLD) or noncoding deletions (atypical ADLD) in the LMNB1 locus. METHODS High-throughput chromosome conformation capture, RNA sequencing, histopathological analyses of postmortem brain tissues, and clinical and neuroradiological investigations were performed. RESULTS We collected data from >20 families worldwide carrying SVs in the LMNB1 locus and reported strong clinical variability, even among patients carrying duplications of the entire LMNB1 gene, ranging from classical and atypical ADLD to asymptomatic carriers. We showed that patients with classic ADLD always carried intra-TAD duplications, resulting in a simple gene dose gain. Atypical ADLD was caused by LMNB1 forebrain-specific misexpression due to inter-TAD deletions or duplications. The inter-TAD duplication, which extends centromerically and crosses the 2 TAD boundaries, did not cause ADLD. Our results provide evidence that astrocytes are key players in ADLD pathology. INTERPRETATION Our study sheds light on the 3D genome and TAD structural changes associated with SVs in the LMNB1 locus, and shows that a duplication encompassing LMNB1 is not sufficient per se to diagnose ADLD, thereby strongly affecting genetic counseling. Our study supports breaking TADs as an emerging pathogenic mechanism that should be considered when studying brain diseases. ANN NEUROL 2024;96:855-870.
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Affiliation(s)
- Paola Dimartino
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Mariia Zadorozhna
- Neurogenetics Research Center, IRCCS Mondino Foundation, Pavia, Italy
| | - Verónica Yumiceba
- Institute of Human Genetics, Universitätsklinikum Schleswig Holstein, University of Lübeck and University of Kiel, Lübeck, Germany
| | - Anna Basile
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Ilaria Cani
- Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
- Functional and Molecular Neuroimaging Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Uirá Souto Melo
- Max Planck Institute for Molecular Genetics, Human Molecular Genomics Group, Berlin, Germany
- Institute for Medical Genetics and Human Genetics, Charité University Medicine Berlin, Berlin, Germany
| | - Jana Henck
- Max Planck Institute for Molecular Genetics, Human Molecular Genomics Group, Berlin, Germany
| | - Marjolein Breur
- Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Caterina Tonon
- Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
- Functional and Molecular Neuroimaging Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Raffaele Lodi
- Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
- Functional and Molecular Neuroimaging Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Alfredo Brusco
- Department of Neurosciences Rita Levi-Montalcini, University of Turin, Turin, Italy
- Unit of Medical Genetics, Città della Salute e della Scienza University Hospital, Turin, Italy
| | - Tommaso Pippucci
- Medical Genetics Unit, Sant'Orsola-Malpighi University Hospital, Bologna, Italy
| | - Foteini-Dionysia Koufi
- Cellular Signalling Laboratory, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
| | - Elisa Boschetti
- Cellular Signalling Laboratory, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
| | - Giulia Ramazzotti
- Cellular Signalling Laboratory, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
| | - Lucia Manzoli
- Cellular Signalling Laboratory, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
| | - Stefano Ratti
- Cellular Signalling Laboratory, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
| | - Filippo Pinto E Vairo
- Center for Individualized Medicine and Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA
| | - Martin B Delatycki
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia
| | - Giovanna Vaula
- Department of Neuroscience, Azienda Ospedaliera-Universitaria Città della Salute e della Scienza, Turin, Italy
| | - Pietro Cortelli
- Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
- Functional and Molecular Neuroimaging Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Marianna Bugiani
- Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, the Netherlands
- Department of Pathology, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Malte Spielmann
- Institute of Human Genetics, Universitätsklinikum Schleswig Holstein, University of Lübeck and University of Kiel, Lübeck, Germany
- Max Planck Institute for Molecular Genetics, Human Molecular Genomics Group, Berlin, Germany
- Institute of Human Genetics, Universitätsklinikum Schleswig Holstein Campus Kiel and Christian-Albrechts-Universität, Kiel, Germany
| | - Elisa Giorgio
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
- Neurogenetics Research Center, IRCCS Mondino Foundation, Pavia, Italy
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Zaman A, Özçelik H, Yücel E, Su Akkan S, Onsinejad T, Mert Yüksel S, Bülbül M. Effect of sex on chronic stress induced alterations in hindbrain catecholaminergic system and autonomic dysfunction resulting in gastrointestinal dysmotility. Brain Res 2024; 1842:149112. [PMID: 38969083 DOI: 10.1016/j.brainres.2024.149112] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 06/29/2024] [Accepted: 07/02/2024] [Indexed: 07/07/2024]
Abstract
It has been reported that the clinical symptoms of functional dyspepsia (FD) exacerbate upon stress while the gender-related factors have been incompletely understood. This study aims to investigate the role of sex in chronic heterotypic stress (CHS)-induced autonomic and gastric motor dysfunction. For CHS, the rats were exposed to the combination of different stressors for 7 consecutive days. Subsequently, electrocardiography was recorded in anesthetized rats to evaluate heart rate variability (HRV) for the determination of autonomic outflow and sympathovagal balance. Solid gastric emptying (GE) was measured in control and CHS-loaded male and female rats. The immunoreactivities of catecholaminergic cell marker tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), corticotropin releasing factor (CRF), and estrogen receptor (ER-α/β) were evaluated in medullary and pontine brainstem sections by immunohistochemistry. Compared with the controls, CHS significantly delayed GE in males but not in females. There was no significant sex-related difference in parasympathetic indicator HF under either control or CHS conditions. Sympathetic indicator LF was significantly higher in control females compared to the males. The higher sympathetic output in females was found to be attenuated upon CHS; in contrast, the elevated sympathetic output was detected in CHS-loaded males. No sex- or stress-related effect was observed on ChAT immunoreactivity in the dorsal motor nucleus of N.vagus (DMV). In males, greater number of TH-ir cells was observed in the caudal locus coeruleus (LC), while they were more densely detected in the rostral LC of females. Regardless of sex, CHS elevated immunoreactivity of TH throughout the LC. Under basal conditions, greater number of TH-ir cells was detected in the rostral ventrolateral medulla (RVLM) of females. In contrast, CHS remarkably increased the number of TH-ir cells in the RVLM of males which was found to be decreased in females. There was no sex-related alteration in TH immunoreactivity in the nucleus tractus solitarius (NTS) of control rats, while CHS affected both sexes in a similar manner. Compared with females, CRF immunoreactivity was prominently observed in control males, while both of which were stimulated by CHS. ER-α/β was found to be co-expressed with TH in the NTS and LC which exhibit no alteration related to either sex or stress status. These results indicate a sexual dimorphism in the catecholaminergic and the CRF system in brainstem which might be involved in the CHS-induced autonomic and visceral dysfunction occurred in males.
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Affiliation(s)
- Amirali Zaman
- Akdeniz University, Faculty of Medicine, Antalya, Turkey
| | | | - Elif Yücel
- Akdeniz University, Faculty of Medicine, Antalya, Turkey
| | - Simla Su Akkan
- Department of Physiology, Akdeniz University, Faculty of Medicine, Antalya, Turkey
| | - Tanaz Onsinejad
- Department of Physiology, Akdeniz University, Faculty of Medicine, Antalya, Turkey
| | - Sadettin Mert Yüksel
- Department of Physiology, Akdeniz University, Faculty of Medicine, Antalya, Turkey
| | - Mehmet Bülbül
- Department of Physiology, Akdeniz University, Faculty of Medicine, Antalya, Turkey.
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Nagata K, Tagami K, Okuzawa T, Hayakawa M, Nomura A, Nishimura T, Ikeda K, Kitada K, Kobuchi S, Fujisawa Y, Nishiyama A, Murohara T. Comparison of the effects of renal denervation at early or advanced stages of hypertension on cardiac, renal, and adipose tissue pathology in Dahl salt-sensitive rats. Hypertens Res 2024; 47:2731-2744. [PMID: 38355818 PMCID: PMC11456506 DOI: 10.1038/s41440-024-01605-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 12/05/2023] [Accepted: 01/17/2024] [Indexed: 02/16/2024]
Abstract
Renal denervation (RDN) has emerged as a novel therapy for drug-resistant hypertension. We here examined the effects of RDN at early versus advanced stages of hypertension on blood pressure and organ pathology in rats with salt-sensitive hypertension. Dahl salt-sensitive (DahlS) rats fed an 8% NaCl diet from 6 weeks of age were subjected to RDN (surgical ablation and application of 10% phenol in ethanol) or sham surgery at 7 (early stage) or 9 (advanced stage) weeks and were studied at 12 weeks. RDN at early or advanced stages resulted in a moderate lowering of blood pressure. Although RDN at neither stage affected left ventricular (LV) and cardiomyocyte hypertrophy, it ameliorated LV diastolic dysfunction, fibrosis, and inflammation at both stages. Intervention at both stages also attenuated renal injury as well as downregulated the expression of angiotensinogen and angiotensin-converting enzyme (ACE) genes and angiotensin II type 1 receptor protein in the kidney. Furthermore, RDN at both stages inhibited proinflammatory gene expression in adipose tissue. The early intervention reduced both visceral fat mass and adipocyte size in association with downregulation of angiotensinogen and ACE gene expression. In contrast, the late intervention increased fat mass without affecting adipocyte size as well as attenuated angiotensinogen and ACE gene expression. Our results thus indicate that RDN at early or late stages after salt loading moderately alleviated hypertension and substantially ameliorated cardiac and renal injury and adipose tissue inflammation in DahlS rats. They also suggest that cross talk among the kidney, cardiovascular system, and adipose tissue may contribute to salt-sensitive hypertension. Supposed mechanism for the beneficial effects of RDN on hypertension and target organ damage in DahlS rats. RDN at early or late stages after salt loading moderately alleviated hypertension and substantially ameliorated renal injury in DahlS rats. Cross talk among the kidney, cardiovascular system, and adipose tissue possibly mediated by circulating RAS may contribute to salt-sensitive hypertension. LV; left ventricular, NE; norepinephrine, RAS; renin-angiotensin system, RDN; renal denervation.
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Affiliation(s)
- Kohzo Nagata
- Pathophysiology Sciences, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Kaito Tagami
- Pathophysiology Sciences, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Touko Okuzawa
- Pathophysiology Sciences, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Misaki Hayakawa
- Pathophysiology Sciences, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akane Nomura
- Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan
| | - Tomo Nishimura
- Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan
| | - Katsuhide Ikeda
- Pathophysiology Sciences, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kento Kitada
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Shuhei Kobuchi
- Division of Pharmacology, School of Pharmacy, Department of Pharmacy, Hyogo Medical University, Kobe, Japan
| | - Yoshihide Fujisawa
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Toyoaki Murohara
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Kusayama T, Nagamori Y, Takeuchi K, Nakagawa Y, Takamura M. Renal autonomic dynamics in hypertension: how can we evaluate sympathetic activity for renal denervation? Hypertens Res 2024; 47:2685-2692. [PMID: 39095482 DOI: 10.1038/s41440-024-01816-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 06/10/2024] [Accepted: 06/29/2024] [Indexed: 08/04/2024]
Abstract
This review explores the various pathophysiological factors influencing antihypertensive effects, involving the regulation of vascular resistance, plasma volume, cardiac function, and the autonomic nervous system, emphasizing the interconnected processes regulating blood pressure (BP). The kidney's pivotal role in BP control and its potential contribution to hypertension is complicated but important to understand the effective mechanisms of renal denervation (RDN), which may be a promising treatment for resistant hypertension. Excessive stimulation of the sympathetic nervous system or the renin-angiotensin-aldosterone system (RAAS) can elevate BP through various physiological changes, contributing to chronic hypertension. Renal sympathetic efferent nerve activation leads to elevated norepinephrine levels and subsequent cascading effects on vasoconstriction, renin release, and sodium reabsorption. RDN reduces BP in resistant hypertension by potentially disrupting sensory afferent nerves, decreasing feedback activation to the central nervous system, and reducing efferent sympathetic nerve activity in the heart and other structures. RDN may also modulate central sympathetic outflow and inhibit renal renin-angiotensin system overactivation. While evidence for RDN efficacy in hypertension is increasing, accurate patient selection becomes crucial, considering complex interactions that vary among patients. This review also discusses methods to evaluate autonomic nerve activity from the golden standard to new potential examination for finding out optimization in stimulation parameters or rigorous patient selection based on appropriate biomarkers.
