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Coverdell TC, Abbott SBG, Campbell JN. Molecular cell types as functional units of the efferent vagus nerve. Semin Cell Dev Biol 2024; 156:210-218. [PMID: 37507330 PMCID: PMC10811285 DOI: 10.1016/j.semcdb.2023.07.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 07/20/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023]
Abstract
The vagus nerve vitally connects the brain and body to coordinate digestive, cardiorespiratory, and immune functions. Its efferent neurons, which project their axons from the brainstem to the viscera, are thought to comprise "functional units" - neuron populations dedicated to the control of specific vagal reflexes or organ functions. Previous research indicates that these functional units differ from one another anatomically, neurochemically, and physiologically but have yet to define their identity in an experimentally tractable way. However, recent work with genetic technology and single-cell genomics suggests that genetically distinct subtypes of neurons may be the functional units of the efferent vagus. Here we review how these approaches are revealing the organizational principles of the efferent vagus in unprecedented detail.
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Affiliation(s)
- Tatiana C Coverdell
- Biomedical Sciences Graduate Program, University of Virginia, Charlottesville, VA 22903, USA
| | - Stephen B G Abbott
- Department of Pharmacology, University of Virginia, Charlottesville, VA 22903, USA
| | - John N Campbell
- Department of Biology, University of Virginia, Charlottesville, VA 22903, USA.
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Keller BN, Randall PA, Arnold AC, Browning KN, Silberman Y. Ethanol inhibits pancreatic projecting neurons in the dorsal motor nucleus of the vagus. Brain Res Bull 2022; 189:121-129. [PMID: 35998791 PMCID: PMC11753193 DOI: 10.1016/j.brainresbull.2022.08.020] [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: 03/23/2022] [Revised: 07/29/2022] [Accepted: 08/18/2022] [Indexed: 11/02/2022]
Abstract
Alcohol use disorder (AUD) is a rapidly growing concern in the United States. Current trending escalations of alcohol use are associated with a concurrent rise in alcohol-related end-organ damage, increasing risk for further diseases. Alcohol-related end-organ damage can be driven by autonomic nervous system dysfunction, however studies on alcohol effects on autonomic control of end-organ function are lacking. Alcohol intake has been shown to reduce insulin secretions from the pancreas. Pancreatic insulin release is controlled in part by preganglionic parasympathetic motor neurons residing in the dorsal motor nucleus of the vagus (DMV) that project to the pancreas. How these neurons are affected by alcohol exposure has not been directly examined. Here we investigated the effects of acute ethanol (EtOH) application on DMV pancreatic-projecting neurons with whole-cell patch-clamp electrophysiology. We found that bath application of EtOH (50 mM) for greater than 30 min significantly enhanced the frequency of spontaneous inhibitory post synaptic current (sIPSC) events of DMV pancreatic-projecting neurons suggesting a presynaptic mechanism of EtOH to increase GABAergic transmission. Thirty-minute EtOH application also decreased action potential firing of these neurons. Pretreatment of DMV slices with 20 μM fluoxetine, a selective serotonin reuptake inhibitor, also increased GABAergic transmission and decreased action potential firing of these DMV neurons while occluding any further effects of EtOH application, suggesting a critical role for serotonin in mediating EtOH effects in the DMV. Ultimately, decreased DMV motor output may lead to alterations in pancreatic secretions. Further studies are needed to fully understand EtOH's influence on DMV neurons as well as the consequences of changes in parasympathetic output to the pancreas.
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Affiliation(s)
- Bailey N Keller
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, USA
| | - Patrick A Randall
- Department of Anesthesiology, Penn State College of Medicine, Hershey, PA, USA; Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA
| | - Amy C Arnold
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, USA
| | - Kirsteen N Browning
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, USA
| | - Yuval Silberman
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, USA.
