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Vagal and spinal afferent innervation of the portal hepatic area has not been studied as thoroughly as the innervation of other important organs. It is generally agreed that unlike noradrenergic sympathetic efferent nerve fibers, sensory nerve fibers of either vagal or dorsal root/spinal origin do not directly innervate hepatocytes, but are restricted to the stroma surrounding triades of hepatic vasculature and bile ducts, and to extrahepatic portions of the portal vein and bile ducts. For vagal afferent innervation, retrograde and anterograde tracing studies in the rat have clearly shown that only a minor portion of the common hepatic branch innervates the liver area, while the major portion descends in the gastroduodenal branch toward duodenum, pancreas, and pylorus. Hepatic paraganglia, bile ducts, and portal vein receive the densest vagal afferent innervation. Calretinin may be a relatively specific marker for vagal afferent innervation of the portal-hepatic space. Calcitonin gene-related peptide (CGRP) is a specific marker for dorsal root afferents, and CGRP-immunoreactive fibers are mainly present near the intrahepatic vascular bundles and bile ducts, and in the same extrahepatic compartments that contain vagal afferents. Because of the specific anatomical organization of hepatic nerves, selective hepatic denervation, whether selective for the vagal or sympathetic division, or for efferents and afferents, is nearly impossible. Great caution is therefore necessary when interpreting functional outcomes of so-called specific hepatic denervation studies.

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BACKGROUND/AIMS: To investigate the effect of parasympathetic blockade on the hepatic circulation, a study was performed in healthy men because the precise knowledge of factors to affect the hepatic circulation is required for the evaluation of liver diseases. METHODOLOGY: Doppler measurements of the hepatic venous and portal venous flow were obtained with measurements of cardiac function before and after the administration of atropine sulfate, 0.02 mg/kg. RESULTS: Parasympathetic blockade increased heart rate and cardiac output and changed diastolic right ventricular filling pattern. However, portal venous flow remained unchanged. Hepatic venous flow was triphasic at rest in 15 of the 20 subjects (75%). The amplitude of the oscillation of hepatic venous flow velocity was significantly reduced in association with an increase in heart rate and the hepatic venous flow pattern was significantly influenced by parasympathetic blockade in accordance with a change in right ventricular filling pattern. CONCLUSIONS: The autoregulation of portal venous flow was suggested to exist and that the influences of parasympathetic activity and/or heart rate affected hepatic venous flow pattern.

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We studied the distribution of neuronal nitric oxide synthase (nNOS) in the rat liver with a specific polyclonal antibody by using immunocytochemical procedures in the light microscopic level. Immunoreactive varicose nerve fibers were found forming a dense plexus around the interlobular hepatic artery and the interlobular bile duct in the hepatic hilus, and in the hepatic artery ramifications of the portal triads. The density of nNOS positive nerve fibers decreases with successive portal ramifications, and some non-immune positive nerve fibers were found in the distal portions of the arterial vessels. The presence of the nNOS positive nerve fibers suggests that the possible main functional role could be related with the regulation of hepatic blood circulation and hepatobiliary activities.

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If a peptide hormone secreted from the gastroenteropancreatic (GEP) system is monitored by the hepatic vagal nerve, the nerve can signal the central nervous system and thereby exert control on its target organs. In this review, we offer a line of evidence for the hypothesis. When a physiological dose of somatostatin (SS), one of the GEP hormones, was injected into the rat portal vein, the spike discharge rate in the hepatic afferent vagus increased significantly. This SS-induced activation of the vagus was completely abolished by a prior administration of our monoclonal antibody to SS receptor into the portal vein. We further disclosed a morphological basis for this neural reception to SS in the hepatoportal area: the neural bodies, located beneath the endothelium of the rat portal vein, preferentially bound the exogenous SS injected intraportally as revealed immunohistologically. The bodies contained a structure of the nerve fiber arborizations resembling those of the afferent apparatus of Krause, on which the presence of SS receptor was confirmed histochemically using the anti-SS receptor antibody. These results provide a new insight into the receptor-mediated neural reception to GEP hormones in the hepatoportal area, implying the potential role of the reception in the GEP physiology.

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The effect of intraportal administrations of interleukin 1 beta (IL-1 beta) on the afferent activity of the hepatic branch of the vagus nerve was observed in urethane anesthetized rats. An intraportal injection of IL-1 beta in doses of 10 pg and 100 pg per animal (300-400 g body wt.) resulted in dose-dependent increase in the afferent activity, which lasted about 70-100 min. Further, intraportal injection of IL-1 beta (100 pg) induced reflex activation of efferent activity of the splenic (sympathetic) nerve and vagal thymic nerve. This reflex activation was not observed in hepatic vagotomized rat and after an administration of the same dose of IL-1 beta into the systemic vein in normal rat. The results suggest the existence of sensors for IL-1 beta which send information on IL-1 beta in the portal venous blood to the central nervous system through the hepatic branch of the vagus nerve and play some role in reflex regulation of immune function.