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Affiliation(s)
- Takashi Kusayama
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan.
| | - Yuta Nagamori
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan
| | - Kazutaka Takeuchi
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan
| | - Yoichiro Nakagawa
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan
| | - Masayuki Takamura
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan
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10
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Guo Y, Gharibani P, Agarwal P, Modi H, Cho SM, Thakor NV, Geocadin RG. Endogenous orexin and hyperacute autonomic responses after resuscitation in a preclinical model of cardiac arrest. Front Neurosci 2024; 18:1437464. [PMID: 39347533 PMCID: PMC11427410 DOI: 10.3389/fnins.2024.1437464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 08/28/2024] [Indexed: 10/01/2024] Open
Abstract
Objectives The study of autonomic responses to cardiac arrest (CA) resuscitation deserves attention due to the impact of autonomic function on survival and arousal. Orexins are known to modulate autonomic function, but the role of endogenous orexin in hyperacute recovery of autonomic function post-resuscitation is not well understood. We hypothesized that endogenous orexin facilitates hyperacute cardiovascular sympathetic activity post-resuscitation, and this response could be attenuated by suvorexant, a dual orexin receptor antagonist. Methods A well-established 7-min asphyxial CA rat model was studied. Heart rate (HR) and blood pressure were monitored from baseline to 90-min post-resuscitation. Autonomic function was evaluated by spectral analysis of HR variability, whereby the ratio of low- and high-frequency components (LF/HF ratio) represents the balance between sympathetic/parasympathetic activities. Plasma orexin-A levels and orexin receptors immunoreactivity in the rostral ventrolateral medulla (RVLM), the key central region for regulating sympathetic output, were measured post-resuscitation. Neurological outcome was assessed via neurologic-deficit score at 4-h post-resuscitation. Key results A significant increase in HR was found over 25-40 min post-resuscitation (p < 0.01 vs. baseline), which was attenuated by suvorexant significantly (p < 0.05). Increased HR (from 15-to 25-min post-resuscitation) was correlated with better neurological outcomes (rs = 0.827, p = 0.005). There was no evident increase in mean arterial pressure over 25-40 min post-resuscitation, while systolic pressure was reduced greatly by suvorexant (p < 0.05). The LF/HF ratio was higher in animals with favorable outcomes than in animals injected with suvorexant over 30-40 min post-resuscitation (p < 0.05). Plasma orexin-A levels elevated at 15-min and peaked at 30-min post-resuscitation (p < 0.01 vs. baseline). Activated orexin receptors-immunoreactive neurons were found co-stained with tyrosine hydroxylase-immunopositive cells in the RVLM at 2-h post-resuscitation. Conclusion Together, increased HR and elevated LF/HF ratio indicative of sympathetic arousal during a critical window (25-40 min) post-resuscitation are observed in animals with favorable outcomes. The orexin system appears to facilitate this hyperacute autonomic response post-CA.
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Affiliation(s)
- Yu Guo
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Payam Gharibani
- Department of Neurology, Division of Neuroimmunology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Prachi Agarwal
- Department of Electrical and Computer Engineering, Johns Hopkins University School of Engineering, Baltimore, MD, United States
| | - Hiren Modi
- Brain Trauma Neuroprotection Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD, United States
| | - Sung-Min Cho
- Departments of Neurology, Anesthesiology-Critical Care Medicine and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Nitish V Thakor
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Romergryko G Geocadin
- Departments of Neurology, Anesthesiology-Critical Care Medicine and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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11
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Seo D, Martins JS, Sinha R. Brain correlates and functional connectivity linking stress, autonomic dysregulation, and alcohol motivation. Neurobiol Stress 2024; 31:100645. [PMID: 38933283 PMCID: PMC11201348 DOI: 10.1016/j.ynstr.2024.100645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 04/22/2024] [Accepted: 05/19/2024] [Indexed: 06/28/2024] Open
Abstract
High stress is a key risk factor for alcohol use disorder (AUD) and often accompanied by physiological dysregulation including autonomic nervous system (ANS) disruptions. However, neural mechanisms underlying drinking behaviors associated with stress and ANS disruptions remain unclear. The current study aims to understand neural correlates of stress, ANS disruptions, and subsequent alcohol intake in social drinkers with risky drinking. Using functional magnetic resonance imaging (fMRI), we investigated brain and heart rate (HR) autonomic responses during brief exposure to stress, alcohol, and neutral cues utilizing a well-validated, individualized imagery paradigm in 48 social drinkers of which 26 reported high-risk drinking (HD) while 22 reported low-risk drinking (LD) patterns. Results indicated that HD individuals showed stress and ANS disruptions with increased basal HR, stress-induced craving, and decreased brain response to stress exposure in frontal-striatal regions including the ventromedial prefrontal cortex (VmPFC), anterior cingulate cortex, striatum, insula, and temporal gyrus. Furthermore, whole-brain correlation analysis indicated that greater basal HR was associated with hypoactive VmPFC, but hyperactive medulla oblongata (MOb) responses during stress, with an inverse association between activity in the VmPFC and Mob (whole-brain corrected (WBC), p < 0.05). Functional connectivity with the MOb as a seed to the whole brain indicated that HD versus LD had decreased functional connectivity between the VmPFC and MOb during stress (WBC, p < 0.05). In addition, those with more compromised functional connectivity between the VmPFC and MOb during stress consumed greater amount of alcohol beverage during an experimental alcohol taste test conducted on a separate day, as well as in their self-reported weekly alcohol intake. Together, these results indicate that stress-related, dysfunctional VmPFC control over brain regions of autonomic arousal contributes to greater alcohol motivation and may be a significant risk factor for hazardous alcohol use in non-dependent social drinkers. Findings also suggest that restoring VmPFC integrity in modulating autonomic arousal during stress may be critical for preventing the development of AUD.
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Affiliation(s)
- Dongju Seo
- Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, 2 Church Street South, New Haven, CT, 06519, USA
| | - Jorge S. Martins
- William James Center for Research, ISPA-Instituto Universitário, Lisbon, Portugal
| | - Rajita Sinha
- Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, 2 Church Street South, New Haven, CT, 06519, USA
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12
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Brown CR, Foster JD. Palmitoylation regulates norepinephrine transporter trafficking and expression and is potentially involved in the pathogenesis of postural orthostatic tachycardia syndrome. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.22.586171. [PMID: 38585862 PMCID: PMC10996475 DOI: 10.1101/2024.03.22.586171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Postural orthostatic tachycardia syndrome (POTS) is an adrenergic signaling disorder characterized by excessive plasma norepinephrine, postural tachycardia, and syncope. The norepinephrine transporter (NET) modulates adrenergic homeostasis via reuptake of extracellular catecholamines and is implicated in the pathogenesis of adrenergic and neurological disorders. Previous research has outlined that NET activity and trafficking is modulated via reversible post-translational modifications like phosphorylation and ubiquitylation. S-palmitoylation, or the addition of a 16-carbon saturated fatty acid, is another post-translational modification responsible for numerous biological mechanisms. In this study, we reveal that NET is dynamically palmitoylated and inhibition of this modification with the palmitoyl acyltransferase (DHHC) inhibitor, 2-bromopalmitate (2BP), results in decreased NET palmitoylation within 90 min of treatment. This result was followed closely with a reduction in transport capacity, cell surface, and total cellular NET expression after 120 min of treatment. Increasing 2BP concentrations and treatment time revealed a nearly complete loss of total NET protein. Co-expression with individual DHHCs revealed a single DHHC enzyme, DHHC1, promoted WT hNET palmitoylation and elevated NET protein levels. The POTS associated NET mutant, A457P, exhibits dramatically decreased transport capacity and cell surface levels which we have confirmed in the current study. In an attempt to recover A457P NET expression we co-expressed the A457P variant with DHHC1 to drive expression as seen with the WT protein but instead saw an increase in NET N-terminal immuno-detectable fragments. Further investigation of A457P NET palmitoylation and surface expression is necessary, but our preliminary novel findings reveal palmitoylation as a mechanism of NET regulation and suggest that dysregulation of this process may contribute to the pathogenesis of POTS.
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13
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Rahman A, Nishiyama A. Inhibiting SGLTs diminishes sympathetic output by reducing rostral ventrolateral medulla (RVLM) neuron activity. Hypertens Res 2024; 47:571-572. [PMID: 37989914 DOI: 10.1038/s41440-023-01522-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 10/27/2023] [Accepted: 10/28/2023] [Indexed: 11/23/2023]
Affiliation(s)
- Asadur Rahman
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
| | - Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
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14
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Chapp AD, Shan Z, Chen QH. Acetic Acid: An Underestimated Metabolite in Ethanol-Induced Changes in Regulating Cardiovascular Function. Antioxidants (Basel) 2024; 13:139. [PMID: 38397737 PMCID: PMC10886048 DOI: 10.3390/antiox13020139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/13/2024] [Accepted: 01/18/2024] [Indexed: 02/25/2024] Open
Abstract
Acetic acid is a bioactive short-chain fatty acid produced in large quantities from ethanol metabolism. In this review, we describe how acetic acid/acetate generates oxidative stress, alters the function of pre-sympathetic neurons, and can potentially influence cardiovascular function in both humans and rodents after ethanol consumption. Our recent findings from in vivo and in vitro studies support the notion that administration of acetic acid/acetate generates oxidative stress and increases sympathetic outflow, leading to alterations in arterial blood pressure. Real-time investigation of how ethanol and acetic acid/acetate modulate neural control of cardiovascular function can be conducted by microinjecting compounds into autonomic control centers of the brain and measuring changes in peripheral sympathetic nerve activity and blood pressure in response to these compounds.
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Affiliation(s)
- Andrew D. Chapp
- Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA
| | - Zhiying Shan
- Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, MI 49931, USA;
| | - Qing-Hui Chen
- Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, MI 49931, USA;
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15
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Sotozawa M, Kinguchi S, Wakui H, Azushima K, Funakoshi K, Nakajima W, Miyazaki T, Takahashi T, Tamura K. Enhancement of angiotensin II type 1 receptor-associated protein in the paraventricular nucleus suppresses angiotensin II-dependent hypertension. Hypertens Res 2024; 47:67-77. [PMID: 37884662 DOI: 10.1038/s41440-023-01480-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 09/29/2023] [Accepted: 10/11/2023] [Indexed: 10/28/2023]
Abstract
The renin-angiotensin system in the brain plays a pivotal role in modulating sympathetic nerve activity and contributes to the pathogenesis of hypertension. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R while suppressing pathological overactivation of AT1R signaling. However, the pathophysiological function of ATRAP in the brain remains unknown. Therefore, this study aims to investigate whether ATRAP in the paraventricular nucleus (PVN) is involved in neurogenic hypertension pathogenesis in Ang II-infused rats. The ATRAP/AT1R ratio, which serves as an indicator of tissue AT1R hyperactivity, tended to decrease within the PVN in the Ang II group than in the vehicle group. This suggests an Ang II-induced hyperactivation of the AT1R signaling pathway in the PVN. Lentiviral vectors were generated to stimulate ATRAP expression. At 6 weeks of age, rats were microinjected with LV-Venus (Venus-expressing lentivirus) or LV-ATRAP (Venus-ATRAP-expressing lentivirus). The rats were then randomly divided into four groups: (1) Vehicle/LV-Venus, (2) Vehicle/LV-ATRAP, (3) Ang II/LV-Venus, and (4) Ang II/LV-ATRAP. Two weeks after microinjection, vehicle or Ang II was administered systemically for 2 weeks. In the Ang II/LV-ATRAP group, systolic blood pressure at 1 and 2 weeks following administration was significantly lower than that in the Ang II/LV-Venus group. Furthermore, urinary adrenaline levels tended to decrease in the Ang II/LV-ATRAP group than in the Ang II/LV-Venus group. These findings suggest that enhanced ATRAP expression in the PVN suppresses Ang II-induced hypertension, potentially by suppressing hyperactivation of the tissue AT1R signaling pathway and, subsequently, sympathetic nerve activity.
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Affiliation(s)
- Mari Sotozawa
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Sho Kinguchi
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hiromichi Wakui
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
| | - Kengo Azushima
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
| | - Kengo Funakoshi
- Department of Neuroanatomy, Yokohama City University School of Medicine, Yokohama, Japan
| | - Waki Nakajima
- Department of Physiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Tomoyuki Miyazaki
- Department of Physiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takuya Takahashi
- Department of Physiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kouichi Tamura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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16
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Yaneva-Sirakova T, Petrov I, Traykov L, Coca A, Cunha PG, Gasecki D, Farukh B, Kotsis V, Vicario A, Manios E, Sierra C, Hering D. Twenty-four-hour ambulatory blood pressure monitoring-from silent to whispering brain damage. Blood Press 2023; 32:2208228. [PMID: 37209040 DOI: 10.1080/08037051.2023.2208228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/20/2023] [Accepted: 04/24/2023] [Indexed: 05/22/2023]
Affiliation(s)
| | - Ivo Petrov
- Acibadem City Clinic UMHAT Cardiovascular Center, Sofia, Bulgaria
| | - Latchezar Traykov
- Department of Neurology, UMHAT "Alexandrovska", Neurology clinic, Medical University Sofia, Bulgaria
| | - Antonio Coca
- Hypertension and Vascular Risk Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Pedro G Cunha
- Center for the Research and Treatment of Arterial Hypertension and Cardiovascular Risk; Hospital Senhora da Oilveira, Life and Health Research Institute, Minho University, Guimarães, Portugal
| | - Dariusz Gasecki
- Department of Adult Neurology, Medical University of Gdansk, Gdansk, Poland
| | - Bushra Farukh
- School of Cardiovascular and Metabolic Medicine and Sciences, King's College London, London, United Kingdom
| | - Vasilios Kotsis
- Third Dept. of Int. Medicine, Papageorgiou Hospital, Aristotle University, Thessaloniki, Greece
| | - Augusto Vicario
- Heart-Brain Unit, Cardiovascular Institute of Buenos Aires (ICBA), Buenos Aires, Argentina
| | - Efstathis Manios
- Dept. of Clinical Therapeutics National, and Kapodistrian University of Athens, Alexandra Hospital, Greece
| | - Cristina Sierra
- Department of Internal Medicine, University of Barcelona, Hospital Clinic, Barcelona, Spain
| | - Dagmara Hering
- Department of Hypertension and Diabetology, Medical University of Gdansk, Gdansk, Poland
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17
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Kharazmi F, Hosseini-Dastgerdi H, Pourshanazari AA, Nematbakhsh M. The denervation or activation of renal sympathetic nerve and renal blood flow. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2023; 28:76. [PMID: 38152073 PMCID: PMC10751519 DOI: 10.4103/jrms.jrms_216_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/09/2023] [Accepted: 07/17/2023] [Indexed: 12/29/2023]
Abstract
The denervation or activation of the sympathetic nerve in the kidney can affect renal hemodynamics. The sympathetic nervous system regulates the physiological functions of the kidneys. Stimulation of sympathetic efferent nerves affects various parameters related to renal hemodynamics, including sodium excretion, renin secretion, and renal blood flow (RBF). Hence, renal sympathetic fibers may also play an essential role in regulating systemic vascular resistance and controlling blood pressure. In the absence of renal nerves, the hemodynamics response to stimuli is negligible or absent. The effect of renal sympathetic denervation on RBF is dependent on several factors such as interspecies differences, the basic level of nerve activity in the vessels or local density of adrenergic receptor in the vascular bed. The role of renal denervation has been investigated therapeutically in hypertension and related disorders. Hence, the dynamic impact of renal nerves on RBF enables using RBF dynamic criteria as a marker for renal denervation therapy.
