Sympathetic Input Into the Enteric Nervous System Gut: First Published As 10.1136/Gut.47.Suppl 4.Iv33 on 1 December 2000

Home , Enterochromaffin cell, Gastrointestinal wall, Submucosal plexus

Gut 2000;(Suppl IV)47:iv33–iv35 iv33

Sympathetic input into the enteric nervous system Gut: first published as 10.1136/gut.47.suppl_4.iv33 on 1 December 2000. Downloaded from

O Lundgren

Introduction nerves to the gut elicits a blood flow response The basic concepts of the autonomic nervous which is very characteristic. Immediately on system of organs and tissues were formulated electrically stimulating the splanchnic nerves, around the turn of the century and summa- pronounced vasoconstriction is observed rised in a classical monograph by Langley which, however, subsides within a few minutes (1921).1 The detailed distribution of the to reach a steady state level of blood flow. It sympathetic nerves was, however, not eluci- seems probable that flow during steady state dated until it became possible to stain sympa- represents the “physiological” response to thetic neurones specifically using the Falck- nerve activation. Intestinal flow resistance is Hillarp technique. When this technique was thus only moderately increased (2–3 times) applied to the gastrointestinal tract the picture even when stimulating the sympathetic vaso- seen was in some respects surprising. At the constrictor nerves at high rates (8–16 Hz). time it was generally believed that most organs When investigating blood flow distribution and tissues had a dual innervation (sympa- within the intestinal wall it has been demon- thetic and parasympathetic) with opposite strated that villus blood flow is not under neu- eVects on function. It seemed, therefore, ral influence during the steady state part of puzzling when the Falck-Hillarp technique vasoconstriction. The decrease in blood flow revealed that innervation of a major part of the occurs in the crypts and muscle layers.3 gastrointestinal wall, the smooth muscle layers, The sympathetic nerves not only control was very scarce. Instead it was found that most resistance vessels; stimulation frequency de- adrenergic fibres make contact with one of the pendent constriction of the veins is observed, two major plexuses in the alimentary canal. decreasing regional blood volume by 40% at Adrenergic innervation is seen in the mucosa, most. Furthermore, the capillary filtration in particular around the crypt epithelium.2 The coeYcient is markedly decreased, which indi- functional consequences of this distribution are cates that the number of perfused capillaries is discussed below. attenuated, presumably secondary to constric- Department of This brief review of the interplay between tion of precapillary sphincters. Physiology, the sympathetic and enteric nervous systems The enteric nervous system (ENS) also con- Gothenburg will discuss the control of blood vessels, epithe- trols intestinal blood flow. In vivo studies have University, lial transport, motility, and endocrine cells (the shown that mechanical stimulation of the Medicinaregatan 11, enterochromaYn cells in particular). intestinal mucosa evokes marked vasodilata- http://gut.bmj.com/ 400 33 Gothenburg, Sweden tion. This response is apparently neurally mediated as it is abolished by nerve blocking O Lundgren Blood flow There is dense adrenergic innervation of both agents (tetrodotoxin or lidocaine). The vaso- Corresponding author: precapillary and postcapillary vessels in the dilatation cannot be blocked by cholinergic Professor O Lundgren. receptor blockers, suggesting that there is no [email protected] digestive tract. Stimulating the sympathetic cholinergic synapse in the reflex. Furthermore,

