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Path. Res. Pract. 165, 333-348 (1979)
Department of Pathology, Universit y of Basle, Switzerland
Review
The Neuroendocrine System of the GastrointestinalTract
PH. U.HEITZ
SummaryThe use of increasingly refin ed techniques in endocrinologi c research resulted in a
challenge to the classical concept of hormones. The regulatory activity of the highlycomplicated neuroendocrine system is mediated not only by hormones but by neurotransmitters, paracrine substances, and possibly by substances secreted into the gast rointestinallumen as well. The system is divid ed into the central and per ipheral nervous system and theendocrine system. The latter consists of the endocrine glands and the disseminated endocrine system. Research into the act ivities of the system will result in important ad vancesin the fields of physiology, pathophysiology and pathology.
1. Introduction
The term "hormone" was first used after the discovery of secretin byBayliss and Starling in J 902. Since then hormones have been defined astrace substances produced by endocrine organs or cells which serve as chemical messengers carried by the blood to target organs or cells where theyregulate a variety of metabolic activities. Until the late J 950'S little ifanything was known of the molecular structure of hormones and the biochemical mechanisms of their action. The advent of modern techniques hasenabled the biochemist to elucidate the molecular structure of many hormones. The production of antibodies to hormones has led to the development of methods sensitive enough to detect hormones at the cellular leveland to determine hormonal concentration in blood and tissues. These methods provide new insights into the site of production, regulation of hormone secretion, and their action on target cells.
A large number of experiments using increasingly refined techniqueshas resulted in findings challenging the classical concept of hormones. Anincreasingly large class of peptides appear to have a paracrine rather than
23 Path. Res. Pracl. Vol. 165
334 . Ph. U. Heitz
a hormonal activity. Furthermore, many "hormonal" peptides are commonboth to the endocrine peptide producing cells, and to the nervous systemwhere they appear to act as neurotransmitters. At the molecular level themessengers of the neural and endocrine systems appear to be similar,though probably not identical. It may be concluded that control of theinnumerable activities of the entire organism is exerted by one complexcontrol system, the neuroendocrine system. The investigation of this control system is currently one of the most exciting and rapidly expandingfields of research.
This review deals with some implications of the control exerted by theneuroendocrine system on the regulation of various activities of the gastrointestinal tract.
2. Gastrointestinal TractThe activity of the gastrointestinal tract and its accessory glands is
intimately related to that of the liver, adipose tissue, and skeletal muscle,which are involved in intermediate metabolism. The extent and numberof different activities of these organs are important. The luminal surfaceof the small intestine (which is a tube approx. 3 m long) is of the order of200 m''. This enormous surface results from the organization of the mucosainto folds (folds of Kerkring), villi and microvilli. In the human the dailycell-turnover in the gastrointestinal tract amounts to billions of cells; theentire enteric epithelium is completely replaced within 3 to 6 days, thecolonic epithelium is replaced within 4 to 8 days. The gastrointestinal tractsecretes from 6 to 10 liters per 24 hours of fluid containing large quantitiesof proteins, mucus, bile-salts, ions, and water. Under physiologic conditions substantial amounts of the secretory products are reabsorbed by thedistal ileum and the colon.
The liver, adipose tissue and skeletal muscle are involved in the flowand storage of metabolic fuel and in the translation of stored energy intoenergy used for all activities of the organism. For example, adipose tissueis involved in lipogenesis, converting glucose via acetyl-Co A into fattyacids, which are then esterified with glycerol to form triglycerides. Aninefficient fuel on a weight basis is thereby converted to an efficient formof energy storage.
Coordination of the innumerable chemical reactions participating in thedigestion and absorption of nutrients and in the flow and storage of metabolic fuel is, therefore, essential for the individual to survive.
The Neuroendocrine System of the Gastrointestinal Tract . 335
3. Neuroendocrine System
The highly complex neuroendocrine control system is divided into threesystems: The central nervous system integrates the activities of the gastrointestinal tract and the flow of metabolic fuels with those of the organismas a whole, e.g. circadian rhythm, physical activity, psychological situation(stress), hunger, thirst, satiety, or eating; the peripheral nervous systemand the endocrine system are involved in regulation of the activity of thegastrointestinal tract and intermediate metabolism.