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Affiliation(s)
- Fatemeh Kharazmi
- Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hajaralsadat Hosseini-Dastgerdi
- Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Mehdi Nematbakhsh
- Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran
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18
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Zhang S, Wang X, Chen G, Tong L, Dai T, Wang L, Zhu L, Zhang H, Du D. CircRNA Galntl6 sponges miR-335 to ameliorate stress-induced hypertension through upregulating Lig3 in rostral ventrolateral medulla. Redox Biol 2023; 64:102782. [PMID: 37315345 PMCID: PMC10363431 DOI: 10.1016/j.redox.2023.102782] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/08/2023] [Accepted: 06/08/2023] [Indexed: 06/16/2023] Open
Abstract
Rostral ventrolateral medulla (RVLM) is thought to serve as a major vasomotor center that participates in controlling the progression of stress-induced hypertension (SIH). Circular RNAs (circRNAs) perform important functions in the regulation of diverse physiological and pathological processes. However, information concerning the functions of RVLM circRNAs on SIH remains limited. RNA sequencing was performed to profile circRNA expression in RVLMs from SIH rats, which were induced by electric foot shocks and noises. The functions of circRNA Galntl6 in reducing blood pressure (BP) and its potential molecular mechanisms on SIH were investigated via various experiments, such as Western blot and intra-RVLM microinjection. A total of 12,242 circRNA transcripts were identified, among which circRNA Galntl6 was dramatically downregulated in SIH rats. The upregulation of circRNA Galntl6 in RVLM effectively decreased the BP, sympathetic outflow, and neuronal excitability in SIH rats. Mechanistically, circRNA Galntl6 directly sponged microRNA-335 (miR-335) and restrained it to reduce oxidative stress. Reintroduction of miR-335 observably reversed the circRNA Galntl6-induced attenuation of oxidative stress. Furthermore, Lig3 can be a direct target of miR-335. MiR-335 inhibition substantially increased the expression of Lig3 and suppressed oxidative stress, and these favorable effects were blocked by Lig3 knockdown. CircRNA Galntl6 is a novel factor that impedes SIH development, and the circRNA Galntl6/miR-335/Lig3 axis represents one of the possible mechanisms. These findings demonstrated circRNA Galntl6 as a possibly useful target for the prevention of SIH.
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Affiliation(s)
- Shuai Zhang
- International Cooperation Laboratory of Molecular Medicine, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China
| | - Xueping Wang
- College of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Gaojun Chen
- College of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Lei Tong
- College of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Tengteng Dai
- College of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Linping Wang
- College of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Liucun Zhu
- College of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Haili Zhang
- College of Agriculture and Bioengineering, Heze University, Heze, Shandong, 274015, China
| | - Dongshu Du
- College of Life Sciences, Shanghai University, Shanghai, 200444, China; College of Agriculture and Bioengineering, Heze University, Heze, Shandong, 274015, China; Shaoxing Institute of Shanghai University, Shaoxing, Zhejiang, 312000, China.
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19
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Kishi T. Clarification of hypertension mechanisms provided by the research of central circulatory regulation. Hypertens Res 2023; 46:1908-1916. [PMID: 37277436 DOI: 10.1038/s41440-023-01335-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/28/2023] [Accepted: 05/02/2023] [Indexed: 06/07/2023]
Abstract
Sympathoexcitation, under the regulatory control of the brain, plays a pivotal role in the etiology of hypertension. Within the brainstem, significant structures involved in the modulation of sympathetic nerve activity include the rostral ventrolateral medulla (RVLM), caudal ventrolateral medulla (CVLM), nucleus tractus solitarius (NTS), and paraventricular nucleus (paraventricular). The RVLM, in particular, is recognized as the vasomotor center. Over the past five decades, fundamental investigations on central circulatory regulation have underscored the involvement of nitric oxide (NO), oxidative stress, the renin-angiotensin system, and brain inflammation in regulating the sympathetic nervous system. Notably, numerous significant findings have come to light through chronic experiments conducted in conscious subjects employing radio-telemetry systems, gene transfer techniques, and knockout methodologies. Our research has centered on elucidating the role of NO and angiotensin II type 1 (AT1) receptor-induced oxidative stress within the RVLM and NTS in regulating the sympathetic nervous system. Additionally, we have observed that various orally administered AT1 receptor blockers effectively induce sympathoinhibition by reducing oxidative stress via blockade of the AT1 receptor in the RVLM of hypertensive rats. Recent advances have witnessed the development of several clinical interventions targeting brain mechanisms. Nonetheless, Future and further basic and clinical research are needed.
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Affiliation(s)
- Takuya Kishi
- Department of Graduate School of Medicine (Cardiology), International University of Health and Welfare, Okawa, Japan.
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20
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Ramirez JM, Carroll MS, Burgraff N, Rand CM, Weese-Mayer DE. A narrative review of the mechanisms and consequences of intermittent hypoxia and the role of advanced analytic techniques in pediatric autonomic disorders. Clin Auton Res 2023; 33:287-300. [PMID: 37326924 DOI: 10.1007/s10286-023-00958-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 05/25/2023] [Indexed: 06/17/2023]
Abstract
Disorders of autonomic functions are typically characterized by disturbances in multiple organ systems. These disturbances are often comorbidities of common and rare diseases, such as epilepsy, sleep apnea, Rett syndrome, congenital heart disease or mitochondrial diseases. Characteristic of many autonomic disorders is the association with intermittent hypoxia and oxidative stress, which can cause or exaggerate a variety of other autonomic dysfunctions, making the treatment and management of these syndromes very complex. In this review we discuss the cellular mechanisms by which intermittent hypoxia can trigger a cascade of molecular, cellular and network events that result in the dysregulation of multiple organ systems. We also describe the importance of computational approaches, artificial intelligence and the analysis of big data to better characterize and recognize the interconnectedness of the various autonomic and non-autonomic symptoms. These techniques can lead to a better understanding of the progression of autonomic disorders, ultimately resulting in better care and management.
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Affiliation(s)
- Jan-Marino Ramirez
- Center for Integrative Brain Research, Seattle Children's Research Institute, 1900 Ninth Avenue, Seattle, WA, 98101, USA.
- Departments of Neurological Surgery and Pediatrics, University of Washington School of Medicine, 1900 Ninth Avenue, Seattle, WA, 98101, USA.
| | - Michael S Carroll
- Data Analytics and Reporting, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Division of Autonomic Medicine, Stanley Manne Children's Research Institute at Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Nicholas Burgraff
- Center for Integrative Brain Research, Seattle Children's Research Institute, 1900 Ninth Avenue, Seattle, WA, 98101, USA
| | - Casey M Rand
- Division of Autonomic Medicine, Stanley Manne Children's Research Institute at Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Debra E Weese-Mayer
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Division of Autonomic Medicine, Stanley Manne Children's Research Institute at Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
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Liu T, Wang L, Chen G, Tong L, Ye X, Yang H, Liu H, Zhang H, Lu W, Zhang S, Du D. PDZD8-mediated endoplasmic reticulum-mitochondria associations regulate sympathetic drive and blood pressure through the intervention of neuronal mitochondrial homeostasis in stress-induced hypertension. Neurobiol Dis 2023:106173. [PMID: 37247681 DOI: 10.1016/j.nbd.2023.106173] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/24/2023] [Accepted: 05/25/2023] [Indexed: 05/31/2023] Open
Abstract
Neuronal hyperexcitation in the rostral ventrolateral medulla (RVLM) drives heightened sympathetic nerve activity and contributes to the etiology of stress-induced hypertension (SIH). Maintenance of mitochondrial functions is central to neuronal homeostasis. PDZD8, an endoplasmic reticulum (ER) transmembrane protein, tethers ER to mitochondria. However, the mechanisms of PDZD8-mediated ER-mitochondria associations regulating neuronal mitochondrial functions and thereby mediating blood pressure (BP) in the RVLM of SIH were largely unknown. SIH rats were subjected to intermittent electric foot shocks plus noise for 2 h twice daily for 15 consecutive days. The underlying mechanisms of PDZD8 were investigated through in vitro experiments by using small interfering RNA and through in vivo experiments, such as intra-RVLM microinjection and Western blot analysis. The function of PDZD8 on BP regulation in the RVLM was determined in vivo via the intra-RVLM microinjection of adeno-associated virus (AAV)2-r-Pdzd8. We found that the c-Fos-positive RVLM tyrosine hydroxylase (TH) neurons, renal sympathetic nerve activity (RSNA), plasma norepinephrine (NE) level, BP, and heart rate (HR) were elevated in SIH rats. ER-mitochondria associations in RVLM neurons were significantly reduced in SIH rats. PDZD8 was mainly expressed in RVLM neurons, and mRNA and protein levels were markedly decreased in SIH rats. In N2a cells, PDZD8 knockdown disrupted ER-mitochondria associations and mitochondrial structure, decreased mitochondrial membrane potential (MMP) and respiratory metabolism, enhanced ROS levels, and reduced catalase (CAT) activity. These effects suggested that PDZD8 dysregulation induced mitochondrial malfunction. By contrast, PDZD8 upregulation in the RVLM of SIH rats could rescue neuronal mitochondrial function, thereby suppressing c-Fos expression in TH neurons and decreasing RSNA, plasma NE, BP, and HR. Our results indicated that the dysregulation of PDZD8-mediated ER-mitochondria associations led to the loss of the activity homeostasis of RVLM neurons by disrupting mitochondrial functions, thereby participating in the regulation of SIH pathology.
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Affiliation(s)
- Tianfeng Liu
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China; College of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Linping Wang
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China; College of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Gaojun Chen
- College of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Lei Tong
- College of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Xuanxuan Ye
- College of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Hui Yang
- College of Life Sciences, Shanghai University, Shanghai 200444, China
| | - Haisheng Liu
- College of Agriculture and Bioengineering, Heze University, Heze 274000, China
| | - Haili Zhang
- College of Agriculture and Bioengineering, Heze University, Heze 274000, China
| | - Wen Lu
- College of Agriculture and Bioengineering, Heze University, Heze 274000, China
| | - Shuai Zhang
- International Cooperation Laboratory of Molecular Medicine, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
| | - Dongshu Du
- School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China; College of Life Sciences, Shanghai University, Shanghai 200444, China; Shaoxing Institute of Shanghai University, Shaoxing, Zhejiang 312000, China; College of Agriculture and Bioengineering, Heze University, Heze 274000, China.
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22
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Abstract
The cardiovascular system is hardwired to the brain via multilayered afferent and efferent polysynaptic axonal connections. Two major anatomically and functionally distinct though closely interacting subcircuits within the cardiovascular system have recently been defined: The artery-brain circuit and the heart-brain circuit. However, how the nervous system impacts cardiovascular disease progression remains poorly understood. Here, we review recent findings on the anatomy, structures, and inner workings of the lesser-known artery-brain circuit and the better-established heart-brain circuit. We explore the evidence that signals from arteries or the heart form a systemic and finely tuned cardiovascular brain circuit: afferent inputs originating in the arterial tree or the heart are conveyed to distinct sensory neurons in the brain. There, primary integration centers act as hubs that receive and integrate artery-brain circuit-derived and heart-brain circuit-derived signals and process them together with axonal connections and humoral cues from distant brain regions. To conclude the cardiovascular brain circuit, integration centers transmit the constantly modified signals to efferent neurons which transfer them back to the cardiovascular system. Importantly, primary integration centers are wired to and receive information from secondary brain centers that control a wide variety of brain traits encoded in engrams including immune memory, stress-regulating hormone release, pain, reward, emotions, and even motivated types of behavior. Finally, we explore the important possibility that brain effector neurons in the cardiovascular brain circuit network connect efferent signals to other peripheral organs including the immune system, the gut, the liver, and adipose tissue. The enormous recent progress vis-à-vis the cardiovascular brain circuit allows us to propose a novel neurobiology-centered cardiovascular disease hypothesis that we term the neuroimmune cardiovascular circuit hypothesis.
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Affiliation(s)
- Sarajo K Mohanta
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University (LMU), Munich, Germany (S.K.M., C.Y., C.W., A.J.R.H.)
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance (S.K.M., C.W., A.J.R.H.)
| | - Changjun Yin
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University (LMU), Munich, Germany (S.K.M., C.Y., C.W., A.J.R.H.)
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China (C.Y.)
| | - Christian Weber
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University (LMU), Munich, Germany (S.K.M., C.Y., C.W., A.J.R.H.)
