Effects of nitric oxide synthase blockade on dorsal vagal stimulation-induced pancreatic insulin secretion

Mussa, Bashair M; Sartor, Daniela M.; Rantzau, Christian; Verberne, Anthony J.M.

doi:10.1016/j.brainres.2011.04.015

Cited by 23 publications

(32 citation statements)

References 29 publications

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“…Brainstem vagal gastric neurocircuits are under tonic influence of inhibitory γ‐aminobutyric acid (GABA) inputs (Sivarao et al 1998; Babic et al 2011), while glutamatergic synapses do not appear to have a relevant role in controlling baseline gastric motility (Sivarao et al 1998). Similarly, PES and insulin secretion are under tonic GABAergic control (Mussa & Verberne, 2008; Mussa et al 2011); it is not known, however, whether ionotropic glutamatergic inputs within the brainstem neurocircuitry play a relevant role in their regulation.…”

Section: Discussionmentioning

confidence: 99%

“…Increasing evidence suggests that different vagally mediated gastrointestinal (GI) and pancreatic functions are controlled by segregated neural circuits (Browning et al 1999, 2005 a ; Mussa & Verberne, 2008; Babic et al 2011; Mussa et al 2011). These vagal circuits are modulated selectively by a range of neurotransmitters, including glutamate acting on metabotropic glutamate receptors (mGluRs).…”

Section: Introductionmentioning

confidence: 99%

“…Both in vivo and in vitro studies have demonstrated that sensory‐motor vagal neurocircuits exert critical control over pancreatic exocrine secretion (PES) and insulin secretion, by integrating neural and humoral signals and adjusting pancreatic secretions to respond to on demand physiological needs (Ionescu et al 1983; Singer et al 1986; Inui et al 1986; Rinaman & Miselis, 1987; Ami et al 1993; Gicquel et al 1994; Siaud et al 1995; Mussa et al 2011). In fact, in vivo studies have shown that microinjection of either the GABA A receptor antagonist bicuculline, or CCK into the DMV increases, whereas microinjection of pancreatic polypeptide (PP) or somatostatin decreases, PES (Okumura et al 1995; Liao et al 2005; Viard et al 2007; Mussa & Verberne, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Pancreatic insulin and exocrine secretion are under the modulatory control of distinct subpopulations of vagal motoneurones in the rat

Babic

Browning

Kawaguchi

et al. 2012

The Journal of Physiology

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Key points• The pancreas consists of two functional parts, exocrine, which releases digestive enzymes, and endocrine, which releases hormones, such as insulin.• Both parts are under neural regulatory control by the vagus nerve. Vago-vagal neurocircuits integrate the sensory information, chemical or mechanical, from the gastrointestinal tract with the motor output back to the gastrointestinal system, including the pancreas.• Both excitatory and inhibitory vago-vagal neural circuits are regulated by many neurotransmitters, including glutamate acting on different types of metabotropic glutamate receptors.• In this study, we show that different subtypes of metabotropic glutamate receptors regulate differentially exocrine and endocrine pancreatic functions by affecting different neurocircuits.• The present study provides the physiological basis to develop pharmacological strategies aimed to provide a better understanding of pathophysiological conditions, such as pancreatitis or diabetes, that affect selectively the exocrine or endocrine pancreas.Abstract Brainstem vago-vagal neurocircuits modulate upper gastrointestinal functions. Derangement of these sensory-motor circuits is implicated in several pathophysiological states, such as gastroesophageal reflux disease (GERD), functional dyspepsia and, possibly, pancreatitis. While vagal circuits controlling the stomach have received more attention, the organization of brainstem pancreatic neurocircuits is still largely unknown. We aimed to investigate the in vitro and in vivo modulation of brainstem vagal circuits controlling pancreatic secretion. Using patch clamp techniques on identified vagal pancreas-projecting neurones, we studied the effects of metabotropic glutamate receptor (mGluR) agents in relation to the effects of exendin-4, a glucagon-like peptide 1 analogue, cholecystokinin (CCK) and pancreatic polypeptide (PP). An in vivo anaesthetized rat preparation was used to measure pancreatic exocrine secretion (PES) and plasma insulin following microinjection of metabotropic glutamate receptor (mGluR) agonists and exendin-4 in the brainstem. Group II and III mGluR agonists (2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC) and L(+)-2-amino-4-phosphonobutyric acid (L-AP4), respectively) decreased the frequency of miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSCs, respectively) in the majority of the neurones tested. All neurones responsive to L-AP4 were also responsive to APDC, but not vice versa. Further, in neurones where L-AP4 decreased mIPSC frequency, exendin-4 increased, while PP had no effect upon, mIPSC frequency. Brainstem microinjection of APDC or L-AP4 decreased plasma insulin secretion, whereas only APDC microinjections increased PES. Exendin-4 microinjections increased plasma insulin. Our results indicate a discrete organization of vagal circuits, which

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pancreatic insulin and exocrine secretion are under the modulatory control of distinct subpopulations of vagal motoneurones in the rat

Babic

Browning

Kawaguchi

et al. 2012

The Journal of Physiology

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“…Electrical and chemical stimulation of the DMV activates both endocrine and exocrine secretion via cholinergic pathways which can be blunted by vagotomy or chemical inhibition [167][168][169]. Activation of the DMV by bilateral microinjection of a GABA antagonist results in a rapid increase in glucose-induced insulin secretion, and this effect can be inhibited by a muscarinic receptor antagonist or significantly increased by inhibition of nitric oxide synthesis [168]. Additionally, a population of DMV neurons projects to the pancreas which can be depolarized by exogenous GLP1.…”