SF PF SF the response is not influenced by “chronic” on September 26, 2021 by guest. Protected copyright. Myenteric denervation of the intestine, implying that plexus vasodilatation is not mediated via an axon Muscle reflex of the “classical” type. However, layer 5-hydroxytryptamine (5-HT) tachyphylaxis or serotonin receptor blockers attenuate the Submucosal vasodilatation caused by mucosal mechanical Submucosa plexus stimulation. Based on such observations it was suggested that mechanical stimulation causes release of 5-HT from enterochromaYn (EC) cells which in turn stimulate dendrites located 4 Mucosa just underneath the intestinal epithelium. This is illustrated schematically in fig lA. It should be emphasised that the detailed arrangement of this vasodilator reflex is not known. Some AB C observations made by Surprenant5 suggest the Figure 1 (A) Schematic illustration of the vasodilator reflex elicited by mechanical possibility that an axon reflex may be involved. stimulation of the intestinal mucosa. The reflex is probably activated via release of In contrast with sympathetic control of 5-hydroxytryptamine (5-HT) from enterochromaYn cells functioning as mechanoreceptors. motility and epithelial transport, vasodilatation (B) Sympathetic nervous control of secretory nervous reflexes of the enteric nervous system. Sympathetic fibres (SF) exert their action at a synapse in the submucosal plexus and evoked by mechanical mucosal stimulation is possibly also in the myenteric plexus. (C) Schematic illustration of the sympathetic control not influenced by stimulating sympathetic of gastrointestinal motility. In analogy with the sympathetic control of fluid and electrolyte transport, SF exert their control at a ganglionic site. In the figure, SF inhibits the motor activity induced by parasympathetic fibres (PF). SF may also inhibit intrinsic excitatory Abbreviations used in this paper: 5-HT, motor reflexes. Inhibitory action of a neurone is indicated by a filled circle at the end of the 5-hydroxytryptamine; EC, enterochromaYn; CNS, neurone. central nervous system; ENS, enteric nervous system.

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vasoconstrictor fibres.4 The nervous arrange- Enterochromaffin cell Gut: first published as 10.1136/gut.47.suppl_4.iv33 on 1 December 2000. Downloaded from ment of the local vasodilator mechanism is apparently organised in a diVerent way from that of motility and fluid transport. Adrenergic Cholinergic receptors receptor Fluid and electrolyte transport The morphological observations of the adrenergic innervation briefly summarised in the introduction suggest two sites of action for the α control of epithelial transport: a direct action 2 _ on epithelial cells and an indirect action on + [cAMP] [Ca] M3 enteric neurones, in particular those of the + submucous plexus. Evidence for the latter β mechanism has been obtained in electrophysiological studies which have shown that the non-cholinergic submucous neurones, presumably controlling epithelial functions, are under Capillary adrenergic influence via inhibitory postsynap- atic potentials.6 This action evokes a decrease Figure 2 Adrenergic and cholinergic control of the release of 5-hydroxytryptamine (5-HT) from enterochromaYn in electrolyte and fluid tissue to lumen cells. cAMP,cyclic adenosine monophosphate. transport, for example. Interestingly, cholinergic submucous neurones do not receive any smooth muscle layers in a manner similar to such innervation.6 that described for sympathetic control of fluid It is well established that many secretory and electrolyte transport (fig 1C).9 states of the intestinal tract, including cholera, It is apparent from figure 1 that sympathetic are evoked via activation of the ENS. Figure lB nervous control of epithelial transport and illustrates the simplest model for the nervous motility is organised in a similar way, namely secretory reflex of the ENS stimulated by chol- control is exerted at a synaptic site. The era toxin that can be constructed from our cur- sympathetic nerve may exert its action at a syn- rent knowledge. There is experimental evi- apse in at least two ways. It may inhibit the dence for the view that cholera toxin and some release of acetylcholine, for example, from an bile salts, at least in part, activate the ENS via intramural synapse, and/or noradrenaline re- release of 5-HT from EC cells. In line with the leased from sympathetic nerves may hyperpo- electrophysiological observation described larise the membrane potential of the postsyn- above it has been shown that splanchnic nerve aptic neurone. There is experimental evidence stimulation inhibits fluid secretion caused by for both mechanisms. ENS control of blood cholera toxin. This eVect is more pronounced flow, lacking at least a cholinergic synapse, is the higher the rate of fluid secretion and is not influenced by sympathetic neurones. probably explained by a higher activity in the http://gut.bmj.com/ ENS when toxin induced fluid secretion is EnterochromaYn cells large. Hence the sympathetic inhibitory influ- The gastrointestinal tract is the largest endo- ence is dependent on the level of activity in the crine organ in the body, containing a large secretory nervous reflexes of the ENS (fig 1B).7 number of peptides/amines located in endo- There is also experimental evidence for a direct crine cells dispersed among the transporting action of neurally released noradrenaline on epithelial cells. It is well established that diVer-