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance (S.K.M., C.W., A.J.R.H.)
| | - Cristina Godinho-Silva
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal (C.G.-S., H.V.-F.)
| | | | - Qian J Xu
- Department of Neuroscience, Department of Cellular and Molecular Physiology, Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT (Q.J.X., R.B.C.)
| | - Rui B Chang
- Department of Neuroscience, Department of Cellular and Molecular Physiology, Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT (Q.J.X., R.B.C.)
| | - Andreas J R Habenicht
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University (LMU), Munich, Germany (S.K.M., C.Y., C.W., A.J.R.H.)
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance (S.K.M., C.W., A.J.R.H.)
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23
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Renal sympathetic activity: A key modulator of pressure natriuresis in hypertension. Biochem Pharmacol 2023; 208:115386. [PMID: 36535529 DOI: 10.1016/j.bcp.2022.115386] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/11/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
Hypertension is a complex disorder ensuing necessarily from alterations in the pressure-natriuresis relationship, the main determinant of long-term control of blood pressure. This mechanism sets natriuresis to the level of blood pressure, so that increasing pressure translates into higher osmotically driven diuresis to reduce volemia and control blood pressure. External factors affecting the renal handling of sodium regulate the pressure-natriuresis relationship so that more or less natriuresis is attained for each level of blood pressure. Hypertension can thus only develop following primary alterations in the pressure to natriuresis balance, or by abnormal activity of the regulation network. On the other hand, increased sympathetic tone is a very frequent finding in most forms of hypertension, long regarded as a key element in the pathophysiological scenario. In this article, we critically analyze the interplay of the renal component of the sympathetic nervous system and the pressure-natriuresis mechanism in the development of hypertension. A special focus is placed on discussing recent findings supporting a role of baroreceptors as a component, along with the afference of reno-renal reflex, of the input to the nucleus tractus solitarius, the central structure governing the long-term regulation of renal sympathetic efferent tone.
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24
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Relationships among norepinephrine levels, exercise capacity, and chronotropic responses in heart failure patients. Heart Fail Rev 2023; 28:35-45. [PMID: 35325323 DOI: 10.1007/s10741-022-10232-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/15/2022] [Indexed: 02/07/2023]
Abstract
In heart failure (HF) patients, the pathophysiological mechanisms of severe exercise intolerance and impaired exercise capacity are related to both central and peripheral abnormalities. The central abnormalities in HF patients include impaired cardiac function and chronotropic incompetence (CI). Indeed, CI, the inability to adequately increase heart rate (HR) from rest to exercise often exhibited by HF patients, is related to activation of the sympathetic nervous system (SNS) yielding a rise in circulating norepinephrine (NE). CI may result from downregulation of β-adrenergic receptors, β-blocker usage, high baseline HR, or due to a combination of factors. This paper discusses the role of elevated NE in altering chronotropic responses in HF patients and consequently resulting in impaired exercise capacity. We suggest that future research should focus on the potential treatment of CI with rate-adaptive pacing, using a sensor to measure physical activity, without inducing deleterious hormonal activation of the sympathetic system.
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25
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Almeida LVD, Garcia-Araujo A, Lopez M, Rocha DS, Mendes RG, Borghi-Silva A, Dibai-Filho AV, Dibai DB. Results and effects of patients who have recovered from COVID-19: identifying the relationship with risk factors and comorbidities. CIENCIA & SAUDE COLETIVA 2022; 27:2963-2972. [PMID: 35894310 DOI: 10.1590/1413-81232022278.18672021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 11/06/2021] [Indexed: 01/08/2023] Open
Abstract
The number of deaths from COVID-19 is closely associated with multimorbidities. This study aimed to review the clinical and functional conditions of patients who recovered from COVID-19. Additionally, identify the relationship with risk factors and comorbidities. Systemic arterial hypertension (SAH) was more frequently observed in patients with severe COVID-19. Diabetes mellitus (DM) is one of the comorbidities that has contributed the most to the increase in the number of hospitalizations due to complications and the number of deaths due to infection by COVID-19. Obesity has been shown to be a risk factor for hospitalization in patients with COVID-19 under 60 years of age. Most survivors of COVID-19 suffer primarily from muscle fatigue or weakness. In addition, patients who were more seriously ill during their hospital stay have greater impairment of functional capacity, pulmonary diffusion and fatigue symptoms, and are the main target population for long-term recovery interventions. To optimize the post-hospitalization rehabilitation of patients after discharge from COVID-19, the need for multidisciplinary work in rehabilitation, the reinforcement of public policies to ensure equity in access to the public health system and training should be considered of the health team in view of the new demands and realities generated by COVID-19.
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Affiliation(s)
- Lucivalda Viegas de Almeida
- Programa de Pós-Graduação em Gestão de Programas e Serviços de Saúde, Universidade Ceuma. São Luís MA Brasil
| | - Adriana Garcia-Araujo
- Departmento de Fisioterapia, Universidade Federal de São Carlos. São Carlos SP Brasil
| | - Mildred Lopez
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud. Monterrey México
| | - Daniel Santos Rocha
- Departmento de Fisioterapia, Centro de Ciências da Saúde, Universidade Ceuma. Rua Josué Montello 1, Jardim Renascença. 65075-120 São Luís MA Brasil.
| | | | - Audrey Borghi-Silva
- Departmento de Fisioterapia, Universidade Federal de São Carlos. São Carlos SP Brasil
| | | | - Daniela Bassi Dibai
- Programa de Pós-Graduação em Gestão de Programas e Serviços de Saúde, Universidade Ceuma. São Luís MA Brasil.,Departmento de Fisioterapia, Centro de Ciências da Saúde, Universidade Ceuma. Rua Josué Montello 1, Jardim Renascença. 65075-120 São Luís MA Brasil.
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26
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Koracevic G, Micic S, Stojanovic M, Radovanovic RV, Pavlovic MP, Kostic T, Djordjevic D, Antonijevic N, Koracevic M, Atanaskovic V, Dakic S. Beta Blockers can mask not only Hypoglycemia, but also Hypotension. Curr Pharm Des 2022; 28:1660-1668. [DOI: 10.2174/1381612828666220421135523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 02/01/2022] [Indexed: 11/22/2022]
Abstract
Background:
Beta-adrenergic (β-AR) receptor blockers (BBs) are an essential class of drugs as they have numerous indications. On the other hand, they have numerous unwanted effects which decrease the compliance, adherence, and persistence of this very useful group of drugs.
Objective:
The paper aims to analyze the possibility that an unnoticed side effect may contribute to a less favorable pharmacologic profile of BBs, e.g., a diminished reaction to a sudden fall in BP.
Methods:
We searched two medical databases for abstracts and citations (Medline and SCOPUS). Moreover, we searched the internet for drug prescription leaflets (of the individual BBs).
Results:
Whichever cause of stress is considered, the somatic manifestations of stress will be (partially) masked if a patient takes BB. Stress–induced hypercatecholaminemia acts on β-AR of cardiomyocytes; it increases heart rate and contractility, effects suppressed by BBs. The answers of the organism to hypoglycemia and hypotension share the main mechanisms such as sympathetic nervous system activation and hypercatecholaminemia. Thus, there is a striking analogy: BBs can cover up symptoms of both hypoglycemia (which is widely known) and of hypotension (which is not recognized). It is widely known that BBs can cause hypotension. However, they can also complicate recovery by spoiling the defense mechanisms in hypotension as they interfere with the crucial compensatory reflex to increase blood pressure in hypotension.
Conclusion:
Beta blockers can cause hypotension, mask it, and make recovery more difficult. This is clinically important and deserves to be more investigated and probably to be stated as a warning.
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Affiliation(s)
- Goran Koracevic
- Department for Cardiovascular Diseases, University Clinical Centre Nis, Nis, Serbia
| | | | | | | | - Milan Pavlovic Pavlovic
- Department for Cardiovascular Diseases, University Clinical Centre Nis, Nis, Serbia
- Faculty of Medicine, University of Nis, Nis, Serbia
| | - Tomislav Kostic
- Department for Cardiovascular Diseases, University Clinical Centre Nis, Nis, Serbia
- Faculty of Medicine, University of Nis, Nis, Serbia
| | - Dragan Djordjevic
- Faculty of Medicine, University of Nis, Nis, Serbia
- Institute for Treatment and Rehabilitation Niska Banja, Nis, Serbia
| | - Nebojsa Antonijevic
- Clinic for Cardiology, University Clinical Centre of Serbia, Belgrade, Serbia
| | - Maja Koracevic
- Faculty of Medicine, University of Nis, Nis, Serbia
- Innovation Centre, University of Nis, Nis, Serbia
| | - Vesna Atanaskovic
- Department for Cardiovascular Diseases, University Clinical Centre Nis, Nis, Serbia
| | - Sonja Dakic
- Department for Cardiovascular Diseases, University Clinical Centre Nis, Nis, Serbia
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27
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Hyun U, Sohn JW. Autonomic control of energy balance and glucose homeostasis. Exp Mol Med 2022; 54:370-376. [PMID: 35474336 PMCID: PMC9076646 DOI: 10.1038/s12276-021-00705-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/07/2021] [Indexed: 11/21/2022] Open
Abstract
Neurons in the central nervous system (CNS) communicate with peripheral organs largely via the autonomic nervous system (ANS). Through such communications, the sympathetic and parasympathetic efferent divisions of the ANS may affect thermogenesis and blood glucose levels. In contrast, peripheral organs send feedback to the CNS via hormones and autonomic afferent nerves. These humoral and neural feedbacks, as well as neural commands from higher brain centers directly or indirectly shape the metabolic function of autonomic neurons. Notably, recent developments in mouse genetics have enabled more detailed studies of ANS neurons and circuits, which have helped elucidate autonomic control of metabolism. Here, we will summarize the functional organization of the ANS and discuss recent updates on the roles of neural and humoral factors in the regulation of energy balance and glucose homeostasis by the ANS. Cutting-edge techniques should be harnessed to unravel how metabolism is modulated by a key part of the body’s nervous system. The autonomic nervous system (ANS) regulates many involuntary physiological processes, such as heart rate, breathing, and blood pressure. Scientists now believe that the ANS is involved in regulating metabolism, but its precise roles are unclear. Jong-Woo Sohn and Uisu Hyun at the Korea Advanced Institute of Science and Technology, Daejeon, Korea, reviewed understanding of how the ANS regulates energy balance, appetite, and glucose homeostasis. Recently-developed mouse models have provided insights into how ANS neurons translate neuronal and hormonal signals into commands during feeding, sending instructions to the liver, and mediating blood glucose levels. Several hormones have been identified that may act on a specific part of the ANS to influence appetite and metabolism.
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Affiliation(s)
- Uisu Hyun
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 34141, South Korea
| | - Jong-Woo Sohn
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 34141, South Korea.
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28
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Almeida RL, Ogihara CA, de Souza JS, Oliveira KC, Cafarchio EM, Tescaro L, Maciel RMB, Giannocco G, Sato MA. Regularly swimming exercise modifies opioidergic neuromodulation in rostral ventrolateral medulla in hypertensive rats. Brain Res 2022; 1774:147726. [PMID: 34785257 DOI: 10.1016/j.brainres.2021.147726] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 10/14/2021] [Accepted: 11/09/2021] [Indexed: 11/02/2022]
Abstract
Moderate exercise reduces arterial pressure (AP) and heart rate (HR) in spontaneously hypertensive rats (SHR) and changes neurotransmission in medullary areas involved in cardiovascular regulation. We investigated if regularly swimming exercise (SW) affects the cardiovascular adjustments mediated by opioidergic neuromodulation in the RVLM in SHR and Wistar-Kyoto (WKY) rats. Rats were submitted to 6 wks of SW. The day after the last exercise bout, α-chloralose-anesthetized rats underwent a cannulation of the femoral artery for AP and HR recordings, and Doppler flow probes were placed around the lower abdominal aorta and superior mesenteric artery. Bilateral injection of endomorphin-2 (EM-2, 0.4 mmol/L, 60 nL) into the RVLM increased MAP in SW-SHR (20 ± 4 mmHg, N = 6), which was lower than in sedentary (SED)-SHR (35 ± 4 mmHg, N = 6). The increase in MAP in SW-SHR induced by EM-2 into the RVLM was similar in SED- and SW-WKY. Naloxone (0.5 mmol/L, 60 nL) injected into the RVLM evoked an enhanced hypotension in SW-SHR (-66 ± 8 mmHg, N = 6) compared to SED-SHR (-25 ± 3 mmHg, N = 6), which was similar in SED- and SW-WKY. No significant changes were observed in HR after EM-2 or naloxone injections into the RVLM. Changes in hindquarter and mesenteric conductances evoked by EM-2 or naloxone injections into the RVLM in SW- or SED-SHR were not different. Mu Opioid Receptor expression by Western blotting was reduced in SW-SHR than in SED-SHR and SW-WKY. Therefore, regularly SW alters the opioidergic neuromodulation in the RVLM in SHR and modifies the mu opioid receptor expression in this medullary area.