Section: Autonomic Modulation Of the Pancreas On Glucose Homeostasismentioning

confidence: 99%

Hypothalamic-autonomic control of energy homeostasis

et al. 2015

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Regulation of energy homeostasis is tightly controlled by the central nervous system (CNS). Several key areas such as the hypothalamus and brainstem receive and integrate signals conveying energy status from the periphery, such as leptin, thyroid hormones, and insulin, ultimately leading to modulation of food intake, energy expenditure (EE), and peripheral metabolism. The autonomic nervous system (ANS) plays a key role in the response to such signals, innervating peripheral metabolic tissues, including brown and white adipose tissue (BAT and WAT), liver, pancreas, and skeletal muscle. The ANS consists of two parts, the sympathetic and parasympathetic nervous systems (SNS and PSNS). The SNS regulates BAT thermogenesis and EE, controlled by central areas such as the preoptic area (POA) and the ventromedial, dorsomedial, and arcuate hypothalamic nuclei (VMH, DMH, and ARC). The SNS also regulates lipid metabolism in WAT, controlled by the lateral hypothalamic area (LHA), VMH, and ARC. Control of hepatic glucose production and pancreatic insulin secretion also involves the LHA, VMH, and ARC as well as the dorsal vagal complex (DVC), via splanchnic sympathetic and the vagal parasympathetic nerves. Muscle glucose uptake is also controlled by the SNS via hypothalamic nuclei such as the VMH. There is recent evidence of novel pathways connecting the CNS and ANS. These include the hypothalamic AMP-activated protein kinase-SNS-BAT axis which has been demonstrated to be a key modulator of thermogenesis. In this review, we summarize current knowledge of the role of the ANS in the modulation of energy balance.

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“…The vagus nerve tract seems to have a major role in both pathways of this complex metabolic reflex [9]. Experimental models in mice suggest that the nucleus ambiguus is a source of vagal motoneurons that facilitate insulin secretion by the pancreas [10] and that the dorsal nucleus of the vagus nerve is the source of excitatory and inhibitory inputs that modulate insulin secretion [11]. The extent of the role of vagus nerve nuclei in the modulation of insulin secretion in humans is not well known.…”

Section: Introductionmentioning

confidence: 99%

Ischemic Vagus Nuclei Lesions and Hyperglycemia: A Study in 26 Patients with Lateral Medullary Infarction and Matched Controls

Ruano

Alves²,

Barreto³

et al. 2012

Cerebrovasc Dis

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Background: Hyperglycemia is common after stroke in diabetic and nondiabetic patients. Furthermore, it has been associated with infarct expansion, worse functional outcomes and higher mortality. In a previous study, infarction of the insular region was related to higher poststroke glucose levels than infarcts in other cortical areas. Experimental studies in animal models suggested that the lower brainstem nuclei of the vagus nerve modulate insulin secretion. These nuclei are usually affected in lateral medullary infarction (LMI). We evaluated whether patients with lateral medullary stroke have worse poststroke glycemic control than other stroke patients. Methods: A hospital-based stroke registry was used to identify 26 patients from the years 2000 to 2010 who fulfilled the following inclusion criteria: (1) a first-ever stroke; (2) neurological deficits compatible with LMI; (3) MRI confirmation of an ischemic lesion of the lateral medulla involving the vagus nerve nuclei, and (4) no simultaneous infarcts. Patients were excluded if they were admitted to the hospital more than 24 h after stroke onset or died in the first 24 h after hospital admission. A control group of other stroke patients was randomly selected from the same stroke registry and over the same time period, matching for the age and gender of the LMI group. The average glycemia was compared between the two groups using a linear regression model adjusted for confounders. Glycated hemoglobin at admission was used to estimate prestroke glycemic control. Prestroke glycemic averages were then compared with poststroke glycemia for the two groups using the Wilcoxon signed test for related samples. Results: The average glycemia of the LMI patients in the first 24 h after stroke was 9.4 mmol/l (SD 3.2), and from 24 to 72 h it was 7.6 mmol/l (SD 2.8). In the comparison group, these values were 7.7 (SD 2.8) and 7.1 mmol/l (SD 2.7), respectively. As expected, diabetic patients had a significantly higher glycemia than nondiabetic patients (p < 0.0001). The adjusted linear regression model showed the average glycemia differences to be significant for the first 24 h (p = 0.001; R² = 55.6%) but not for the 24– 72 h period. The frequency of previous diabetes mellitus was similar in both groups. As compared to prestroke glycemic estimates, glycemia in lateral medullary stroke patients increased significantly more than in controls during the first 24 h after stroke (p = 0.01), but again there were no significant differences for the 24–72 h period. Conclusions: This study suggests that ischemic lesions of the vagus nerve nuclei are associated with worse early poststroke glycemic control than stroke in other locations. Confirmation of this hypothesis and the long-term implications of glucose control impairment warrant further prospective studies.

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Effects of nitric oxide synthase blockade on dorsal vagal stimulation-induced pancreatic insulin secretion

Cited by 23 publications

References 29 publications

Pancreatic insulin and exocrine secretion are under the modulatory control of distinct subpopulations of vagal motoneurones in the rat

Pancreatic insulin and exocrine secretion are under the modulatory control of distinct subpopulations of vagal motoneurones in the rat

Hypothalamic-autonomic control of energy homeostasis

Ischemic Vagus Nuclei Lesions and Hyperglycemia: A Study in 26 Patients with Lateral Medullary Infarction and Matched Controls

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