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The gut microbiota has the capacity to affect host appetite via intestinal satiety pathways, as well as complex feeding behaviors. In this Review, we highlight recent evidence that the gut microbiota can modulate food preference across model organisms. We discuss effects of the gut microbiota on the vagus nerve and brain regions including the hypothalamus, mesolimbic system, and prefrontal cortex, which play key roles in regulating feeding behavior. Crosstalk between commensal bacteria and the central and peripheral nervous systems is associated with alterations in signaling of neurotransmitters and neuropeptides such as dopamine, brain-derived neurotrophic factor (BDNF), and glucagon-like peptide-1 (GLP-1). We further consider areas for future research on mechanisms by which gut microbes may influence feeding behavior involving these neural pathways. Understanding roles for the gut microbiota in feeding regulation will be important for informing therapeutic strategies to treat metabolic and eating disorders., Introduction Understanding the biological bases of feeding behaviors is key to developing treatments for increasingly prevalent metabolic and eating disorders, including obesity and anorexia nervosa (1-3). Neurobiological regulation of feeding [...]

Given the crucial role of the gastrointestinal tract and associated organs in handling nutrient assimilation and metabolism, it has long been known that its communication with the brain is important for the control of ingestive behavior and body weight regulation. It is also clear that gut-brain communication is bidirectional and utilizes both rapid neural and slower humoral mechanisms and pathways. However, progress in understanding these mechanisms and leveraging them for the treatment of obesity and metabolic disease has been hindered by the enormous dimension of the gut mucosa, the complexity of the signaling systems, and lack of specific tools. With the ascent of modern neurobiological technology, our understanding of the role of vagal afferents in gut-brain communication has begun to change. The first function-specific populations of vagal afferents providing nutritional feedback as well as feed-forward signals have been identified with genetics- guided methodology, and it is hoped that extension of the methodology to other neural communication pathways will follow soon. Currently, efficient clinical leveraging of gut-brain communication to treat obesity and metabolic disease is limited to a few gut hormones, but a more complete understanding of function-specific and projection-specific neuronal populations should make it possible to develop selective and more effective neuromodulation approaches., Introduction Given that the prevalence of obesity is approaching 50% in some countries (1), it is hard to argue that body weight/adiposity is regulated at healthy levels through biological mechanisms [...]

The physiological mechanisms that preserve pancreatic [beta]-cell mass (BCM) are not fully understood. Although the regulation of islet function by the autonomic nervous system (ANS) is well established, its potential roles in BCM homeostasis and compensatory growth have not been adequately explored. The parasympathetic vagal branch of the ANS serves to facilitate gastrointestinal function, metabolism, and pancreatic islet regulation of glucose homeostasis, including insulin secretion. Given the functional importance of the vagus nerve and its branches to the liver, gut, and pancreas in control of digestion, motility, feeding behavior, and glucose metabolism, it may also play a role in BCM regulation. We have begun to examine the potential roles of the parasympathetic nervous system in short-term BCM maintenance by performing a selective bilateral celiac branch-vagus nerve transection (CVX) in normal Sprague-Dawley rats. CVX resuited in no detectable effects on basic metabolic parameters or food intake through 1 wk postsurgery. Although there were no differences in BCM or apoptosis in this 1-wk time frame, [beta]-cell proliferation was reduced 50% in the CVX rats, correlating with a marked reduction in activated protein kinase B/Akt. Unexpectedly, acinar proliferation was increased 50% in these rats. These data suggest that the ANS, via the vagus nerve, contributes to the regulation of BCM maintenance at the level of cell proliferation and may also mediate the drive for enhanced growth under physiological conditions when insulin requirements have increased. Furthermore, the disparate effects of CVX on [beta]-cell and acinar cells suggest that the endocrine and exocrine pancreas respond to different neural signals in regard to mass homeostasis. [beta]-cell mass; celiac vagotomy doi: 10.1152/ajpendo.00202.2010.

