دورية أكاديمية
أعرض في EDS

PPG neurons in the nucleus of the solitary tract modulate heart rate but do not mediate GLP-1 receptor agonist-induced tachycardia in mice.

التفاصيل البيبلوغرافية
العنوان: PPG neurons in the nucleus of the solitary tract modulate heart rate but do not mediate GLP-1 receptor agonist-induced tachycardia in mice.
المؤلفون: Holt MK; Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, UCL, London, UK., Cook DR; Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, UCL, London, UK., Brierley DI; Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, UCL, London, UK., Richards JE; Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, UCL, London, UK., Reimann F; Wellcome Trust/MRC Institute of Metabolic Science (IMS), Addenbrookes Hospital, University of Cambridge, Cambridge, UK., Gourine AV; Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, UCL, London, UK., Marina N; Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, UCL, London, UK. Electronic address: n.marina@ucl.ac.uk., Trapp S; Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, UCL, London, UK. Electronic address: s.trapp@ucl.ac.uk.
المصدر: Molecular metabolism [Mol Metab] 2020 Sep; Vol. 39, pp. 101024. Date of Electronic Publication: 2020 May 21.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier GmbH Country of Publication: Germany NLM ID: 101605730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2212-8778 (Electronic) Linking ISSN: 22128778 NLM ISO Abbreviation: Mol Metab Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [München] : Elsevier GmbH, 2012-
مواضيع طبية MeSH: Heart Rate*/drug effects, Glucagon-Like Peptide-1 Receptor/*agonists , Neurons/*metabolism , Proglucagon/*biosynthesis , Solitary Nucleus/*physiology , Tachycardia/*etiology , Tachycardia/*metabolism, Animals ; Disease Models, Animal ; Electrocardiography ; Exenatide/pharmacology ; Glucagon-Like Peptide-1 Receptor/metabolism ; Mice ; Mice, Transgenic ; Neurons/drug effects ; Solitary Nucleus/cytology ; Spinal Cord/drug effects ; Spinal Cord/metabolism ; Sympathetic Nervous System/drug effects ; Sympathetic Nervous System/metabolism ; Tachycardia/diagnosis
مستخلص: Objective: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as anti-diabetic drugs and are approved for obesity treatment. However, GLP-1RAs also affect heart rate (HR) and arterial blood pressure (ABP) in rodents and humans. Although the activation of GLP-1 receptors (GLP-1R) is known to increase HR, the circuits recruited are unclear, and in particular, it is unknown whether GLP-1RAs activate preproglucagon (PPG) neurons, the brain source of GLP-1, to elicit these effects.
Methods: We investigated the effect of GLP-1RAs on heart rate in anaesthetized adult mice. In a separate study, we manipulated the activity of nucleus tractus solitarius (NTS) PPG neurons (PPG NTS ) in awake, freely behaving transgenic Glu-Cre mice implanted with biotelemetry probes and injected with AAV-DIO-hM3Dq:mCherry or AAV-mCherry-FLEX-DTA.
Results: Systemic administration of the GLP-1RA Ex-4 increased resting HR in anaesthetized or conscious mice, but had no effect on ABP in conscious mice. This effect was abolished by β-adrenoceptor blockade with atenolol, but unaffected by the muscarinic antagonist atropine. Furthermore, Ex-4-induced tachycardia persisted when PPG NTS neurons were ablated, and Ex-4 did not induce expression of the neuronal activity marker cFos in PPG NTS neurons. PPG NTS ablation or acute chemogenetic inhibition of these neurons via hM4Di receptors had no effect on resting HR. In contrast, chemogenetic activation of PPG NTS neurons increased resting HR. Furthermore, the application of GLP-1 within the subarachnoid space of the middle thoracic spinal cord, a major projection target of PPG neurons, increased HR.
Conclusions: These results demonstrate that both systemic application of Ex-4 or GLP-1 and chemogenetic activation of PPG NTS neurons increases HR. Ex-4 increases the activity of cardiac sympathetic preganglionic neurons of the spinal cord without recruitment of PPG NTS neurons, and thus likely recapitulates the physiological effects of PPG neuron activation. These neurons therefore do not play a significant role in controlling resting HR and ABP but are capable of inducing tachycardia and so are likely involved in cardiovascular responses to acute stress.
(Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
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معلومات مُعتمدة: 200893 United Kingdom WT_ Wellcome Trust; FS/14/43/30960 United Kingdom BHF_ British Heart Foundation; 200893/Z/16/Z United Kingdom WT_ Wellcome Trust; MR/N02589X/1 United Kingdom MRC_ Medical Research Council; MC_UU_12012/3 United Kingdom MRC_ Medical Research Council; MC_UU_00014/3 United Kingdom MRC_ Medical Research Council
فهرسة مساهمة: Keywords: Biotelemetry; Cardiovascular function; Chemogenetics; GLP-1; PPG neurons; Sympathetic outflow
المشرفين على المادة: 0 (Glucagon-Like Peptide-1 Receptor)
55963-74-1 (Proglucagon)
9P1872D4OL (Exenatide)
تواريخ الأحداث: Date Created: 20200525 Date Completed: 20210708 Latest Revision: 20220324
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC7317700
DOI: 10.1016/j.molmet.2020.101024
PMID: 32446875
قاعدة البيانات: MEDLINE
الوصف
تدمد:2212-8778
DOI:10.1016/j.molmet.2020.101024