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The existence of amino acid sensors sensitive to arginine, alanine, leucine and glycine in the hepato-portal region was previously reported based on recording of the afferent signals from the hepatic branch of the vagus nerve. The present study was carried out to investigate the effects of fifteen different amino acids on the activity of the vagal hepatic afferents. Intraportal administration (10 mM, 0.1 mL) of alanine, arginine, histidine, leucine, lysine, serine, tryptophane and valine increased vagal afferent discharge rate, and that of cysteine, glycine, isoleucine, methionine, phenylalanine, proline and threonine suppressed it. The results indicate the existence of two groups of amino acids sensors which exhibit excitatory or inhibitory effect on the afferent activity of the hepatic branch of the vagus nerve. The change in afferent activity to the hypothalamus may affect reflex regulation of the visceral functions and thereby influence appetite.

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We earlier reported the existence of vagal arginine, alanine, and leucine sensors in the liver which modulate amino acid-induced pancreatic hormone secretion. To determine the possible existence of glycine sensors in the liver and their reflex effects, afferent discharges from the hepatic branch and efferent discharges from the pancreatic branch of the vagus nerve were recorded. Intraportal administration of 0.1, 1, and 10 mM of L-glycine solution (0.1 ml) depressed the afferent discharge rate of the hepatic branch of the nerve in a dose-dependent manner, and increased the efferent discharge rate of the pancreatic vagal branch. The results suggest the existence of glycine sensors in the hepato-portal system that exert reflex regulation on the pancreatic vagus nerve activity.

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We have studied changes in the pattern of intrinsic hepatic innervation in sequential liver biopsies from 16 patients who underwent orthotopic liver transplantation. Seventy-one needle biopsies were used, including specimens obtained at the time of transplantation (time zero) and up to 4 years post-transplantation; five transplant hepatectomy tissue blocks removed 3-32 months after transplantation were also assessed. Paraffin sections were immunostained with anti-PGP 9.5 and anti-S-100 to identify nerve fibres. All 'time zero' biopsies contained portal nerves and all but two showed staining of parenchymal fibres. After 1 week, no subsequent biopsies contained parenchymal fibres. The disappearance of portal fibres was less rapid and showed greater variability between patients, but they had all disappeared by 6 weeks and there was no positive staining between 6 and 60 weeks. Thereafter, a minority of biopsies showed innervation of a few small portal tracts. Samples from the porta hepatis, hepatectomy specimens, and needle biopsies containing large tracts showed persistence of major nerve trunks at all stages. Abnormally large nerve bundles were seen in some of these areas. The pattern of nerve staining showed no obvious relationship to the intensity of rejection changes. Our results suggest that there is a limited, delayed capacity for regeneration of portal, but not parenchymal, fibres in the transplanted human liver. The physiological significance of this long-term parenchymal denervation in transplanted livers remains to be determined.

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Innervation of rat hepatic portal system consisting of stem (portal vein) and peripheral portions (superior mesenteric vein, inferior mesenteric vein, splenogastric vein) was investigated by catecholamine fluorescence, acetylcholinesterase and immunohistochemical methods. Catecholamine fluorescent and Neuropeptide Y (NPY) immunoreactive (ir) nerve fibers were distributed throughout the hepatic portal system. Greater density was demonstrated in the peripheral portions. Catecholamine fluorescent and NPY ir nerve fibers formed ground plexus around the hepatic portal system. Acetylcholinesterase positive and vasoactive intestinal polypeptide-ir nerve fibers were sparsely distributed and no significant difference in density was noticed in the stem and the peripheral portions. Density of substance P ir, neurokinin A ir and calcitonin gene-related peptide ir nerve fibers was greater in the peripheral than the stem portion. All these fibers reticular showed pattern.

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We studied physiological effects of portal vein ligation on the longitudinal and circular muscles of the dog portal tree. Portal venous blood pressure after portal ligation was higher in dogs that died than in those that survived. The portal veins isolated from dogs that died after portal ligation exhibited both lower rate of onset and decreased intensity of spontaneous activity, compared with those from dogs that survived. Responsiveness of longitudinal muscles of each of the four portal segments to noradrenaline, acetylcholine, histamine and KCl was markedly reduced in dogs that died, compared with those that survived, although the responsiveness of circular muscle was nearly equal in both groups of dogs. The longitudinal muscle of the truncal portal vein from dogs that died responded less strongly to electrical transmural stimulation than that from surviving dogs. The nonadrenergic, noncholinergic response was almost abolished in dogs that died rapidly. The degree of spontaneous activity or responsiveness to various stimulations in smooth muscles of the portal tree is considered to reflect muscular development. The degree of development of the longitudinal muscle of the portal tree may determine the survival of dogs after portal ligation.