Toyomasu Y, Moehiki E, Yanai M, Ogata K, Tabe Y, Ando H, Ohno T, Aihara R, Zai H, Kuwano H Intragastric monosodium L-glutamate stimulates motility of the gut via vagus nerve in conscious dogs. Am J Physiol Regul Integr Comp Physiol 298: Rl125-R1135, 2010. First published January 13, 2010; doi:10.1152/ajpregu.00691.2009.--Monosodium Lglutamate (MSG) is a substance known to produce the umami taste. Recent studies indicate that MSG also stimulates a variety of activities in the gastrointestinal tract through its receptor in the gut, but no study has reported the activity in conscious large experimental animals. The aim of our study was to investigate whether direct intragastric MSG stimulates gut motility and to identify the mechanism in conscious dogs. Contractile response to intraluminal injection of MSG was studied in the fed and fasted states by means of chronically implanted force transducers. MSG (5, 15, 45, and 90 mM/kg) dissolved in water was injected into the stomach and duodenum in normal and vagotomized dogs. MSG solution was administered into the stomach before feeding, and gastric emptying was evaluated. Several inhibitors of gastrointestinal motility (atropine, hexamethonium, and granisetron) were injected intravenously before MSG administration to the stomach. The effect of MSG was investigated in Parlor (vagully innervated corpus pouch), Heidenhain (vagally denervated corpus pouch), and antral pouch (vagally innervated) dogs. Upper gut motility was significantly increased by intragastric MSG but not significantly stimulated by intraduodenal MSG. Intragastric MSG (45 mM/kg) stimulated postprandial motility and accelerated gastric emptying. MSG-induced contractions were inhibited by truncal vagotomy, atropine, hexamethonium, and granisetron. Gut motility was increased by intrapouch injection of MSG in the Pavlov pouch, but it was not affected in the Heidenhain or antral pouch dogs. We conclude that intragastric MSG stimulates upper gut motility and accelerates gastric emptying. The sensory structure of MSG is present in the gastric corpus, and the signal is mediated by the vagus nerve. gut nutrient sensing; gastrointestinal motility doi: 10.1152/ajpregu.00691.2009.

Vagal nerve stimulation has been suggested to ameliorate left ventricular (LV) remodeling in heart failure. However, it is not known whether and to what degree vagal nerve stimulation affects matrix metalloproteinase (MMP) and tissue inhibitor of MMP (TIMP) in myocardium, which are known to play crucial roles in LV remodeling. We therefore investigated the effects of electrical stimulation of efferent vagal nerve on myocardial expression and activation of MMPs and TIMPs in a rabbit model of myocardial ischemia-reperfusion (I/R) injury. Anesthetized rabbits were subjected to 60 min of left coronary artery occlusion and 180 min of reperfusion with (I/R-VS, n : 8) or without vagal nerve stimulation (I/R, n = 7). Rabbits not subjected to coronary occlusion with (VS, n = 7) or without vagal stimulation (sham, n = 7) were used as controls. Total MMP-9 protein increased significantly after left coronary artery occlusion in I/R-VS and I/R to a similar degree compared with VS and sham values. Endogenous active MMP-9 protein level was significantly lower in I/R-VS compared with I/R. TIMP-1 mRNA expression was significantly increased in I/R-VS compared with the I/R, VS, and sham groups. TIMP-1 protein was significantly increased in I/R-VS and VS compared with the I/R and sham groups. Cardiac microdialysis technique demonstrated that topical perfusion of acetylcholine increased dialysate TIMP-1 protein level, which was suppressed by coperfusion of atropine. Immunohistochemistry demonstrated a strong expression of TIMP-1 protein in cardiomyocytes around the dialysis probe used to perfuse acetylcholine. In conclusion, in a rabbit model of myocardial I/R injury, vagal nerve stimulation induced TIMP-1 expression in cardiomyocytes and reduced active MMP-9. myocardial remodeling; matrix metalloproteinase; acetylcholine

Learned flavor preferences can be established after intragastric nutrient administration by two different behavioral procedures, concurrent and sequential. In a concurrent procedure, two flavored stimuli are offered separately but at the same time on a daily basis: one stimulus is paired with the simultaneous intragastric administration of partially digested food and the other with physiological saline. In sequential learning, the two stimuli are presented during alternate sessions. Neural mechanisms underlying these learning modalities have yet to be fully elucidated. The aim of this study was to examine the role of vagal afferent fibers in the visceral processing of rewarding nutrients during concurrent (experiment 1) and sequential (experiment 2) flavor preference learning in Wistar rats. For this purpose, capsaicin, a neurotoxin that destroys slightly myelinated or unmyelinated sensory axons, was applied to the subdiaphragmatic region of the esophagus to selectively damage most of the vagal afferent pathways that originate in the gastrointestinal system. Results showed that capsaicin [1 mg of capsaicin dissolved in 1 ml of vehicle (10% Tween 80 in oil)] blocked acquisition of concurrent but not sequential flavor preference learning. These results are interpreted in terms of a dual neurobiological system involved in processing the rewarding effects of intragastrically administered nutrients. The vagus nerve, specifically capsaicin-sensitive vagal afferent fibers, would only be essential in concurrent flavor preference learning, which requires rapid processing of visceral information. vagus nerve; concurrent flavor preference learning; sequential flavor preference learning