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Affiliation(s)
- Roberto L Almeida
- Dept. Morphology and Physiology, Faculdade de Medicina do ABC, Centro Universitário FMABC, Santo Andre, SP, Brazil
| | - Cristiana A Ogihara
- Dept. Morphology and Physiology, Faculdade de Medicina do ABC, Centro Universitário FMABC, Santo Andre, SP, Brazil
| | | | - Kelen C Oliveira
- Dept. Medicine, Federal University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Eduardo M Cafarchio
- Dept. Morphology and Physiology, Faculdade de Medicina do ABC, Centro Universitário FMABC, Santo Andre, SP, Brazil.
| | - Larissa Tescaro
- Dept. Morphology and Physiology, Faculdade de Medicina do ABC, Centro Universitário FMABC, Santo Andre, SP, Brazil
| | - Rui M B Maciel
- Dept. Medicine, Federal University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Gisele Giannocco
- Dept. Medicine, Federal University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Monica A Sato
- Dept. Morphology and Physiology, Faculdade de Medicina do ABC, Centro Universitário FMABC, Santo Andre, SP, Brazil
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29
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Fischer L, Barop H, Ludin SM, Schaible HG. Regulation of acute reflectory hyperinflammation in viral and other diseases by means of stellate ganglion block. A conceptual view with a focus on Covid-19. Auton Neurosci 2022; 237:102903. [PMID: 34894589 PMCID: PMC9761017 DOI: 10.1016/j.autneu.2021.102903] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 10/23/2021] [Accepted: 11/01/2021] [Indexed: 12/15/2022]
Abstract
Whereas the autonomic nervous system (ANS) and the immune system used to be assigned separate functions, it has now become clear that the ANS and the immune system (and thereby inflammatory cascades) work closely together. During an acute immune response (e. g., in viral infection like Covid-19) the ANS and the immune system establish a fast interaction resulting in "physiological" inflammation. Based on our knowledge of the modulation of inflammation by the ANS we propose that a reflectory malfunction of the ANS with hyperactivity of the sympathetic nervous system (SNS) may be involved in the generation of acute hyperinflammation. We believe that sympathetic hyperactivity triggers a hyperresponsiveness of the immune system ("cytokine storm") with consecutive tissue damage. These reflectory neuroimmunological and inflammatory cascades constitute a general reaction principle of the organism under the leadership of the ANS and does not only occur in viral infections, although Covid-19 is a typical current example therefore. Within the overreaction several interdependent pathological positive feedback loops can be detected in which the SNS plays an important part. Consequently, there is a chance to regulate the hyperinflammation by influencing the SNS. This can be achieved by a stellate ganglion block (SGB) with local anesthetics, temporarily disrupting the pathological positive feedback loops. Thereafter, the complex neuroimmune system has the chance to reorganize itself. Previous clinical and experimental data have confirmed a favorable outcome in hyperinflammation (including pneumonia) after SGB (measurable e. g. by a reduction in proinflammatory cytokines).
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Affiliation(s)
- Lorenz Fischer
- University of Bern, Interventional Pain Management, General Internal Medicine, Schwanengasse 5/7, 3011 Bern, Switzerland.
| | - Hans Barop
- Neural Therapy, Friedrich-Legahn-Str. 2, 22587 Hamburg, Germany
| | | | - Hans-Georg Schaible
- University Hospital Jena, Institute of Physiology1/Neurophysiology, Teichgraben 8, 07743 Jena, Germany.
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30
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Han TH, Lee HW, Kang EA, Song MS, Lee SY, Ryu PD. Microglial activation induced by LPS mediates excitation of neurons in the hypothalamic paraventricular nucleus projecting to the rostral ventrolateral medulla. BMB Rep 2021. [PMID: 34814975 PMCID: PMC8728541 DOI: 10.5483/bmbrep.2021.54.12.105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Microglia are known to be activated in the hypothalamic para-ventricular nucleus (PVN) of rats with cardiovascular diseases. However, the exact role of microglial activation in the plasticity of presympathetic PVN neurons associated with the modulation of sympathetic outflow remains poorly investigated. In this study, we analyzed the direct link between microglial activation and spontaneous firing rate along with the underlying synaptic mechanisms in PVN neurons projecting to the rostral ventrolateral medulla (RVLM). Systemic injection of LPS induced microglial activation in the PVN, increased the frequency of spontaneous firing activity of PVN-RVLM neurons, reduced GABAergic inputs into these neurons, and increased plasma NE levels and heart rate. Systemic minocycline injection blocked all the observed LPS-induced effects. Our results indicate that LPS increases the firing rate and decreases GABAergic transmission in PVN-RVLM neurons associated with sympathetic outflow and the alteration is largely attributed to the activation of microglia. Our findings provide some insights into the role of microglial activation in regulating the activity of PVN-RVLM neurons associated with modulation of sympathetic outflow in cardiovascular diseases.
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Affiliation(s)
- Tae Hee Han
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Korea
| | - Heow Won Lee
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Korea
| | - Eun A Kang
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Korea
| | - Min Seok Song
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Korea
| | - So Yeong Lee
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Korea
| | - Pan Dong Ryu
- Laboratory of Veterinary Pharmacology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Korea
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31
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Ooishi Y, Kobayashi M, Kashino M, Ueno K. Presence of Three-Dimensional Sound Field Facilitates Listeners' Mood, Felt Emotion, and Respiration Rate When Listening to Music. Front Psychol 2021; 12:650777. [PMID: 34867569 PMCID: PMC8637927 DOI: 10.3389/fpsyg.2021.650777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 10/15/2021] [Indexed: 11/23/2022] Open
Abstract
Many studies have investigated the effects of music listening from the viewpoint of music features such as tempo or key by measuring psychological or psychophysiological responses. In addition, technologies for three-dimensional sound field (3D-SF) reproduction and binaural recording have been developed to induce a realistic sensation of sound. However, it is still unclear whether music listened to in the presence of 3D-SF is more impressive than in the absence of it. We hypothesized that the presence of a 3D-SF when listening to music facilitates listeners' moods, emotions for music, and physiological activities such as respiration rate. Here, we examined this hypothesis by evaluating differences between a reproduction condition with headphones (HD condition) and one with a 3D-SF reproduction system (3D-SF condition). We used a 3D-SF reproduction system based on the boundary surface control principle (BoSC system) to reproduce a sound field of music in the 3D-SF condition. Music in the 3D-SF condition was binaurally recorded through a dummy head in the BoSC reproduction room and reproduced with headphones in the HD condition. Therefore, music in the HD condition was auditorily as rich in information as that in the 3D-SF condition, but the 3D-sound field surrounding listeners was absent. We measured the respiration rate and heart rate of participants listening to acousmonium and pipe organ music. The participants rated their felt moods before and after they listened to music, and after they listened, they also rated their felt emotion. We found that the increase in respiration rate, the degree of decrease in well-being, and unpleasantness for both pieces in the 3D-SF condition were greater than in the HD condition. These results suggest that the presence of 3D-SF enhances changes in mood, felt emotion for music, and respiration rate when listening to music.
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Affiliation(s)
- Yuuki Ooishi
- NTT Communication Science Laboratories, NTT Corporation, Atsugi, Japan
| | - Maori Kobayashi
- Faculty of Human Sciences, School of Human Sciences, Waseda University, Tokorozawa, Japan
- Department of Architecture, School of Science and Technology, Meiji University, Kawasaki, Japan
| | - Makio Kashino
- NTT Communication Science Laboratories, NTT Corporation, Atsugi, Japan
| | - Kanako Ueno
- Department of Architecture, School of Science and Technology, Meiji University, Kawasaki, Japan
- Core Research for Evolutional Science and Technology, Japan Science and Technology Agency (CREST, JST), Tokyo, Japan
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Angiotensin II and the Cardiac Parasympathetic Nervous System in Hypertension. Int J Mol Sci 2021; 22:ijms222212305. [PMID: 34830184 PMCID: PMC8624735 DOI: 10.3390/ijms222212305] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/09/2021] [Accepted: 11/10/2021] [Indexed: 01/08/2023] Open
Abstract
The renin-angiotensin-aldosterone system (RAAS) impacts cardiovascular homeostasis via direct actions on peripheral blood vessels and via modulation of the autonomic nervous system. To date, research has primarily focused on the actions of the RAAS on the sympathetic nervous system. Here, we review the critical role of the RAAS on parasympathetic nerve function during normal physiology and its role in cardiovascular disease, focusing on hypertension. Angiotensin (Ang) II receptors are present throughout the parasympathetic nerves and can modulate vagal activity via actions at the level of the nerve endings as well as via the circumventricular organs and as a neuromodulator acting within brain regions. There is tonic inhibition of cardiac vagal tone by endogenous Ang II. We review the actions of Ang II via peripheral nerve endings as well as via central actions on brain regions. We review the evidence that Ang II modulates arterial baroreflex function and examine the pathways via which Ang II can modulate baroreflex control of cardiac vagal drive. Although there is evidence that Ang II can modulate parasympathetic activity and has the potential to contribute to impaired baseline levels and impaired baroreflex control during hypertension, the exact central regions where Ang II acts need further investigation. The beneficial actions of angiotensin receptor blockers in hypertension may be mediated in part via actions on the parasympathetic nervous system. We highlight important unknown questions about the interaction between the RAAS and the parasympathetic nervous system and conclude that this remains an important area where future research is needed.
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Wee HN, Liu JJ, Ching J, Kovalik JP, Lim SC. The Kynurenine Pathway in Acute Kidney Injury and Chronic Kidney Disease. Am J Nephrol 2021; 52:771-787. [PMID: 34753140 PMCID: PMC8743908 DOI: 10.1159/000519811] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND The kynurenine pathway (KP) is the major catabolic pathway for tryptophan degradation. The KP plays an important role as the sole de novo nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway in normal human physiology and functions as a counter-regulatory mechanism to mitigate immune responses during inflammation. Although the KP has been implicated in a variety of disorders including Huntington's disease, seizures, cardiovascular disease, and osteoporosis, its role in renal diseases is seldom discussed. SUMMARY This review summarizes the roles of the KP and its metabolites in acute kidney injury (AKI) and chronic kidney disease (CKD) based on current literature evidence. Metabolomics studies demonstrated that the KP metabolites were significantly altered in patients and animal models with AKI or CKD. The diagnostic and prognostic values of the KP metabolites in AKI and CKD were highlighted in cross-sectional and longitudinal human observational studies. The biological impact of the KP on the pathophysiology of AKI and CKD has been studied in experimental models of different etiologies. In particular, the activation of the KP was found to confer protection in animal models of glomerulonephritis, and its immunomodulatory mechanism may involve the regulation of T cell subsets such as Th17 and regulatory T cells. Manipulation of the KP to increase NAD+ production or diversion toward specific KP metabolites was also found to be beneficial in animal models of AKI. Key Messages: KP metabolites are reported to be dysregulated in human observational and animal experimental studies of AKI and CKD. In AKI, the magnitude and direction of changes in the KP depend on the etiology of the damage. In CKD, KP metabolites are altered with the onset and progression of CKD all the way to advanced stages of the disease, including uremia and its related vascular complications. The activation of the KP and diversion to specific sub-branches are currently being explored as therapeutic strategies in these diseases, especially with regards to the immunomodulatory effects of certain KP metabolites. Further elucidation of the KP may hold promise for the development of biomarkers and targeted therapies for these kidney diseases.
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Affiliation(s)
| | - Jian-Jun Liu
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore
| | - Jianhong Ching
- Duke-NUS Medical School, Singapore, Singapore
- KK Research Centre, KK Women's and Children's Hospital, Singapore, Singapore
| | | | - Su Chi Lim
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
- Diabetes Centre, Admiralty Medical Centre, Singapore, Singapore
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Gemici A, Sinen O, Bülbül M. Sexual dimorphism in rats exposed to maternal high fat diet: alterations in medullary sympathetic network. Metab Brain Dis 2021; 36:1305-1314. [PMID: 33914222 DOI: 10.1007/s11011-021-00736-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 04/08/2021] [Indexed: 10/21/2022]
Abstract
Exposure to high fat diet during perinatal period (PHFD) leads to neuroplastic changes in autonomic circuits, however, the role of gender has been incompletely understood. This study aims to investigate (i) short, and (ii) long-term effects of PHFD on autonomic outflow, and (iii) sexual dimorphic variations emerge at adulthood. Male and female rats were fed a control diet (13.5 % kcal from fat) or PHFD (60 % kcal from fat) from embryonic day-14 to postnatal day-21. To assess changes in autonomic outflow, heart rate variability (HRV) was analyzed at 10- and 20-week-old ages. Expressions of tyrosine hydroxylase (TH), metabotropic glutamate2/3 receptor (mGlu2/3R), N-methyl-D-aspartate1 receptor (NMDA1R), and gamma aminobutyric acidA receptor (GABAAR) were evaluated by immunohistochemistry. PHFD did not affect the body weight of 4-, 10-or 20-week-old male or female offsprings. PHFD significantly increased the sympathetic marker low frequency (LF) component, and sympatho-vagal balance (LF:HF) only in 10-week-old PHFD males. Compared with control, the propranolol-induced (4 mg·kg- 1, ip) decline in LF was observed more prominently in PHFD rats, however, these changes were found to be restored at the age of 20 weeks. In caudal ventrolateral medulla and nucleus tractus solitarius, expression of mGlu2/3R was downregulated in PHFD males, whereas no change was detected in NMDA1R. The number of GABAAR-expressing TH-immunoreactive cells was decreased in rostral ventrolateral medulla of PHFD males. The findings of this study suggest that exposure to maternal high-fat diet could lead to autonomic imbalance with increased sympathetic tone in the early adulthood of male offspring rats without developing obesity.
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Affiliation(s)
- Ayşegül Gemici
- Department of Physiology, Faculty of Medicine, Akdeniz University, 07070, Antalya, Turkey
| | - Osman Sinen
- Department of Physiology, Faculty of Medicine, Akdeniz University, 07070, Antalya, Turkey
| | - Mehmet Bülbül
- Department of Physiology, Faculty of Medicine, Akdeniz University, 07070, Antalya, Turkey.