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Verberne AJM, Mussa BM. Neural control of pancreatic peptide hormone secretion. Peptides 2022; 152:170768. [PMID: 35189258 DOI: 10.1016/j.peptides.2022.170768] [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: 01/24/2022] [Revised: 02/10/2022] [Accepted: 02/12/2022] [Indexed: 11/20/2022]
Abstract
Pancreatic peptide hormone secretion is inextricably linked to maintenance of normal levels of blood glucose. In animals and man, pancreatic peptide hormone secretion is controlled, at least in part, by input from parasympathetic (vagal) premotor neurons that are found principally in the dorsal motor nucleus of the vagus (DMV). Iatrogenic (insulin-induced) hypoglycaemia evokes a homeostatic response commonly referred to as the glucose counter-regulatory response. This homeostatic response is of particular importance in Type 1 diabetes in which episodes of hypoglycaemia are common, debilitating and lead to suboptimal control of blood glucose. Glucagon is the principal counterregulatory hormone but for reasons unknown, its secretion during insulin-induced hypoglycaemia is impaired. Pancreatic parasympathetic neurons are distinguishable electrophysiologically from those that control other (e.g. gastric) functions and are controlled by supramedullary inputs from hypothalamic structures such as the perifornical region. During hypoglycaemia, glucose-sensitive, GABAergic neurons in the ventromedial hypothalamus are inhibited leading to disinhibition of perifornical orexin neurons with projections to the DMV which, in turn, leads to increased secretion of glucagon.
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Affiliation(s)
- Anthony J M Verberne
- Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
| | - Bashair M Mussa
- Basic Medical Science Department, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
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Lkhagvasuren B, Mee-Inta O, Zhao ZW, Hiramoto T, Boldbaatar D, Kuo YM. Pancreas-Brain Crosstalk. Front Neuroanat 2021; 15:691777. [PMID: 34354571 PMCID: PMC8329585 DOI: 10.3389/fnana.2021.691777] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/30/2021] [Indexed: 12/19/2022] Open
Abstract
The neural regulation of glucose homeostasis in normal and challenged conditions involves the modulation of pancreatic islet-cell function. Compromising the pancreas innervation causes islet autoimmunity in type 1 diabetes and islet cell dysfunction in type 2 diabetes. However, despite the richly innervated nature of the pancreas, islet innervation remains ill-defined. Here, we review the neuroanatomical and humoral basis of the cross-talk between the endocrine pancreas and autonomic and sensory neurons. Identifying the neurocircuitry and neurochemistry of the neuro-insular network would provide clues to neuromodulation-based approaches for the prevention and treatment of diabetes and obesity.
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Affiliation(s)
- Battuvshin Lkhagvasuren
- Brain Science Institute, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Onanong Mee-Inta
- Institute of Basic Medical Sciences, National Cheng Kung University College of Medicine, Tainan, Taiwan
| | - Zi-Wei Zhao
- Institute of Basic Medical Sciences, National Cheng Kung University College of Medicine, Tainan, Taiwan
| | - Tetsuya Hiramoto
- Department of Psychosomatic Medicine, Fukuoka Hospital, National Hospital Organization, Fukuoka, Japan
| | - Damdindorj Boldbaatar
- Brain Science Institute, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Yu-Min Kuo
- Institute of Basic Medical Sciences, National Cheng Kung University College of Medicine, Tainan, Taiwan.,Department of Cell Biology and Anatomy, National Cheng Kung University College of Medicine, Tainan, Taiwan
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Mussa BM, Sood S, Verberne AJM. Implication of neurohormonal-coupled mechanisms of gastric emptying and pancreatic secretory function in diabetic gastroparesis. World J Gastroenterol 2018; 24:3821-3833. [PMID: 30228777 PMCID: PMC6141338 DOI: 10.3748/wjg.v24.i34.3821] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 06/22/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Recently, diabetic gastroparesis (DGP) has received much attention as its prevalence is increasing in a dramatic fashion and management of patients with DGP represents a challenge in the clinical practice due to the limited therapeutic options. DGP highlights an interrelationship between the gastric emptying and pancreatic secretory function that regulate a wide range of digestive and metabolic functions, respectively. It well documented that both gastric emptying and pancreatic secretion are under delicate control by multiple neurohormonal mechanisms including extrinsic parasympathetic pathways and gastrointestinal (GI) hormones. Interestingly, the latter released in response to various determinants that related to the rate and quality of gastric emptying. Others and we have provided strong evidence that the central autonomic nuclei send a dual output (excitatory and inhibitory) to the stomach and the pancreas in response to a variety of hormonal signals from the abdominal viscera. Most of these hormones released upon gastric emptying to provide feedback, and control this process and simultaneously regulate pancreatic secretion and postprandial glycemia. These findings emphasize an important link between gastric emptying and pancreatic secretion and its role in maintaining homeostatic processes within the GI tract. The present review deals with the neurohormonal-coupled mechanisms of gastric emptying and pancreatic secretory function that implicated in DGP and this provides new insights in our understanding of the pathophysiology of DGP. This also enhances the process of identifying potential therapeutic targets to treat DGP and limit the complications of current management practices.