Immunoreactivity of leptin receptor (Ob-R) has been detected in rat dorsal motor nucleus of the vagus (DMNV). Here, we confirmed the presence of Ob-R immunoreactivity on retrograde-labeled parasympathetic preganglionic neurons in the DMNV of neonatal rats. The present study investigated the effects of leptin on DMNV neurons, including parasympathetic preganglionic neurons, by using whole cell patch-clamp recording technique in brain stem slices of neonatal rats. Leptin (30-300 nM) induced membrane depolarization and hyperpolarization, respectively, in 14 and 15 out of 80 DMNV neurons tested. Both leptin-induced inward and outward currents persisted in the presence of TTX, indicating that leptin affected DNMV neurons postsynaptically. The current-voltage (I-V) curve of leptin-induced inward currents is characterized by negative slope conductance and has an average reversal potential of -90 [+ or -] 3 mV. The reversal potential of the leptin-induced inward current was shifted to a more positive potential level in a high-potassium medium. These results indicate that a decrease in potassium conductance is likely the main ionic mechanism underlying the leptin-induced depolarization. On the other hand, the I-V curve of leptin-induced outward currents is characterized by positive slope conductance and has an average reversal potential of -88 [+ or -] 3 mV, suggesting that an increase in potassium conductance may underlie leptin-induced hyperpolarization. Most of the leptin-responsive DMNV neurons were identified as being parasympathetic preganglionic neurons. These results suggest that the DMNV is one of the central target sites of leptin, and leptin can regulate parasympathetic outflow from the DMNV by directly acting on the parasympathetic preganglionic neurons of the DMNV. Ob-R; brain slice; potassium channel; whole cell patch-clamp; immunohistochemistry doi:10.1152/ajpregu.00563.2006

Previous studies have suggested that somatostatin inhibits pancreatic secretion at a central vagal site, and the dorsal vagal complex (DVC) is involved in central feedback inhibition of the exocrine pancreas. The aim of this study was to investigate the effect of exogenous somatostatin in the DVC on pancreatic secretion and the somatostatin receptor subtype(s) responsible for the effect. The effects of somatostatin microinjected into the DVC on pancreatic secretion stimulated by cholecystokinin octapeptide (CCK-8) or 2-deoxy-D-glucose (2-DG) were examined in anesthetized rats. To investigate the somatostatin inhibitory action site, a somatostatin receptor antagonist [SRA; cyclo(7-aminoheptanoyl-Phe-D-Trp-Lys-Thr)] was microinjected into the DVC before intravenous infusion of somatostatin and CCK-8/2-DG. The effects of injection of a somatostatin receptor-2 agonist (seglitide) and combined injection of somatostatin and a somatostatin receptor-2 antagonist (CYN 154806) in the DVC on the pancreatic secretion were also investigated. Somatostatin injected into the DVC significantly inhibited pancreatic secretion evoked by CCK-8 or 2-DG in a dose-dependent manner. SRA injected into the DVC completely reversed the inhibitory effect of intravenous administration of somatostatin. Seglitide injected into the DVC also inhibited CCK-8/2-DG-induced pancreatic protein secretion. However, combined injection of somatostatin and CYN 154806 did not affect the CCK-8/2-DG-induced pancreatic secretion. Somatostatin in the DVC inhibits pancreatic secretion via somatostatin receptor-2, and the DVC is the action site of somatostatin for its inhibitory effect. somatostatin; pancreatic exocrine secretion; dorsal vagal complex; dorsal motor nucleus of the vagus nerve; somatostatin receptor antagonist; somatostatin receptor-2 agonist; cholecystokinin octapeptide; 2-deoxy-D-glucose

Systemic infection produces a highly regulated set of responses such as fever, anorexia, adipsia, inactivity, and cachexia, collectively referred to as sickness behavior. Although the expression of sickness behavior requires immune-brain communication, the mechanisms by which peripheral cytokines signal the brain are unclear. Several mechanisms have been proposed for neuroimmune communication, including the interaction of cytokines with peripheral nerves. A critical role has been ascribed to the vagus nerve in mediating sickness behavior after intraperitoneally delivered immune activation, and converging evidence suggests that this communication may involve neurochemical intermediaries afferent and/or efferent to this nerve. Mice lacking functional CC[K.sub.2/gastrin] receptors (CC[K.sub.2]KO) and wild-type (WT) controls were administered LPS (50, 500, or 2,500 [micro]g/kg; serotype 011l:B4; ip). Results indicate a role for CC[K.sub.2] receptor activation in the initiation and maintenance of LPS-induced sickness behavior. Compared with WT controls, CC[K.sub.2]KO mice were significantly less affected by LPS on measures of body temperature, activity, body weight, and food intake, with the magnitude of effects increasing with increasing LPS dose. Although activation of CC[K.sub.2] receptors at the level of the vagus nerve cannot be excluded, a possible role for these receptors in nonvagal routes of immune-brain communication is suggested. cholecystokinin; lipopolysaccharide; infection; vagus; fever