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35
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Ooishi Y, Fujino M, Inoue V, Nomura M, Kitagawa N. Differential Effects of Focused Attention and Open Monitoring Meditation on Autonomic Cardiac Modulation and Cortisol Secretion. Front Physiol 2021; 12:675899. [PMID: 34335292 PMCID: PMC8320390 DOI: 10.3389/fphys.2021.675899] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 06/22/2021] [Indexed: 12/18/2022] Open
Abstract
Mindfulness-based interventions (MBIs) have been used widely as a useful tool for the alleviation of various stress-related symptoms. However, the effects of MBIs on stress-related physiological activity have not yet been ascertained. MBIs primarily consist of focused-attention (FA) and open-monitoring (OM) meditation. Since differing effects of FA and OM meditation on brain activities and cognitive tasks have been mentioned, we hypothesized that FA and OM meditation have also differing effects on stress-related physiological activity. In this study, we examined the effects of FA and OM meditation on autonomic cardiac modulation and cortisol secretion. Forty-one healthy adults (aged 20-46 years) who were meditation novices experienced 30-min FA and OM meditation tasks by listening to instructions. During resting- and meditation-states, electrocardiogram transducers were attached to participants to measure the R-R interval, which were used to evaluate heart rate (HR) and perform heart rate variability (HRV) analyses. Saliva samples were obtained from participants pre- and post-meditation to measure salivary cortisol levels. Results showed that FA meditation induced a decrease in HR and an increase in the root mean square of successive differences (rMSDD). In contrast, OM meditation induced an increase in the standard deviation of the normal-to-normal interval (SDNN) to rMSSD ratio (SDNN/rMSSD) and a decrease in salivary cortisol levels. These results suggest that FA meditation elevates physiological relaxation, whereas OM meditation elevates physiological arousal and reduces stress.
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Affiliation(s)
- Yuuki Ooishi
- NTT Communication Science Laboratories, NTT Corporation, Atsugi, Japan
| | - Masahiro Fujino
- Open Innovation Institute, Kyoto University, Kyoto, Japan.,Division of Cognitive Psychology in Education, Graduate School of Education, Kyoto University, Kyoto, Japan
| | - Vimala Inoue
- Faculty of Health Science, Health Science University, Fujikawaguchiko, Japan
| | - Michio Nomura
- Division of Cognitive Psychology in Education, Graduate School of Education, Kyoto University, Kyoto, Japan
| | - Norimichi Kitagawa
- NTT Communication Science Laboratories, NTT Corporation, Atsugi, Japan.,BKC Research Organization of Social Sciences, Ritsumeikan University, Kusatsu, Japan.,Yoshika Institute of Psychology, Kanoashi, Japan
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36
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Proskurnina EV, Sokolova SV, Portnova GV. Touch-induced emotional comfort results in an increase in the salivary antioxidant potential: A correlational study. Psychophysiology 2021; 58:e13854. [PMID: 34061347 DOI: 10.1111/psyp.13854] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 05/05/2021] [Accepted: 05/05/2021] [Indexed: 12/19/2022]
Abstract
A pleasant touch reduces psychoemotional stress via the oxytocin mechanism due to its anti-inflammatory and antioxidant effects. Our research is aimed to reveal the correlations between the subjectively perceived pleasantness of touch, the antioxidant potential of saliva, and salivary oxytocin. A total of 56 healthy volunteers aged 18-38 years participated in the study. The control group consisted of 24 volunteers. The participants were subjected to tactile stimulation using a specially designed protocol. They ranked the touch pleasantness on a scale from 1 to 10. Heart rate variability and low-frequency/high-frequency ratios from the power spectral density of ECG were determined to assess psychoemotional relaxation. Salivary oxytocin and antioxidant capacity were quantified before and after the touch test. We found a significant increase in salivary antioxidant potential and oxytocin after pleasant tactile stimulation for the participants compared to the control group. The difference in antioxidant capacity values before and after the test positively correlated with mean pleasantness in the touch test (r = 0.57) and the difference in heart rate variability (r = 0.67); it negatively correlated with the difference in low-frequency/high-frequency ECG band ratio (r = -0.59). Oxytocin ratio positively correlated with the difference in antioxidant capacity values (r = 0.47). As a result of tactile stimulation, a significant increase in the antioxidant capacity of saliva and salivary oxytocin was found in the test group compared to the control group. These findings support further studies of the effects of pleasant touch on hormonal and oxidative metabolism.
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Affiliation(s)
- Elena V Proskurnina
- Laboratory of Molecular Biology, Research Centre for Medical Genetics, Moscow, Russia
| | - Svetlana V Sokolova
- Medical Research and Educational Center, Lomonosov Moscow State University, Moscow, Russia
| | - Galina V Portnova
- Laboratory of the Human Higher Nervous Activity, Institute of Higher Nervous Activity and Neurophysiology of Russian Academy of Sciences, Moscow, Russia
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37
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Li TL, Lee YH, Wu FH, Hwang LL. Orexin-A directly depolarizes dorsomedial hypothalamic neurons, including those innervating the rostral ventrolateral medulla. Eur J Pharmacol 2021; 899:174033. [PMID: 33727058 DOI: 10.1016/j.ejphar.2021.174033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 02/10/2021] [Accepted: 03/10/2021] [Indexed: 02/04/2023]
Abstract
The dorsomedial hypothalamus (DMH) receives dense orexinergic innervation. Intra-DMH application of orexins increases arterial pressure and heart rate in rats. We studied the effects of orexin-A on DMH neurons, including those innervating the medullary cardiovascular center, the rostral ventrolateral medulla (RVLM), by using whole-cell recordings in brain slices. In the presence of tetrodotoxin, orexin-A (30-1000 nM) depolarized 56% of DMH neurons (EC50 82.4 ± 4.4 nM). Under voltage-clamp recording, orexin-A (300 nM) induced three types of responses characterized by different current-voltage relationships, namely unchanged, increased, and decreased slope conductance in 68%, 14%, and 18% of orexin-A-responsive neurons, respectively. The reversal potential of the decreased-conductance response was near the equilibrium potential of K+ and became more positive in a high-K+ solution, suggesting that K+ conductance blockade is the underlying mechanism. In a low-Na+ solution, unchanged-, increased-, and decreased-conductance responses were observed in 56%, 11%, and 33% of orexin-A-responsive neurons, respectively, implying that a non-selective cation current (NSCC) underlies orexin-A-induced responses in a small population of DMH neurons. KBR-7943 (70 μM), an inhibitor of Na+-Ca2+ exchanger (NCX), suppressed orexin-A-induced depolarization in 7 of 10 neurons. In the presence of KBR-7943, the majority of orexin-A-responsive neurons exhibited decreased-conductance responses. These findings suggest that NCX activation may underlie orexin-A-induced depolarization in the majority of orexin-responsive DMH neurons. Of 19 RVLM-projecting DMH neurons identified by retrograde labeling, 17 (90%) were orexin-A responsive. In conclusion, orexin-A directly excited over half of DMH neurons, including those innervating the RVLM, through decreasing K+ conductance, activating NCX, and/or increasing NSCC.
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Affiliation(s)
- Tzu-Ling Li
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
| | - Yen-Hsien Lee
- Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu, Taiwan.
| | - Feng-Hsu Wu
- Division of General Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.
| | - Ling-Ling Hwang
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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38
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P11 deficiency increases stress reactivity along with HPA axis and autonomic hyperresponsiveness. Mol Psychiatry 2021; 26:3253-3265. [PMID: 33005029 PMCID: PMC8505237 DOI: 10.1038/s41380-020-00887-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/02/2020] [Accepted: 09/11/2020] [Indexed: 12/22/2022]
Abstract
Patients suffering from mood disorders and anxiety commonly exhibit hypothalamic-pituitary-adrenocortical (HPA) axis and autonomic hyperresponsiveness. A wealth of data using preclinical animal models and human patient samples indicate that p11 deficiency is implicated in depression-like phenotypes. In the present study, we used p11-deficient (p11KO) mice to study potential roles of p11 in stress responsiveness. We measured stress response using behavioral, endocrine, and physiological readouts across early postnatal and adult life. Our data show that p11KO pups respond more strongly to maternal separation than wild-type pups, even though their mothers show no deficits in maternal behavior. Adult p11KO mice display hyperactivity of the HPA axis, which is paralleled by depression- and anxiety-like behaviors. p11 was found to be highly enriched in vasopressinergic cells of the paraventricular nucleus and regulates HPA hyperactivity in a V1B receptor-dependent manner. Moreover, p11KO mice display sympathetic-adrenal-medullary (SAM) axis hyperactivity, with elevated adrenal norepinephrine and epinephrine levels. Using conditional p11KO mice, we demonstrate that this SAM hyperactivity is partially regulated by the loss of p11 in serotonergic neurons of the raphe nuclei. Telemetric electrocardiogram measurements show delayed heart rate recovery in p11KO mice in response to novelty exposure and during expression of fear following auditory trace fear conditioning. Furthermore, p11KO mice have elevated basal heart rate in fear conditioning tests indicating increased autonomic responsiveness. This set of experiments provide strong and versatile evidence that p11 deficiency leads to HPA and SAM axes hyperresponsiveness along with increased stress reactivity.
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39
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Líšková S, Bališ P, Mičurová A, Kluknavský M, Okuliarová M, Puzserová A, Škrátek M, Sekaj I, Maňka J, Valovič P, Bernátová I. Effect of iron oxide nanoparticles on vascular function and nitric oxide production in acute stress-exposed rats. Physiol Res 2020; 69:1067-1083. [PMID: 33129250 DOI: 10.33549/physiolres.934567] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
We investigated whether polyethylene glycol-coated Fe3O4 nanoparticles (IONs), acute stress and their combination modifies vascular functions, nitric oxide synthase (NOS) activity, mean arterial pressure (MAP) as well as hepcidin and ferritin H gene expressions in Wistar-Kyoto rats. Rats were divided into control, ION-treated rats (1 mg Fe/kg i.v.), repeated acute air-jet stress-exposed rats and IONs-and-stress co-exposed rats. Maximal acetylcholine (ACh)-induced and sodium nitroprusside (SNP)-induced relaxations in the femoral arteries did not differ among the groups. IONs alone significantly elevated the N?-nitro-L-arginine methyl ester (L-NAME)-sensitive component of ACh-induced relaxation and reduced the sensitivity of vascular smooth muscle cells to SNP. IONs alone also elevated NOS activity in the brainstem and hypothalamus, reduced NOS activity in the kidneys and had no effect in the liver. Acute stress alone failed to affect vascular function and NOS activities in all the tissues investigated but it elevated ferritin H expression in the liver. In the ION-and-stress group, NOS activity was elevated in the kidneys and liver, but reduced in the brainstem and hypothalamus vs. IONs alone. IONs also accentuated air-jet stress-induced MAP responses vs. stress alone. Interestingly, stress reduced ION-originated iron content in blood and liver while it was elevated in the kidneys. In conclusion, the results showed that 1) acute administration of IONs altered vascular function, increased L-NAME-sensitive component of ACh-induced relaxation and had tissue-dependent effects on NOS activity, 2) ION effects were considerably reduced by co-exposure to repeated acute stress, likely related to decrease of ION-originated iron in blood due to elevated decomposition and/or excretion.
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Affiliation(s)
- S Líšková
- Institute of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Comenius University, Bratislava, Slovakia, , and Institute of Normal and Pathological Physiology, Centre of Experimental Medicine, Slovak Academy of Sciences, Bratislava, Slovakia,
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40
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Tian L, Tang G, Liu Q, Yin Y, Li Y, Zhong Y. Blockade of adenosine A1 receptor in nucleus tractus solitarius attenuates baroreflex sensitivity response to dexmedetomidine in rats. Brain Res 2020; 1743:146949. [PMID: 32522627 DOI: 10.1016/j.brainres.2020.146949] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 05/07/2020] [Accepted: 06/04/2020] [Indexed: 12/30/2022]
Abstract
The α2-adrenergic receptor (α2-AR) agonist dexmedetomidine increases baroreflex sensitivity (BRS). In the current study, we examined the potential role of adenosine A1 receptor (A1R) within the nucleus tractus solitaries (NTS) in such a response. Briefly, adult male Sprague-Dawley rats were anesthetized and randomly received microinjection of selective A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.1 pmol/1 μl) or saline vehicle into the right NTS. Ten min after the microinjection, dexmedetomidine infusion started at a rate of 30 μg/kg over 15 min followed by infusion at 15 μg·kg-1·h-1 for 105 min, or 100 μg/kg over 15 min followed by infusion at 50 μg·kg-1·h-1 for 105 min. BRS was examined using a standard phenylephrine method prior to infusion (T0), 60 min (T1) and 120 min (T2) after dexmedetomidine infusion started. Adenosine concentration in plasma and brainstem was measured with high-performance liquid chromatography with vs. without α2-AR antagonist atipamezole pretreatment (0.5 mg/kg, i.p.). Dexmedetomidine increased BRS at both 30 (T0: 0.55 ± 0.25 vs. T1: 2.45 ± 0.37, T2: 2.26 ± 0.56 ms/mmHg, P < 0.05) and 100 μg/kg (T0: 0.63 ± 0.24 vs. T1: 6.21 ± 1.87, T2: 6.30 ± 2.12 ms/mmHg, P < 0.05). DPCPX pretreatment obliterated BRS response to 100-μg/kg dexmedetomidine. At 100 μg/kg, dexmedetomidine increased adenosine concentration in plasma (0.23 ± 0.11 to 0.45 ± 0.07 μg/ml, P < 0.05) and brainstem (1.46 ± 0.30 to 2.52 ± 0.22 μg/ml, P < 0.05); such effect was blocked by atipamezole pretreatment. Western blot analysis showed α2-AR up-regulation by 100-μg/kg dexmedetomidine, which can be prevented by DPCPX. Double-labeling with glial fibrillary acidic protein showed α2-AR up-regulation in astrocytes in the NTS. These results suggest that dexmedetomidine enhances baroreflex sensitivity, possibly by increasing adenosine in NTS and α2-AR expression in astrocytes.