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Affiliation(s)
- Bashair M Mussa
- Department of Basic Medical Science, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Sanjay Sood
- Department of Basic Medical Science, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Anthony JM Verberne
- Department of Medicine, Austin Health, University of Melbourne, Melbourne 3084, Australia
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Ballaz S. The unappreciated roles of the cholecystokinin receptor CCK(1) in brain functioning. Rev Neurosci 2017; 28:573-585. [DOI: 10.1515/revneuro-2016-0088] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 02/05/2017] [Indexed: 12/13/2022]
Abstract
AbstractThe CCK(1) receptor is a G-protein-coupled receptor activated by the sulfated forms of cholecystokinin (CCK), a gastrin-like peptide released in the gastrointestinal tract and mammal brain. A substantial body of research supports the hypothesis that CCK(1)r stimulates gallbladder contraction and pancreatic secretion in the gut, as well as satiety in brain. However, this receptor may also fulfill relevant roles in behavior, thanks to its widespread distribution in the brain. The strategic location of CCK(1)r in mesolimbic structures and specific hypothalamic and brainstem nuclei lead to complex interactions with neurotransmitters like dopamine, serotonin, and glutamate, as well as hypothalamic hormones and neuropeptides. The activity of CCK(1)r maintains adequate levels of dopamine and regulates the activity of serotonin neurons of raphe nuclei, which makes CCK(1)r an interesting therapeutic target for the development of adjuvant treatments for schizophrenia, drug addiction, and mood disorders. Unexplored functions of CCK(1)r, like the transmission of interoceptive sensitivity in addition to the regulation of hypothalamic hormones and neurotransmitters affecting emotional states, well-being, and attachment behaviors, may open exciting roads of research. The absence of specific ligands for the CCK(1) receptor has complicated the study of its distribution in brain so that research about its impact on behavior has been published sporadically over the last 30 years. The present review reunites all this body of evidence in a comprehensive way to summarize our knowledge about the actual role of CCK in the neurobiology of mental illness.
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Affiliation(s)
- Santiago Ballaz
- School of Biological Sciences and Engineering, Yachay Tech University, Hacienda San Jose y Proyecto Yachay s/n, San Miguel de Urcuquí 100119, Ecuador
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Browning KN. Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology. Front Neurosci 2015; 9:413. [PMID: 26578870 PMCID: PMC4625078 DOI: 10.3389/fnins.2015.00413] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 10/15/2015] [Indexed: 12/21/2022] Open
Abstract
Vagal neurocircuits are vitally important in the co-ordination and modulation of GI reflexes and homeostatic functions. 5-hydroxytryptamine (5-HT; serotonin) is critically important in the regulation of several of these autonomic gastrointestinal (GI) functions including motility, secretion and visceral sensitivity. While several 5-HT receptors are involved in these physiological responses, the ligand-gated 5-HT3 receptor appears intimately involved in gut-brain signaling, particularly via the afferent (sensory) vagus nerve. 5-HT is released from enterochromaffin cells in response to mechanical or chemical stimulation of the GI tract which leads to activation of 5-HT3 receptors on the terminals of vagal afferents. 5-HT3 receptors are also present on the soma of vagal afferent neurons, including GI vagal afferent neurons, where they can be activated by circulating 5-HT. The central terminals of vagal afferents also exhibit 5-HT3 receptors that function to increase glutamatergic synaptic transmission to second order neurons of the nucleus tractus solitarius within the brainstem. While activation of central brainstem 5-HT3 receptors modulates visceral functions, it is still unclear whether central vagal neurons, i.e., nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) neurons themselves also display functional 5-HT3 receptors. Thus, activation of 5-HT3 receptors may modulate the excitability and activity of gastrointestinal vagal afferents at multiple sites and may be involved in several physiological and pathophysiological conditions, including distention- and chemical-evoked vagal reflexes, nausea, and vomiting, as well as visceral hypersensitivity.