Vago-vagal reflex circuits modulate digestive functions from the oral cavity to the transverse colon. Previous articles in this series have described events at the level of the sensory receptors encoding the peripheral stimuli, the transmission of information in the afferent vagus, and the conversion of this data within the dorsal vagal complex (DVC) to impulses in the preganglionic efferents. The control by vagal efferents of the postganglionic neurons impinging on the glands and smooth muscles of the target organs has also been illustrated. Here we focus on some of the mechanisms by which these apparently static reflex circuits can be made quite plastic as a consequence of the action of modulatory inputs from other central nervous system sources. A large body of evidence has shown that the neuronal elements that constitute these brain stern circuits have nonuniform properties and function differently according to status of their target organs and the level of activity in critical modulatory inputs. We propose that DVC circuits undergo a certain amount of short-term plasticity that allows the brain stem neuronal elements to act in harmony with neural systems that control behavioral and physiological homeostasis. dorsal motor nucleus of the vagus; nucleus of the solitary tract; brain stem; gastrointestinal motility

We determined if blocking transmission in the fibers of the vagus nerves would affect basal hepatic glucose metabolism in the 18-h-fasted conscious dog. A pancreatic clamp (somatostatin, basal portal insulin, and glucagon) was employed. A 40-rain control period was followed by a 90-min test period. In one group, stainless steel cooling coils (Sham, n = 5) were perfused with a 37[degrees]C solution, while in the other (Cool, n = 6), the coils were perfused with -20[degrees]C solution. Vagal blockade was verified by heart rate change (80 [+ or -] 9 to 84 [+ or -] 14 beats/rain in Sham; 98 [ or -] + 12 to 193 [+ or -] 22 beats/min in Cool). The arterial glucose level was kept euglycemic by glucose infusion. No change in tracer-determined glucose production occurred in Sham, whereas in Cool it dropped significantly (2.4 [+ or -] 0.4 to 1.9 [+ or -] 0.4 mg*[kg.sup.-1]* [min.sup.-1]). Net hepatic glucose output did not change in Sham but decreased from 1.9 [+ or -] 0.3 to 1.3 [+ or -] 0.3 mg*[kg.sup.-1* [min.sup.-1] in the Cool group. Hepatic gluconeogenesis did not change in either group. These data suggest that vagal blockade acutely modulates hepatic glucose production by inhibiting glycogenolysis. vagal cooling; liver nerves; parasympathetic blockade; gluconeogenesis; glycogenolysis

A complex sensitivity of afferent nerves in the mesentery of the rat jejunum to systemic administration of histamine has recently been demonstrated. In the present study, we aimed to characterize subpopulations of mesenteric afferents that mediate this afferent nerve response. Multiunit afferent discharge was recorded from mesenteric nerves supplying the proximal jejunum in anesthetized rats. The majority of mesenteric bundles (84%) exhibited biphasic responses to histamine (8 [micro]mol/kg), and these bundles also responded to 2-methyl-5-HT (2m5HT). In contrast, monophasic responses lacked a short-latency component, and these bundles failed to respond to 2m5HT. Single-unit analysis revealed a population of afferents that possessed cosensitivity for 2m5HT and histamine. This population of afferents was absent in chronically vagotomized animals, whereas mucosal anesthesia with luminal lidocaine reversibly converted the biphasic profile to a monophasic one. Ondansetron (500 [micro]g/kg) blocked the response to 2m5HT with no effect on the profile of the histamine response, whereas pyrilamine (5 mg/kg) blocked the histamine response without affecting the response to 2m5HT. We conclude that histamine-sensitive afferents exist in the rat proximal jejunum that also respond to 5-HT via the 5-H[T.sub.3] receptor. These fibers appear to be vagal afferents originating in the intestinal mucosa and may be involved in the organization of mast cell-mediated responses. inflammation; intestine; mast cell mediators; mesenteric; neuroimmune interactions

Our previous studies suggested that the cytokine tumor necrosis factor-[alpha] (TNF-[alpha]) may act within the neural circuitry of the medullary dorsal vagal complex (DVC) to affect changes in gastric function, such as gastric stasis, loss of appetite, nausea, and vomiting. The definitive demonstration that endogenously generated TNF-[alpha] is capable of affecting gastric function via the DVC circuitry has been impeded by the lack of an antagonist for TNF-[alpha]. The present' studies used localized central nervous system applications of the TNF-adsorbant construct (TNFR:Fc; TNF-receptor linked to the Fc portion of the human immunoglobulin IgG1) to attempt to neutralize the suppressive effects of endogenously produced TNF-[alpha]. Gastric motility of thiobutabarbital-anesthetized rats was monitored after systemic administration of lipopolysaccharide (LPS) to induce TNF-[alpha] production. Continuous perfusion of the floor of the fourth ventricle with TNFR:Fc reversed the potent gastroinhibition induced by LPS, i.e., central thyrotropin-releasing hormone-induced increases in motility were not inhibited. This disinhibition of gastric stasis was not seen after intravenous administration of similar doses of TNFR:Fc nor ventricular application of the Fc fragment of human immunoglobulin. These results validate our previous studies that suggest that circulating TNF-[alpha] may act directly within the DVC to affect gastric function in a variety of pathophysiological states. tumor necrosis factor-ex; gastric stasis; nausea