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Affiliation(s)
- Lei Tian
- Department of Anesthesiology, Zigong First People's Hospital, Zigong, Sichuan, China
| | - Guoqiang Tang
- Department of Anesthesiology, Zigong First People's Hospital, Zigong, Sichuan, China
| | - Qian Liu
- Department of Anesthesiology, Zigong First People's Hospital, Zigong, Sichuan, China
| | - Yongqiang Yin
- Department of Anesthesiology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Yiping Li
- Department of Anesthesiology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Yi Zhong
- Department of Anesthesiology, Affiliated Hospital of Guizhou Medical University, Guiyang, China.
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Kono Y, Yokota S, Fukushi I, Arima Y, Onimaru H, Okazaki S, Takeda K, Yazawa I, Yoshizawa M, Hasebe Y, Koizumi K, Pokorski M, Toda T, Sugita K, Okada Y. Structural and functional connectivity from the dorsomedial hypothalamus to the ventral medulla as a chronological amplifier of sympathetic outflow. Sci Rep 2020; 10:13325. [PMID: 32770006 PMCID: PMC7414200 DOI: 10.1038/s41598-020-70234-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 07/27/2020] [Indexed: 12/15/2022] Open
Abstract
Psychological stress activates the hypothalamus, augments the sympathetic nervous output, and elevates blood pressure via excitation of the ventral medullary cardiovascular regions. However, anatomical and functional connectivity from the hypothalamus to the ventral medullary cardiovascular regions has not been fully elucidated. We investigated this issue by tract-tracing and functional imaging in rats. Retrograde tracing revealed the rostral ventrolateral medulla was innervated by neurons in the ipsilateral dorsomedial hypothalamus (DMH). Anterograde tracing showed DMH neurons projected to the ventral medullary cardiovascular regions with axon terminals in contiguity with tyrosine hydroxylase-immunoreactive neurons. By voltage-sensitive dye imaging, dynamics of ventral medullary activation evoked by electrical stimulation of the DMH were analyzed in the diencephalon-lower brainstem-spinal cord preparation of rats. Although the activation of the ventral medulla induced by single pulse stimulation of the DMH was brief, tetanic stimulation caused activation of the DMH sustained into the post-stimulus phase, resulting in delayed recovery. We suggest that prolonged excitation of the DMH, which is triggered by tetanic electrical stimulation and could also be triggered by psychological stress in a real life, induces further prolonged excitation of the medullary cardiovascular networks, and could contribute to the pathological elevation of blood pressure. The connectivity from the DMH to the medullary cardiovascular networks serves as a chronological amplifier of stress-induced sympathetic excitation. This notion will be the anatomical and pathophysiological basis to understand the mechanisms of stress-induced sustained augmentation of sympathetic activity.
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Affiliation(s)
- Yosuke Kono
- Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan.,Clinical Research Center, Murayama Medical Center, 2-37-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan
| | - Shigefumi Yokota
- Department of Anatomy and Morphological Neuroscience, Shimane University School of Medicine, Izumo, Shimane, 693-8501, Japan
| | - Isato Fukushi
- Clinical Research Center, Murayama Medical Center, 2-37-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan.,Faculty of Health Sciences, Uekusa Gakuen University, Chiba, 264-0007, Japan
| | - Yosuke Arima
- Department of Anatomy and Morphological Neuroscience, Shimane University School of Medicine, Izumo, Shimane, 693-8501, Japan
| | - Hiroshi Onimaru
- Department of Physiology, Showa University School of Medicine, Shinagawa, Tokyo, 142-8555, Japan
| | - Shuntaro Okazaki
- Faculty of Human Sciences, Waseda University, Tokorozawa, Saitama, 359-1192, Japan
| | - Kotaro Takeda
- Faculty of Rehabilitation, School of Healthcare, Fujita Health University, Toyoake, Aichi, 470-1192, Japan
| | - Itaru Yazawa
- Global Research Center for Innovative Life Science, Hoshi University, Shinagawa, Tokyo, 142-8501, Japan
| | - Masashi Yoshizawa
- Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan.,Clinical Research Center, Murayama Medical Center, 2-37-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan
| | - Yohei Hasebe
- Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan.,Clinical Research Center, Murayama Medical Center, 2-37-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan
| | - Keiichi Koizumi
- Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan
| | | | - Takako Toda
- Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan
| | - Kanji Sugita
- Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, 409-3898, Japan
| | - Yasumasa Okada
- Clinical Research Center, Murayama Medical Center, 2-37-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan.
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42
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Roy SJ, Tanaka H. Whole Milk and Full-Fat Dairy Products and Hypertensive Risks. Curr Hypertens Rev 2020; 17:181-195. [PMID: 32753019 DOI: 10.2174/1573402116666200804152649] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 06/24/2020] [Accepted: 06/29/2020] [Indexed: 11/22/2022]
Abstract
Lifestyle modifications in the form of diet and exercise are generally a first-line approach to reduce hypertensive risk and overall cardiovascular disease (CVD) risk. Accumulating research evidence has revealed that consumption of non- and low-fat dairy products incorporated into the routine diet is an effective means to reduce elevated blood pressure and improve vascular functions. However, the idea of incorporating whole-fat or full-fat dairy products in the normal routine diet as a strategy to reduce CVD risk has been met with controversy. The aim of this review is to review both sides of the argument surrounding saturated fat intake and CVD risk from the standpoint of dairy intake. Throughout the review, we examined observational studies on relationships between CVD risk and dairy consumption, dietary intervention studies using non-fat and whole-fat dairy, and mechanistic studies investigating physiological mechanisms of saturated fat intake that may help to explain increases in cardiovascular disease risk. Currently available data have demonstrated that whole-fat dairy is unlikely to augment hypertensive risk when added to the normal routine diet but may negatively impact CVD risk. In conclusion, whole-fat dairy may not be a recommended alternative to non- or low-fat dairy products as a means to reduce hypertensive or overall CVD risk.
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Affiliation(s)
- Stephen J Roy
- Department of Kinesiology and Health Education, Cardiovascular Aging Research Laboratory, The University of Texas at Austin, TX 78712. United States
| | - Hirofumi Tanaka
- Department of Kinesiology and Health Education, Cardiovascular Aging Research Laboratory, The University of Texas at Austin, TX 78712. United States
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Effects of vascular compression on the rostral ventrolateral medulla for blood pressure variability in stroke patients. J Hypertens 2020; 38:2443-2450. [PMID: 32740401 DOI: 10.1097/hjh.0000000000002575] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUNDS Vascular compression of the rostral ventrolateral medulla (RVLM) has been associated with hypertension or blood pressure (BP) variability. For acute ischemic stroke patients, increased BP variability may cause poor functional outcomes. We tested the hypothesis that RVLM compression was associated with increased BP variability or stroke outcome in acute ischemic stroke patients. METHODS Acute ischemic stroke patients (n = 622) with 24-h ambulatory BP monitoring during the subacute phase of stroke (median 9 days from onset) were retrospectively studied. Variability in BP was evaluated with the SD and coefficient of variation of SBP and DBP. The morning surge was also evaluated. The presence of RVLM compression was evaluated using time-of-flight three-dimensional MRI. A poor outcome was defined as a modified Rankin Scale score of 3-6 at 3 months. RESULTS Patients with RVLM compression (n = 213) had significantly higher 24-h SBP mean, 24-h SBP SD, 24-h SBP coefficient of variation, 24-h DBP mean, 24-h DBP SD, and 24-h DBP coefficient of variation values and a higher prevalence of morning surge than those without (n = 409). Multiple regression analysis revealed that RVLM compression was associated with increased SBP variability, DBP variability, and morning surge. Despite the significant association between RVLM compression and BP variability, RVLM compression was not associated with poor stroke outcome. CONCLUSION Although RVLM compression was closely associated with BP variability in the subacute ischemic stroke phase, an effect of RVLM compression on stroke outcome was not observed.
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Lee HW, Ahmad M, Wang HW, Leenen FHH. Effects of exercise on BDNF-TrkB signaling in the paraventricular nucleus and rostral ventrolateral medulla in rats post myocardial infarction. Neuropeptides 2020; 82:102058. [PMID: 32507324 DOI: 10.1016/j.npep.2020.102058] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 05/19/2020] [Accepted: 05/20/2020] [Indexed: 02/07/2023]
Abstract
Brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling in the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) is associated with cardiovascular regulation. Exercise increases plasma BDNF and attenuates activation of central pathways in the PVN and RVLM post myocardial infarction (MI). The present study assessed whether MI alters BDNF-TrkB signaling and intracellular factors Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Akt in the PVN and RVLM of male Wistar rats with or without exercise or treatment with the TrkB blocker ANA-12. A 4-week period of treadmill exercise training was performed in MI rats. A separate experiment was conducted with 2.5 mg/kg ANA-12 in sedentary MI rats. At 5 weeks post MI, in both the PVN and RVLM, the ratio of full-length TrkB (TrkB.FL) and truncated TrkB (TrkB.T1) was decreased. 0.5 mg/kg ANA-12 did not affect BDNF-TrkB signaling and cardiac function post MI, but 2.5 mg/kg ANA-12 further decreased ejection fraction (EF). Exercise increased mature BDNF (mBDNF) and decreased Akt activity in the PVN, whereas in the RVLM, exercise did not affect mBDNF but lowered p-CaMKIIβ. ANA-12 prevented the exercise-induced increase in mBDNF in the PVN and decrease in p-CaMKIIβ in the RVLM. In conclusion, exercise decreases Akt activity in the PVN and decreases p-CaMKIIβ in the RVLM post MI. BDNF-TrkB signaling only mediates the decrease in p-CaMKIIβ in the RVLM. The exercise-induced decreases in Akt activity in the PVN and p-CaMKIIβ in the RVLM may contribute to the attenuation of the decrease in EF and sympathetic hyperactivity post MI.
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Affiliation(s)
- Heow Won Lee
- Brain and Heart Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Monir Ahmad
- Brain and Heart Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Hong-Wei Wang
- Brain and Heart Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Frans H H Leenen
- Brain and Heart Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
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Wenwen W, Qiongbo WU, Chao Z, Mengya W, Huanhuan Z. [Neural pathway between the nucleus accumbens and the rostral ventrolateral medulla in a rat model of anorexia nervosa]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:609-615. [PMID: 32897201 DOI: 10.12122/j.issn.1673-4254.2020.05.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To investigate the potential neural pathway connecting the nucleus accumbens (NAc) and the rostral ventrolateral medulla (RVLM), and whether the pathway participates in the regulation of cardiovascular function in a model rat of anorexia nervosa (AN). METHODS Rat models of AN were established by allowing voluntary activity in a running wheel with restricted feeding, with the rats having free access to normal chow without exercise as the control group. FluoroGold (FG) retrograde tracing method and multi-channel simultaneous recording technique were used to explore the possible pathway between the NAc and the RVLM. RESULTS The rats in AN group exhibited significantly reduced systolic blood pressure (SBP), mean arterial pressure (MAP) and heart rate (HR) with significantly increased discharge frequency of RVLM neurons in comparison with the control rats. After the injection of FG into the RVLM, retrograde labeled neurons were observed in the NAc of the rats in both the normal control and AN groups. In both groups, SBP and HR were significantly decreased in response to 400 μA electrical stimulation of the NAc accompanied by an obvious increase in the discharge frequency of the RVLM neurons; the diastolic blood pressure (DBP) and MAP were significantly lower in AN model rats than in the normal rats in response to the stimulation. CONCLUSIONS We successfully established a rat model of AN via hyperactivity and restricted feeding and confirm the presence of a neural pathway connecting the NAc and the RVLM. This pathway might participate in the regulation of cardiovascular function in AN model rats.