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Affiliation(s)
- Kirsteen N Browning
- Department of Neural and Behavioral Sciences, Penn State University College of Medicine Hershey, PA, USA
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Zsombok A, Jiang Y, Gao H, Anwar IJ, Rezai-Zadeh K, Enix CL, Münzberg H, Derbenev AV. Regulation of leptin receptor-expressing neurons in the brainstem by TRPV1. Physiol Rep 2014; 2:2/9/e12160. [PMID: 25263209 PMCID: PMC4270226 DOI: 10.14814/phy2.12160] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The central nervous system plays a critical role in the regulation of feeding behavior and whole‐body metabolism via controlling the autonomic output to the visceral organs. Activity of the parasympathetic neurons in the dorsal motor nucleus of the vagus (DMV) determines the vagal tone and thereby modulates the function of the subdiaphragmatic organs. Leptin is highly involved in the regulation of food intake and alters neuronal excitability of brainstem neurons. Transient receptor potential vanilloid type 1 (TRPV1) has also been shown to increase neurotransmission in the brainstem and we tested the hypothesis that TRPV1 regulates presynaptic neurotransmitter release to leptin receptor‐expressing (LepRbEGFP) DMV neurons. Whole‐cell patch‐clamp recordings were performed to determine the effect of TRPV1 activation on excitatory and inhibitory postsynaptic currents (EPSC, IPSC) of LepRbEGFP neurons in the DMV. Capsaicin, a TRPV1 agonist increased the frequency of miniature EPSCs in 50% of LepRbEGFP neurons without altering the frequency of miniature IPSCs in the DMV. Stomach‐projecting LepRbEGFP neurons were identified in the DMV using the transsynaptic retrograde viral tracer PRV‐614. Activation of TRPV1 increased the frequency of mEPSC in ~50% of stomach‐related LepRbEGFP DMV neurons. These data demonstrate that TRPV1 increases excitatory neurotransmission to a subpopulation of LepRbEGFP DMV neurons via presynaptic mechanisms and suggest a potential interaction between TRPV1 and leptin signaling in the DMV. e12160 Our data demonstrate that TRPV1 is involved in the regulation of a subpopulation of leptin receptor‐expressing neurons in the dorsal motor nucleus of the vagus via presynaptic mechanisms.
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Affiliation(s)
- Andrea Zsombok
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana Neuroscience Program, School of Science and Engineering, Tulane University, New Orleans, Louisiana
| | - Yanyan Jiang
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana Neuroscience Program, School of Science and Engineering, Tulane University, New Orleans, Louisiana
| | - Hong Gao
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana
| | - Imran J Anwar
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana
| | - Kavon Rezai-Zadeh
- Central Leptin Signaling, Pennington Biomedical Research Center, LSU System, Baton Rouge, Louisiana
| | - Courtney L Enix
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana
| | - Heike Münzberg
- Central Leptin Signaling, Pennington Biomedical Research Center, LSU System, Baton Rouge, Louisiana
| | - Andrei V Derbenev
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana Neuroscience Program, School of Science and Engineering, Tulane University, New Orleans, Louisiana
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Mussa BM, Verberne AJM. The dorsal motor nucleus of the vagus and regulation of pancreatic secretory function. Exp Physiol 2012; 98:25-37. [PMID: 22660814 DOI: 10.1113/expphysiol.2012.066472] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Recent investigation of the factors and pathways that are involved in regulation of pancreatic secretory function (PSF) has led to development of a pancreatic vagovagal reflex model. This model consists of three elements, including pancreatic vagal afferents, the dorsal motor nucleus of the vagus (DMV) and pancreatic vagal efferents. The DMV has been recognized as a major component of this model and so this review focuses on the role of this nucleus in regulation of PSF. Classically, the control of the PSF has been viewed as being dependent on gastrointestinal hormones and vagovagal reflex pathways. However, recent studies have suggested that these two mechanisms act synergistically to mediate pancreatic secretion. The DMV is the major source of vagal motor output to the pancreas, and this output is modulated by various neurotransmitters and synaptic inputs from other central autonomic regulatory circuits, including the nucleus of the solitary tract. Endogenously occurring excitatory (glutamate) and inhibitory amino acids (GABA) have a marked influence on DMV vagal output to the pancreas. In addition, a variety of neurotransmitters and receptors for gastrointestinal peptides and hormones have been localized in the DMV, emphasizing the direct and indirect involvement of this nucleus in control of PSF.