This study investigated the mechanisms for glucose-induced islet blood flow increase in rats. The effects of adenosine, adenosine receptor antagonists, and vagotomy on islet blood flow were evaluated with a microsphere technique. Vagotomy prevented the islet blood flow increase expected 3, 10, and 20 min after injection of glucose, whereas theophylline (a nonspecific adenosine receptor antagonist) prevented the islet blood flow increase from occurring 10 and 20 min after glucose administration. Administration of selective adenosine receptor antagonists suggested that the response to theophylline was mediated by [A.sub.1] receptors. Exogenous administration of adenosine did not affect islet blood flow, but local accumulation of adenosine, induced by the adenosine uptake inhibitor dipyridamole, caused a doubling of islet blood flow. In conclusion, the increased islet blood flow seen 3 min after induction of hyperglycemia is caused by the vagal nerve, whereas the increase in islet blood perfusion seen at 10 and 20 min after glucose administration is caused by both the vagal nerve and adenosine. adenosine; microcirculation; microspheres; pancreas; vagus nerve

Neuronal activation of brain vagal-regulatory nuclei and gastric/duodenal enteric plexuses in response to insulin (2 U/kg, 2 h) hypoglycemia was studied in rats. Insulin hypoglycemia significantly induced Fos expression in the paraventricular nucleus of the hypothalamus, locus coeruleus, dorsal motor nucleus of the vagus (DMN), and nucleus tractus solitarii (NTS), as well as in the gastric/duodenal myenteric/submucosal plexuses. A substantial number of insulin hypoglycemia-activated DMN and NTS neurons were choline acetyltransferase and tyrosine hydroxylase positive, respectively, whereas the activated enteric neurons included NADPH- and vasoactive intestinal peptide neurons. The numbers of Fos-positive cells in each above-named brain nucleus or in the gastric/duodenal myenteric plexus of insulin-treated rats were negatively correlated with serum glucose levels and significantly increased when glucose levels were lower than 80 mg/dl. Acute bilateral cervical vagotomy did not influence insulin hypoglycemia-induced Fos induction in the brain vagal-regulatory nuclei but completely and partially prevented this response in the gastric and duodenal enteric plexuses, respectively. These results revealed that brain-gut neurons regulating vagal outflow to the stomach/ duodenum are sensitively responsive to insulin hypoglycemia. dorsal motor nucleus of the vagus; nucleus tractus solitarii; glucose; vagus; stomach

Subdiaphragmatic vagotomy fails to inhibit intravenous leptin-induced IL-1[beta] expression in the hypothalamus. Am J Physiol Regulatory Integrative Comp Physiol 282: R627-R631, 2002; 10.1152/ajpregu.00549.2001. --Leptin is known to be an important circulating signal for regulation of food intake and body weight. Recent evidence has suggested that leptin is involved in infection and inflammation. The afferent vagus nerve is known to be an important component for transmitting peripheral immune signals to the brain, such as interleukin (IL)-1[beta] expression in the brain, anorexia, and fever responses. In the present study, we investigated whether intravenous leptin-induced IL-1[beta] expression in the hypothalamus is mediated via afferent vagus nerve. IL-1[beta] transcripts in the hypothalamus were significantly increased on RT-PCR assessment 1 h after the administration of leptin (1 mg/kg iv) to mice. Subdiaphragmatic vagotomy did not significantly modify intravenous leptin-induced IL-1[beta] expression in the hypothalamus compared with that in sham-treated mice. These data suggest that circulating leptin directly acts in the brain independently of afferent vagus nerve input originating from the subdiaphragmatic organs. afferent vagus nerve; immune-to-brain communication; inflammation