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Affiliation(s)
- Wei Wenwen
- Psychophysiology Laboratory, Wannan Medical College, Wuhu 241002, China.,Cell Electrophysiology Laboratory, Wannan Medical College, Wuhu 241002, China
| | - W U Qiongbo
- Psychophysiology Laboratory, Wannan Medical College, Wuhu 241002, China.,Cell Electrophysiology Laboratory, Wannan Medical College, Wuhu 241002, China
| | - Zheng Chao
- Neurobiology Laboratory, Wannan Medical College, Wuhu 241002, China
| | - Wang Mengya
- Cell Electrophysiology Laboratory, Wannan Medical College, Wuhu 241002, China
| | - Zhang Huanhuan
- Psychophysiology Laboratory, Wannan Medical College, Wuhu 241002, China
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Ramachandran CD, Gholami K, Lam SK, Hoe SZ. A preliminary study of the effect of a high-salt diet on transcriptome dynamics in rat hypothalamic forebrain and brainstem cardiovascular control centers. PeerJ 2020; 8:e8528. [PMID: 32175184 PMCID: PMC7059759 DOI: 10.7717/peerj.8528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 01/07/2020] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND High dietary salt intake is strongly correlated with cardiovascular (CV) diseases and it is regarded as a major risk factor associated with the pathogenesis of hypertension. The CV control centres in the brainstem (the nucleus tractus solitarii (NTS) and the rostral ventrolateral medulla (RVLM)) and hypothalamic forebrain (the subfornical organ, SFO; the supraoptic nucleus, SON and the paraventricular nucleus, PVN) have critical roles in regulating CV autonomic motor outflows, and thus maintaining blood pressure (BP). Growing evidence has implicated autonomic regulatory networks in salt-sensitive HPN (SSH), but the genetic basis remains to be delineated. We hypothesized that the development and/ or maintenance of SSH is reliant on the change in the expression of genes in brain regions controlling the CV system. METHODOLOGY We used RNA-Sequencing (RNA-Seq) to describe the differential expression of genes in SFO, SON, PVN, NTS and RVLM of rats being chronically fed with high-salt (HS) diet. Subsequently, a selection of putatively regulated genes was validated with quantitative reverse transcription polymerase chain reaction (qRT-PCR) in both Spontaneously Hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats. RESULTS The findings enabled us to identify number of differentially expressed genes in SFO, SON, PVN, NTS and RVLM; that are either up-regulated in both strains of rats (SON- Caprin2, Sctr), down-regulated in both strains of rats (PVN- Orc, Gkap1), up-regulated only in SHRs (SFO- Apopt1, Lin52, AVP, OXT; SON- AVP, OXT; PVN- Caprin2, Sclt; RVLM- A4galt, Slc29a4, Cmc1) or down-regulated only in SHRs (SON- Ndufaf2, Kcnv1; PVN- Pi4k2a; NTS- Snrpd2l, Ankrd29, St6galnac6, Rnf157, Iglon5, Csrnp3, Rprd1a; RVLM- Ttr, Faim). CONCLUSIONS These findings demonstrated the adverse effects of HS diet on BP, which may be mediated via modulating the signaling systems in CV centers in the hypothalamic forebrain and brainstem.
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Affiliation(s)
- Chitra Devi Ramachandran
- Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Wilayah Perseketuan, Malaysia
| | - Khadijeh Gholami
- Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Wilayah Perseketuan, Malaysia
- Human Biology Division, School of Medicine, International Medical University, Kuala Lumpur, Wilayah Perseketuan, Malaysia
| | - Sau Kuen Lam
- Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Wilayah Perseketuan, Malaysia
- Department of Pre-Clinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Sungai Long, Selangor, Malaysia
| | - See Ziau Hoe
- Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Wilayah Perseketuan, Malaysia
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Papagiannopoulos-Vatopaidinos IE, Papagiannopoulou M, Sideris V. Dry Fasting Physiology: Responses to Hypovolemia and Hypertonicity. Complement Med Res 2020; 27:242-251. [PMID: 31958788 DOI: 10.1159/000505201] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 12/03/2019] [Indexed: 11/19/2022]
Abstract
OBJECTIVE The aim of this study was to provide a deeper insight into dry fasting (DF) physiology. DESIGN Ten participants performed DF for 5 consecutive days. METHODS The following parameters were monitored daily: cortisol, aldosterone, high-sensitivity C-reactive protein (CRP), erythropoietin, albumin, uric acid, and vitamin C in serum; vasopressin (ADH), adrenocorticotropic hormone (ACTH), renin, angiotensin II, and total antioxidant capacity (TAC) in plasma; hematocrit and erythrocytes in whole blood; osmolality, noradrenaline, dopamine, adrenaline, Na+, and K+ in 24-h urine; waist circumference and body, urine, and stool weight. RESULTS The following parameters increased: ADH (60 ± 11%), ACTH (176 ± 34%), cortisol (495 ± 75%), urine osmolality (20 ± 4%), CRP (167 ± 77%), renin (315 ± 63%), angiotensin II (74 ± 21%), aldosterone (61 ± 21%), TAC (80.4 ± 17%), uric acid (103 ± 19%), albumin (18.4 ± 2.4%), erythrocytes (13.4 ± 2.2%), hematocrit (11 ± 1.8%), and the excretion of noradrenaline (40.3 ± 10%) and dopamine (17 ± 5%). The following parameters decreased: waist circumference (8.20 ± 0.61 cm), body weight (7.010 ± 0.3 kg), erythropoietin (65 ± 18%), and the excretion of adrenaline (38 ± 4%) and Na+ (60 ± 16%). The excretion of K+ remained unchanged. Vitamin C decreased, showing a half-life of 4.8 ± 0.7 days. The percent ratios of lost weight components were: urine (52.2 ± 3.7%), insensible water loss (32.2 ± 1.4%), stool (5 ± 0.3%), and respiratory gases, i.e., expired CO2 - incorporated O2 (10.6 ± 5.4%). CONCLUSION The mechanisms underlying the hypertonicity and hypovolemia compensation and the ratio analysis of lost weight components were presented. DF demonstrated short-term antioxidant, anti-ischemic, immune-stimulating, anti-edematous, and anti-inflammatory effects. The results may have an impact on developing new concepts for the treatment of edema, obesity, and inflammatory and ischemic diseases.
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Affiliation(s)
| | - Maria Papagiannopoulou
- Institute for Social Medicine, Epidemiology, and Health Economics, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Vassilis Sideris
- Hellenic Pasteur Institute, Athens, Greece.,Alexandra Hospital, Athens, Greece
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Kiuchi MG, Ho JK, Nolde JM, Gavidia LML, Carnagarin R, Matthews VB, Schlaich MP. Sympathetic Activation in Hypertensive Chronic Kidney Disease - A Stimulus for Cardiac Arrhythmias and Sudden Cardiac Death? Front Physiol 2020; 10:1546. [PMID: 32009970 PMCID: PMC6974800 DOI: 10.3389/fphys.2019.01546] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 12/09/2019] [Indexed: 12/11/2022] Open
Abstract
Studies have revealed a robust and independent correlation between chronic kidney disease (CKD) and cardiovascular (CV) events, including death, heart failure, and myocardial infarction. Recent clinical trials extend this range of adverse CV events, including malignant ventricular arrhythmias and sudden cardiac death (SCD). Moreover, other studies point out that cardiac structural and electrophysiological changes are a common occurrence in this population. These processes are likely contributors to the heightened hazard of arrhythmias in CKD population and may be useful indicators to detect patients who are at a higher SCD risk. Sympathetic overactivity is associated with increased CV risk, specifically in the population with CKD, and it is a central feature of the hypertensive state, occurring early in its clinical course. Sympathetic hyperactivity is already evident at the earliest clinical stage of CKD and is directly related to the progression of renal failure, being most pronounced in those with end-stage renal disease. Sympathetic efferent and afferent neural activity in kidney failure is a crucial facilitator for the perpetuation and evolvement of the disease. Here, we will revisit the role of the feedback loop of the sympathetic neural cycle in the context of CKD and how it may aggravate several of the risk factors responsible for causing SCD. Targeting the overactive sympathetic nervous system therapeutically, either pharmacologically or with newly available device-based approaches, may prove to be a pivotal intervention to curb the substantial burden of cardiac arrhythmias and SCD in the high-risk population of patients with CKD.
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Affiliation(s)
- Márcio Galindo Kiuchi
- Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Jan K Ho
- Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Janis Marc Nolde
- Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Leslie Marisol Lugo Gavidia
- Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Revathy Carnagarin
- Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Vance B Matthews
- Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Markus P Schlaich
- Dobney Hypertension Centre, School of Medicine - Royal Perth Hospital Unit/Medical Research Foundation, The University of Western Australia, Perth, WA, Australia.,Departments of Cardiology and Nephrology, Royal Perth Hospital, Perth, WA, Australia.,Neurovascular Hypertension & Kidney Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
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Zhang S, Hu L, Jiang J, Li H, Wu Q, Ooi K, Wang J, Feng Y, Zhu D, Xia C. HMGB1/RAGE axis mediates stress-induced RVLM neuroinflammation in mice via impairing mitophagy flux in microglia. J Neuroinflammation 2020; 17:15. [PMID: 31924219 PMCID: PMC6953162 DOI: 10.1186/s12974-019-1673-3] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 12/11/2019] [Indexed: 12/15/2022] Open
Abstract
Background Microglial mediated neuroinflammation in the rostral ventrolateral medulla (RVLM) plays roles in the etiology of stress-induced hypertension (SIH). It was reported that autophagy influenced inflammation via immunophenotypic switching of microglia. High-mobility group box 1 (HMGB1) acts as a regulator of autophagy and initiates the production of proinflammatory cytokines (PICs), but the underlying mechanisms remain unclear. Methods The stressed mice were subjected to intermittent electric foot shocks plus noises administered for 2 h twice daily for 15 consecutive days. In mice, blood pressure (BP) and renal sympathetic nerve activity (RSNA) were monitored by noninvasive tail-cuff method and platinum-iridium electrodes placed respectively. Microinjection of siRNA-HMGB1 (siHMGB1) into the RVLM of mice to study the effect of HMGB1 on microglia M1 activation was done. mRFP-GFP-tandem fluorescent LC3 (tf-LC3) vectors were transfected into the RVLM to evaluate the process of autolysosome formation/autophagy flux. The expression of RAB7, lysosomal-associated membrane protein 1 (LAMP1), and lysosomal pH change were used to evaluate lysosomal function in microglia. Mitophagy was identified by transmission electron microscopic observation or by checking LC3 and MitoTracker colocalization under a confocal microscope. Results We showed chronic stress increased cytoplasmic translocations of HMGB1 and upregulation of its receptor RAGE expression in microglia. The mitochondria injury, oxidative stress, and M1 polarization were attenuated in the RVLM of stressed Cre-CX3CR1/RAGEfl/fl mice. The HMGB1/RAGE axis increased at the early stage of stress-induced mitophagy flux while impairing the late stages of mitophagy flux in microglia, as revealed by decreased GFP fluorescence quenching of GFP-RFP-LC3-II puncta and decreased colocalization of lysosomes with mitochondria. The expressions of RAB7 and LAMP1 were decreased in the stressed microglia, while knockout of RAGE reversed these effects and caused an increase in acidity of lysosomes. siHMGB1 in the RVLM resulted in BP lowering and RSNA decreasing in SIH mice. When the autophagy inducer, rapamycin, is used to facilitate the mitophagy flux, this treatment results in attenuated NF-κB activation and reduced PIC release in exogenous disulfide HMGB1 (ds-HMGB1)-stimulated microglia. Conclusions Collectively, we demonstrated that inhibition of the HMGB1/RAGE axis activation led to increased stress-induced mitophagy flux, hence reducing the activity of microglia-mediated neuroinflammation and consequently reduced the sympathetic vasoconstriction drive in the RVLM. Electronic supplementary material The online version of this article (10.1186/s12974-019-1673-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Shutian Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China.,Clinical Medicine (Eight-year Program), Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Li Hu
- Laboratory of Neuropharmacology and Neurotoxicology, Shanghai Key Laboratory of Bio-Energy Crops, College of Life Science, Shanghai University, Shanghai, 200444, People's Republic of China
| | - Jialun Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China
| | - Hongji Li
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China
| | - Qin Wu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China
| | - Kokwin Ooi
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China
| | - Jijiang Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China
| | - Yi Feng
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People's Republic of China
| | - Danian Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China
| | - Chunmei Xia
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, No. 130, Dongan Road, Shanghai, 200032, People's Republic of China.
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Díaz HS, Toledo C, Andrade DC, Marcus NJ, Del Rio R. Neuroinflammation in heart failure: new insights for an old disease. J Physiol 2020; 598:33-59. [PMID: 31671478 DOI: 10.1113/jp278864] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 09/09/2019] [Indexed: 08/25/2023] Open
Abstract
Heart failure (HF) is a complex clinical syndrome affecting roughly 26 million people worldwide. Increased sympathetic drive is a hallmark of HF and is associated with disease progression and higher mortality risk. Several mechanisms contribute to enhanced sympathetic activity in HF, but these pathways are still incompletely understood. Previous work suggests that inflammation and activation of the renin-angiotensin system (RAS) increases sympathetic drive. Importantly, chronic inflammation in several brain regions is commonly observed in aged populations, and a growing body of evidence suggests neuroinflammation plays a crucial role in HF. In animal models of HF, central inhibition of RAS and pro-inflammatory cytokines normalizes sympathetic drive and improves cardiac function. The precise molecular and cellular mechanisms that lead to neuroinflammation and its effect on HF progression remain undetermined. This review summarizes the most recent advances in the field of neuroinflammation and autonomic control in HF. In addition, it focuses on cellular and molecular mediators of neuroinflammation in HF and in particular on brain regions involved in sympathetic control. Finally, we will comment on what is known about neuroinflammation in the context of preserved vs. reduced ejection fraction HF.
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Affiliation(s)
- Hugo S Díaz
- Laboratory of Cardiorespiratory Control, Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Camilo Toledo
- Laboratory of Cardiorespiratory Control, Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile
| | - David C Andrade
- Laboratory of Cardiorespiratory Control, Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Noah J Marcus
- Department of Physiology and Pharmacology, Des Moines University, Des Moines, IA, USA
| | - Rodrigo Del Rio
- Laboratory of Cardiorespiratory Control, Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile
- Centro de Envejecimiento y Regeneración (CARE-UC), Pontificia Universidad Católica de Chile, Santiago, Chile
- Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile
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