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Affiliation(s)
- Bashair M Mussa
- University of Melbourne, Department of Medicine, Clinical Pharmacology & Therapeutics Unit, Austin Health, Heidelberg, Victoria 3084 Australia
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Autonomic Nervous System In Vitro: Studying Tonically Active Neurons Controlling Vagal Outflow in Rodent Brainstem Slices. ISOLATED CENTRAL NERVOUS SYSTEM CIRCUITS 2012. [DOI: 10.1007/978-1-62703-020-5_1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Abstract
PURPOSE OF REVIEW This review presents recent advancements in the mechanisms by which integrated signaling mechanisms elicit and regulate pancreatic endocrine and exocrine secretion. RECENT FINDINGS Cholecystokinin (CCK) can stimulate exocrine secretion by acting directly on neurons located in the dorsal motor of the vagus or indirectly by acting on pancreatic stellate cells. The importance of small GTPases such as RhoA and Rac1 in CCK-induced pancreatic secretion is also described. Ghrelin attenuates insulin secretion through the AMP-activated protein kinase-uncoupling protein 2 pathway. An exciting new report describes that leptin can influence insulin release by osteoclastin, a hormone produced by osteoblasts. This finding adds a new layer of complexity in the regulation of insulin secretion with implications for glucose and energy homeostasis. In addition, leptin also mediates insulin secretion through the sympathetic system and via pro-opiomelanocortin neurons, which could serve as the cross-road for leptin and melanocortin signaling pathways. Recent reports on the action of numerous other regulators such as atrial natriuretic peptide, neurotensin, and orexin B are also discussed. SUMMARY The pancreas is an extremely complex gland. Elucidation of the secretory and regulatory pathways that control pancreatic secretion will aid in the development of treatment for diseases such as pancreatitis, diabetes, and obesity.
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Mussa BM, Sartor DM, Rantzau C, Verberne AJM. Effects of nitric oxide synthase blockade on dorsal vagal stimulation-induced pancreatic insulin secretion. Brain Res 2011; 1394:62-70. [PMID: 21530944 DOI: 10.1016/j.brainres.2011.04.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Revised: 03/23/2011] [Accepted: 04/09/2011] [Indexed: 01/13/2023]
Abstract
We and others have previously shown that the dorsal motor nucleus of the vagus (DMV) is involved in regulation of pancreatic exocrine secretion. Many pancreatic preganglionic neurons within the DMV are inhibited by pancreatic secretagogues suggesting that an inhibitory pathway may participate in the control of pancreatic exocrine secretion. Accordingly, the present study examined whether chemical stimulation of the DMV activates the endocrine pancreas and whether an inhibitory pathway is involved in this response. All experiments were conducted in overnight fasted isoflurane/urethane-anesthetized Sprague Dawley rats. Activation of the DMV by bilateral microinjection of bicuculline methiodide (BIM, GABA(A) receptor antagonist, 100 pmol/25 nl; 4 mM) resulted in a significant and rapid increase in glucose-induced insulin secretion (9.2±0.1 ng/ml peak response) compared to control microinjection (4.0±0.6 ng/ml). Activation of glucose-induced insulin secretion by chemical stimulation of the DMV was inhibited (2.1±1.1 ng/ml and 1.6±0.1 ng/ml 5 min later) in the presence of the muscarinic receptor antagonist atropine methonitrate (100 μg/kg/min, i.v.). On the other hand, the nitric oxide (NO) synthesis inhibitor l-nitroarginine methyl ester (30 mg/kg, i.v.) significantly increased the excitatory effect of DMV stimulation on glucose-induced insulin secretion to 15.3±3.0 ng/ml and 16.1±3.1 ng/ml 5 min later. These findings suggest that NO may play an inhibitory role in the central regulation of insulin secretion.
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Affiliation(s)
- Bashair M Mussa
- Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia
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