Choate, J. K., E. J. F. Danson, J. F. Morris, and D. J. Paterson. Peripheral vagal control of heart rate is impaired in neuronal NOS knockout mice. Am J Physiol Heart Circ Physiol 281: H2310-H2317, 2001.--The role of nitric oxide (NO) in the vagal control of heart rate (HR) is controversial. We investigated the cholinergic regulation of HR in isolated atrial preparations with an intact right vagus nerve from wild-type (nNOS+/+, n = 81) and neuronal NO synthase (nNOS) knockout (nNOS-/-, n = 43) mice. nNOS was immunofluorescently colocalized within choline-acetyltransferase-positive neurons in nNOS+/+ atria. The rate of decline in HR during vagal nerve stimulation (VNS, 3 and 5 Hz) was slower in nNOS-/- compared with nNOS+/+ atria in vitro (P < 0.01). There was no difference between the HR responses to carbamylcholine in nNOS+/+ and nNOS-/- atria. Selective nNOS inhibitors, vinyl-L-niohydrochloride or 1-2-trifluoromethylphenyl imidazole, or the guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3a]quinoxalin-1-one significantly (P < 0.05) attenuated the decrease in HR with VNS at 3 Hz in nNOS+/+ atria. NOS inhibition had no effect in nNOS-/- atria during VNS. In all atria, the NO donor sodium nitroprusside significantly enhanced the magnitude of the vagal-induced bradycardia, showing the downstream intracellular pathways activated by NO were intact. These results suggest that neuronal NO facilitates vagally induced bradycardia via a presynaptic modulation of neurotransmission. nitric oxide; parasympathetic; sinoatrial node Received 31 May 2001; accepted in final form 5 September 2001

Herring, Neil, Junaid A. B. Zaman, and David J. Paterson. Natriuretic peptides like NO facilitate cardiac vagal neurotransmission and bradycardia via a cGMP pathway. Am J Physiol Heart Circ Physiol 281: H2318-H2327, 2001.--We tested the hypothesis that natriuretic peptide receptors (NPRs) that are coupled to cGMP production act in a similar way to nitric oxide (NO) by enhancing acetylcholine release and vagal-induced bradycardia. The effects of enzyme inhibitors and channel blockers on the action of atrial natriuretic peptide (ANP), brain-derived natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) were evaluated in isolated guinea pig atrial-right vagal nerve preparations. RT-PCR confirmed the presence NPR B and A receptor mRNA in guinea pig sinoatrial node tissue. BNP and CNP significantly (P < 0.05) enhanced the heart rate (HR) response to vagal nerve stimulation. CNP had no effect on the HR response to carbamylcholine and facilitated the release of [sup.3.H]acetylcholine during atrial field stimulation. The particulate guanylyl cyclase-coupled receptor antagonist HS-142-1, the phosphodiesterase 3 inhibitor milrinone, the protein kinase A inhibitor H89, and the N-type calcium channel blocker [omega]-conotoxin all blocked the effect of CNP on vagal-induced bradycardia. Like NO, BNP and CNP facilitate vagal neurotransmission and bradycardia. This may occur via a cGMP-PDE3-dependent pathway increasing cAMP-PKA-dependent phosphorylation of presynaptic N-type calcium channels. nitric oxide; autonomic nervous system; acetylcholine; heart rate Received 3 May 2001; accepted in final form 6 September 2001

The purpose of this study was to examine factors related to vagal tone (V(sub NA)) among preterm infants receiving a l0-minute gentle human touch (GHT) intervention three times daily for 10 days. V(sub NA) was measured continuously for 10 minutes before, during, and after each l0-minute GHT intervention. Findings indicated that there was a significant relationship between VNA and gestational age, although there were no relationships between VNA and measures of motor activity or behavioral distress. There was no difference in pattern of response to GHT or level of morbidity, average daily weight gain, or behavioral organization among infants with low, moderate, and high baseline V(sub NA) levels. There was no difference in V(sub NA) comparing infants in the GHT and control groups or during baseline, touch, and posttouch phases for infants in the GHT group. There is a need for further research to examine the usefulness of V(sub NA) as a measure of stress vulnerability among preterm infants.

The heart rate response to gastric distension, the participation of vagal and sympathetic sensory afferents, adrenergic and cholinergic neural pathways, and the effects of capsaicin on this response in anesthetized rats were investigated. Findings showed that unmyelinated, capsaicin-sensitive vagal afferents are important to the pseudoaffective cardioautonomic response to a noxious gastric stimulus.

The role of vagus nerve in the modulation of secretin binding sites in the rat forestomach has been investigated. A variety of treatments, including vagotomy, vagal ligation, intravenous infusion of tetrodoxin and perivagal application of capsaicin or colchicine, was conducted to examine their effects on secretin receptor binding to forestomach membranes. Results show that vagal input plays an important role in secretin action by mediating the capacity of secretin binding sites through axonal transport.

The effects of saline versus atropine infusion of gastric emptying were investigated using a radiolabeled method that permits simultaneous measurement of the solid and liquid components of a meal in lean and obese male and female subjects. Results showed that obese subjects exhibit altered gastric cholinergic activity compared with lean subjects and that gender differences in gastric emptying may be due to differences in autonomic tone.