crypt enterocytes although this eVect is less ent chemicals in the intestinal lumen can evoke on September 26, 2021 by guest. Protected copyright. important than the nervous eVect on the ENS. the release of specific peptides. Hence glucose Sympathetic nervous control of epithelial causes release of gastric inhibitory peptide, and fluid transport in the small intestine can be long chain fatty acids evoke release of chole- reflexly activated by deloading baroreceptors in cystokinin and neurotensin. Endocrine cells the aorta and neck arteries and/or intrathoracic may also be sensitive to luminal physical volume receptors. Thus sympathetic nerves are variables. EC cells have been proposed as part of the homeostatic system controlling fluid mechanoreceptors, releasing 5-HT on distor- and electrolyte content of the body.8 tion of the villi. Based on studies performed mainly in EC Motility cells, it seems probable that release of hor- As noted in the introduction, the Falck-Hillarp mones from endocrine cells of the gastro- technique showed that few adrenergic fibres intestinal tract are under control of the reached the muscle layers of the gastrointestinal autonomic nervous system. Figure 2 summa- tract. This implies that sympathetic control of rises, in a schematic manner, the adrenergic the smooth muscle layers is to a large extent not and cholinergic control of release of 5-HT a direct but an indirect action, except for the from EC cells. There are both á and â adrener- direct eVect of blood borne catecholamines gic receptors on EC cells. Release studies per- released from the adrenal glands. There is formed in vivo indicate that á adrenergic experimental evidence for adrenergic inhibition agonists inhibit release of 5-HT from cells of local excitatory motor reflexes and/or extrin- whereas the cholinergic influence has the sic excitatory parasympathetic nervous activity. opposite eVect.10 As suggested in figure 2, these Hence the magnitude of the sympathetic eVect eVects may be mediated via changes in is dependent on ongoing activity in, for intracellular cyclic adenosine monophosphate example, the vagal excitatory nerves to the and/or Ca2+ concentrations.

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Autonomic nervous control of endocrine 1 Langley JN. The autonomic nervous system. London: HeVner, 1921. Gut: first published as 10.1136/gut.47.suppl_4.iv33 on 1 December 2000. Downloaded from cells of the gastrointestinal tract may have inter- 2 Norberg K-A. Adrenergic innervation of the intestinal wall esting functional implications. It is well estab- studied by fluorescence microscopy. Int J Neuropharmacol 1964;3:379–82. lished that the sensitivity of the muscle spindles 3 Lundgren O. Microcirculation of the gastrointestinal tract in skeletal muscle is controlled from the central and pancreas. In: Renkin EM, Michel CC, eds. Handbook of physiology: The cardiovascular system. Bethesda: American nervous system (CNS) via eVerent fibres influ- Physiological Society, 1984; IV:799–863. encing the so called intrafusal muscle cells. One 4 Biber B. Vasodilator mechanisms in the small intestine. An experimental study in the cat. Acta Physiol Scand 1973;401: can envisage similar CNS control of the 1–31. sensitivity of endocrine cells of the gastro- 5 Surprenant A. Control of the gastrointestinal tract by enteric neurons. Annu Rev Physiol 1994;56:117–40. intestinal epithelium via the receptors illus- 6 Bornstein JC, Furness JB. Correlated electrophysiological trated in fig 2. Activation of these receptors may and histochemical studies of submucous neurons and their contribution to understanding enteric neural circuits. J change the sensitivity of endocrine cells to Auton Nerv Syst 1988;25:1–13. luminal stimuli by influencing membrane po- 7 Sjövall H. Sympathetic control of jejunal fluid and electrolyte transport. Acta Physiol Scand 1984;(suppl 535): tential. Thus the sympathetic nervous system 1–62. may indirectly influence the activity of ENS 8 Sjövall H, Redfors S, Jodal M, et al. On the mode of action of the sympathetic fibres on intestinal fluid transport: Evi- neurones via control of luminal sensory recep- dence for the existence of a glucose stimulated secretory tors. In the context of the present symposium, nervous pathway in the intestinal wall. Acta Physiol Scand 1983;119:39–48. this may be particularly interesting for those 9 Jansson G, Martinson J. Studies on the ganglionic site of endocrine cells which, via release of peptides/ action of sympathetic outflow to the stomach. Acta Physiol Scand 1966;68:184–92. amines, activate aVerent neurones located adja- 10 Racké K, Schwörer H. Regulation of 5-HT release from cent to their basolateral membrane. enterochromaYn cells. Behav Brain Res 1996;73:83–7. http://gut.bmj.com/ on September 26, 2021 by guest. Protected copyright.