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To investigate the possible existence of arginine sensors in the liver and their reflex effects, afferent discharges from the hepatic branch of the vagus nerve and efferent discharges from the pancreatic branches of the splanchnic and vagus nerves were recorded. Intraportal injection of arginine increased afferent discharge rate of the hepatic branch of the vagus nerve, slightly depressed the efferent discharge rate of the pancreatic vagal branch, and increased the efferent discharge rate of the pancreatic splanchnic branch. The results suggest the existence of arginine sensors in the hepato-portal system that exert reflex regulation of the pancreatic neuroendocrine system.

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Morphological and pharmacological studies were performed in the ductus venosus from near-term fetal and neonatal (1 day of age) lambs. Light and electron microscopic analysis demonstrated a concentration of circularly oriented muscle fibers at the junction of the ductus with the portal sinus (the sphincter region). With the use of histochemical methods, adrenergic and cholinergic fibers were visualized in both the sphincter and extrasphincter regions of the ductus. At either site, nerve fibers were confined to the adventitial layer and never formed a plexus. Norepinephrine and transmural electrical stimulation contracted the ductus sphincter in vitro, and their action was abolished by dibenzyline. In contrast, atropine had no effect on the transmural response. Moreover, acetylcholine contracted the vessel inconsistently. In the fetus, both the norepinephrine-induced and the electrically induced contractions increased on raising the O2 tension of the bathing fluid from 17-31 to 520-705 mmHg. In addition, the transmural response increased with advancing gestation. Norepinephrine and transmural stimulation relaxed dibenzyline-treated preparations in which the tone had been raised with indomethacin. Norepinephrine relaxation was antagonized by propranolol. We conclude that the ductus venosus sphincter contains functional adrenergic nerves, causing contraction and relaxation via, respectively, alpha- and beta-adrenoceptors. The alpha-adrenoceptor-mediated contraction may have a role in postnatal closure of the vessel.

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Innervation of guinea pig livers was investigated by electron microscopy. Thinner unmyelinated autonomic nerves in the portal tract were found to contain many synaptic vesicles in their varicosities: small granular, agranular vesicles and a few large dense-cored vesicles, in addition to a few small mitochondria with sparse cristae, glycogen particles and occasional lysosomes. These adrenergic varicosities showed morphological signs suggesting emiocytotic release of transmitter substance through their naked surface into the portal space; they showed no synaptic contact with cells in the portal space. A cross section of a possible sensory nerve composed of several large axons filled with small mitochondria was identified in the portal space. Occasional large mitochondria-rich axon profiles, probably sensory in nature, were also present in the autonomic nerve. They seemed to be distributed in the hepatic parenchyme making large sensory terminals. In the Disse's spaces thin autonomic nerves composed of varicose axons were observed. Here also, the varicosities contained synaptic vesicles with adrenergic characteristics. Some of them freely terminated in the Disse's space suggesting the release of transmitter substance into the space, but the majority of them made synaptic contacts with hepatocytes. Ito cells received relatively numerous synaptic contacts from the adrenergic terminals. The sinusoidal endothelial lining received no synaptic contacts but only nerve approaches over a wide distance ("synapses per distance"). The Kupffer cell infrequently sent a cytoplasmic process into the Disse's space to form a synaptic contact with an axon varicosity. Presumed sensory terminals were characterized by their extraordinarily large sizes and by their contents of abundant small mitochondria with sparse cristae, glycogen particles and scanty small granular and agranular vesicles. These terminals closely contacted the Ito cell and/or hepatocyte. In guinea pig liver, only adrenergic varicosities or terminals were identified in addition to probable sensory terminals.

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The role of the sensory input involved in the control of the food intake is briefly reviewed. Signals from mouth and throat, as well as signals from the gastrointestinal tract and the liver, are necessary but none of them are sufficient to induce satiation. The oral cues initiated by the food intake have a dual action on the feeding behavior. They first stimulate the intake in the hungry subjects. They sustain it until the amount of food ingested reaches the level necessary to equilibrate the energy balance. Finally, they participate, with the sensory input from the gastrointestinal tract, in the process inhibiting the food intake. The hedonic hypothesis of the food intake control is an attempt to explain this dual action of the peripheral alimentary analyzer in this homeostatic behavior. It was proposed that the alimentary pleasure or displeasure brought by alimentary stimuli acts as a drive for the food intake behavior. Indeed, in normal human subjects, the affective component of the alimentary sensations is not constant, but depends on the subjects' internal state. From pleasant, in subjects requiring some energy supply for long-term or short-term energy regulation, alimentary sensations become less pleasant or unpleasant in satiated subjects or in overfed subjects. This change of the affective component of a peripheral sensation, according to the internal state, was called: negative alimentary alliesthesia. Alliesthesia is a specific and reproducible phenomenon. It has been shown that the internal signal which induces negative alimentary alliesthesia depends on the carbohydrate concentration into the gastrointestinal tract, mainly into the duodenum. This signal may provide information related to the energy content of the ingested food. The neural or humoral nature of the transmission of this information from the gut to the brain is discussed. A neural link possibly involves the enteric glucidoreceptors recently described. In conclusion, the validity and the limits of the hedonic hypothesis of the food intake is briefly discussed.

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