A study was conducted to determine whether intestinal glucoreceptors contribute to the regulation of pancreatic islet blood flow. Anesthetized rats were infused with saline, glucose or 3-O-methylglucose directly into the duodenum. Intraduodenal infusion of D-glucose increased both serum insulin concentration and islet blood flow, while the osmotic control substance 3-O-methylglucose had no such effects.

Mechanisms of cardiac pain, or angina pectoris, are discussed with information about sympathetic and vagal afferent fibers that may have roles in transmitting signals that give rise to pain from the heart in ischemia. Coronary artery occlusion and chemical stimulation of receptors excite the fibers. Sympathetic afferent fibers are responsible for the usual areas of pain referral.

The vagus nerve was stimulated using a Gaussian white noise pattern to estimate the transfer function from vagal stimulation to the heart rate response in anesthetized rabbits. The effects of changes in acetylcholine kinetics on transfer function were investigated. Results showed that even though increases in the mean frequency of vagal stimulation from 5 to 10 Hz did not affect the characteristics of the transfer function, administration of neostigmine increased the dynamic gain.

The branch of the vagus nerve responsible for transducing the peripheral signal that induces the elevation of the body temperature during the febrile response to systemic inflammation is investigated by performing selective vagotomies in rats and monitoring their response to low doses of lipopolysaccharides from Escherichia coli. Results reveal that the hepatic branch of the vagus nerve mediates the transduction of peripheral signals in fever genesis.

A study was conducted to examine the actions of capsaicin on the vagus nerve. Several gastrointestinal functions inhibited by the perivagal administration of capsaicin in rats were analyzed. The dual innervation of rat upper gastrointestinal tract by extrinsic primary afferent neurons were also investigated in the study. Results indicated that perineural capsaicin defunctionalizes afferent neurons of the vagus nerve through a vanilloid receptor subtype.

Adrenomedullin is a peptide related to calcitonin-gene related peptide and has been shown to have gastric protective effects when injected intracisternally prior to gastric infusion of ethanol. This protective effect is abolished with vagotomy, epinephrine, indomethacin and a nitric oxide synthase inhibitor. These results indicate that adrenomedullin exerts its protective effects in the central nervous system probably through modulation of protective mechanisms involving prostaglandins and nitric oxide.

Selective vagotomies were performed in groups of rats to determine the contribution of the different branches of the vagus to the detection of gastric volume. Sham operated rats still exhibited volume-dependent suppression of food intake after the infusion of specific saline volumes to the stomach. Vagotomy modified this suppression and the extent of modification was affected by the branches of the vagus severed and spared.

Intracellular and extracellular recording and intracellular labelling of neurons in the solitary tract nucleus and the vagus nerve motor nucleus were undertaken to investigate the vagovagal reflex response to acid in the proximal small intestine. Results reveal that the neurons in these nuclei were responsive to chemical stimuli and a majority was even sensitive to duodenal distention. These results verify the presence of the vagovagal reflex that may ultimately be protective of the intestinal mucosa.

The role of the vagus nerve in the febrile and sleep response to lipopolysaccharide (LPS) was investigated in normal and vagotomized rats. Vagotomy attenuated the increase in non-rapid eye movement sleep and the suppression of the slow wave activity induced by LPS. Further, vagotomy neutralized the hypothermic episode in the biphasic temperature response to LPS. The subdiaphragmatic segments of the vagus nerve contribute to the induction of the central nervous system effects of LPS.

The effects of age and physical fitness on the modulation of cardiac rate by the activity of the vagus nerve are investigated by monitoring the variability of the R-R segment in the Poincare plots derived from male volunteers at rest and during exercise. Results indicate that the age factor is evident in the vagal activity at rest while the effects of physical conditioning are seen during exercise.

The impact of the relatively selective neuronal NO synthase inhibitor 7-nitroindazole (7-NI) on the baroreflex regulation of heart rate (HR) and renal sympathetic nerve activity (RSNA) was studied in rabbits. Intraperitoneal injection of 7-NI had no effect on resting heart rate, mean arterial pressure (MAP) or RSNA. 7-NI greatly decreased the lower plateau of the HR-MAP baroreflex curve in conscious and anesthetized preparations. On the other hand, there was no substantial difference in the RSNA-MAP curves before and after 7-NI administration in conscious and anesthetized preparations.

Research was conducted to study the mechanisms associated with the gastric hyperemic response to a near-maximal acid-secretory dose of intracisternal RX-77368 in urethan-anesthetized rats. Tracheotomy was carried out to facilitate ventilation in the cisterna magna while results were analyzed by the Student's paired t-test. Results indicated a primary function of muscarinic-nitric oxide (NO) pathways. They also showed that central vagal efferent activation decreases gastric vascular resistance through cholinergic NO-dependent pathways.

Research shows that normal insulin-induced hypoglycemia is not dependent upon vagal transmission. Experiments designed to assess effects of vagal afferent nerve blockage on the hormonal response mechanism in hypoglycemia using fasted mongrel dogs are described. Plasma norepinephrine and epinephrine levels are reported. Arterial plasma insulin levels rise and arterial plasma glucose levels fall over time in fasted dogs.

The effects of antagonists, barium, cesium and UL-FS-49 on the parasympathetic stimulation of the atrial muscle of the heart were determined through analysis of the ionic channel antagonists in anesthetized dogs. Barium inhibited the vagally induced bradycardia without affecting the secondary slowing. Both cesium and UL-FS-49 had no effect on the vagally induced bradycardia, but blocked the acceleratory portion. Potassium current mediated the initial atrial response, while pacemaker current mediated the subequent acceleration.

The site specificity of the interactions between serotonin (5-HT) and thyrotropin-releasing hormone (TRH) was investigated using prototypical selective agonists of the serotonin to delineate the mechanisms of the interactions. The results suggested that an augmentation of the TRH-analog induced increment in the response to gastric acid through activation of 5-carboxyamidotryptamine and 5-HT2 receptors may have come from the 5-HT in the dorsal vagal complex (DVC). The results further suggested that the TRH analog behavior at the DVC may have been inhibited by the 5-HT4 receptor activation.

The state of cholecystokinin (CCK)-A receptor affinity on the vagus nerve that mediates the effect of CCK on pancreatic protein secretion was investigated. Male Sprague-Dawley rats were used as experimental models to determine the interaction between CCK and high-affinity CCK receptors. Results indicated a pharmacological characterization of the vagal afferent receptors in the pancreatic protein secretion. The activation of vagal gastric mechanosensitive afferents was mediated by the interaction between CCK and vagal low-affinity receptors.

Researchers have investigated the impact of mercaptoacetate (MA) on the afferent discharge rate in the common hepatic vagus branch of rats fed a fat-enriched diet. There was an increase in the discharge rate in afferents of the common hepatic vagus branch in relation to intraportal infusion of the Na salt of MA in rats adapted to the fat-enriched diet. It was established that intraportal infusion of MA boosts the discharge rate in afferents of the common hepatic vagus brand. Fatty acid oxidation appears to control afferent vagal activity.

Researchers have investigated whether biphasic fever and hypothermia, which are both thermal responses requiring the intact vagus nerve for their development, are vagus mediated and could be affected by subdiaphragmatic vagotomy. This involved assessing thermal responses to the intravenous injection of Escherichia coli in adult Wistar rats 28 days after vagotomy. It was concluded that signals conveyed by the vagus nerve play a key part in initiating monophasic fever.

Researchers have investigated the impact of peptide YY (PYY) and the Y2 agonist PYY-(13-36) on neurons of the dorsal motor nucleus of the vagus (DMN), both intact in vivo by gastric antral inflation and in the in vitro slice preparation under synaptic blockade and normal conditions. It was concluded that one of the main ways in which PYY suppresses digestive functions is by directly inhibiting cholinergic vagal efferent neurons of the DMN through acting as a Y2 receptor.

The patterns of gatric motor excitation that were evoked by the nucleus raphe obscurus (nROb) of rats were analyzed to determine the efficiency of antisense oligonucleotide treatment in eliminating nROb responsiveness. Microinjections of thyrotropin-releasing hormones (TRH) into the dorsal vagal complex of rats increased intragastric pressure and pyloric motility. However, antisense oligonucleotides to the TRH receptor abolished the elevations in gastric motor function which was evoked by L-glutamate stimulation.

The physiological and pharmacological properties of cardiovascular pressor responses were analyzed in urethan-anesthetized rats to characterize the central organization of the esophagocardiovascular reflex (ECR). Analysis of pressor and tachycardic response during graded esophageal distension in urethan-anesthetized rats indicated the role of vagal afferents in mediating the transfer of sensory input between the ECR and the central nervous system. Furthermore, efferent limb of the reflex mechanism was composed of cardioaccelerator- and vasoconstrictor pre-ganglionic neurons.

The series of peptide-induced gastrointestinal events that contribute to the ability of cholecystokinin (CCK) and gastrin-releasing peptide (GRP) in the stimulation of gastric vagal afferent activity was analyzed in rats. Rodent gastric vagal mechanoreceptive activity was elevated by arterial or intraperitoneal CCK and GRP-(18-27) in a dose-dependent manner. Furthermore, single populations of gastric vagal afferents were activated by the close celiac arterial administration of the brain-gut peptides.