}.1 Disseminated endocrine system
This system is a part of the endocrine system and is synonymous with"diffuse endocrine or paracrine system". The chief characteristic of thissystem is the wide scattering of its cells in such various organs as thegastrointestinal, the respiratory, and the urogenital tracts. This organization contrasts with that of endocrine "glands", the activity of which isregulated by nerve impulses and substances circulating in the blood (eitherin the general circulation or in specialized portal systems).
The vast majority of the cells of the disseminated endocrine system arelocated in the mucosa of the gastrointestinal tract and in the endocrinepancreas. The totality of these cells is known as the gastroenteropancreatic(GEP) endocrine system, and it is by now a common catch phrase to referto the GEP endocrine cells as the "largest endocrine gland of the body".
3. I. I History of the concept, embryology of gastroenteropancreaticendocrine cellsEnterochromaffin cells were described by Heidenhain in 1870 in the gastric mucosa of
several mammalian species. An endocrine function of these cells was first suggested byCiaccio in 1906 and later by Masson in 1914 who used the term "glande endocrine del'inrestin chez l'homme" for the totality of argentaffin (chromaffin) cells. Basigranularnonargentaffin cells were described by Kull in 1913. These cells were found later to beargyrophilic by Hamper]. Langerhans described groups of cells in the exocrine parenchyma of the pancreas in 1869 which are cur, (.fltlt kuown as islets of Langerhans. At theend of the roth century an endocrine activity was ascribed to these pancreatic endocrinecells by Mehring and Minkowsky (1889, 1892).
However, it is Feyrter who is accepted as the founder of the predominantly gastrointestinal system of "clear cells". Later, Pearse recognized the amine-handling characteristics of the majority of peptide producing endocrine cells, including Feyrter's clearcells. This author then developed the concept of the APUD-series (Amine PrecursorUptake and Decarboxylation) and suggested the neural origin of its cells. This could becompletely proved for 6 of 40 amine-handling and peptide producing cells. The originof the GEP endocrine cells is at present a matter of controversy, although there isconsiderable evidence of their neural origin. The unequivocal identification of the embryologic origin of GEP endocrine cells awaits further investigation.
33 6 . Ph. U. He itz
3.2 Technology
After the discovery of secretin, the investigation of the GEP endocrinesystem made little progress until the advent of fundamentally new techniques, because its cells are widely scattered. Improved chemical purification techniques, e.g. ion exchange chromatography, gel chromatography,isoelectric focusing, high pressure liquid chromatography, and isotachophoretic analysis, led to the discovery of many new peptides, the aminoacid sequence of which could be determined. The next step was the synthesis of peptides. Techniques now available allow characterization of thephysicochemical constants and biological properties of purified extracts orsynthetic peptides. Subsequently the production of antibodies to pure peptides led to the introduction of methods of radioimmunologic determination of peptide concentration in serum and tissues. Radioimmunoassay andradioreceptorassay are currently measuring peptides in amounts of theorder of 10-12 to 10-15 mol/I. Progress in the technology of endoscopyhas greatly facilitated the use of new morphologic techniques. The identification of peptides at cellular and subcellular level can be obtained byimmunocytochemical techniques. Stereologic analysis of the gut mucosacombined with radioimmunoassay now enables the investigator to determine the site of highest concentration of peptides and to define pathologicconditions such as hypertrophy or hyperplasia of endocrine cells.
Fig. I. Motilin cell in the human duodenum. Unlabeled antibody enzyme method. X 1,650.
The Neuroendocrine System of the Gastrointestinal Tract . 337
Fig. 2. Basis of a D cell in the human duodenum. Large (260-370 nm), poorly osmiophilic secretory granules with a closely applied membrane and numerous mitochondria.Glutaraldehyde-osmium tetroxide fixation, uranyl acetate, and lead citrate; X 10,15°.
].] Classification of gastroenteropancreattc endocrine cells
First detected by chromaffin (argentaffin) and later by argyrophilicmethods, many cells are now characterized by combining light and electronmicroscopy, formaldehyde-induced fluorescence and immunocytochemistry(Fig. I and 2). A new (though still complicated) international classificationof the cells was established in 1977 (Table I). This classification shouldbe amended in the near future in favor of an entirely functional classification, e.g. the labeling of every cell type according to its major product.
].4 Peptides and amines of the gastroenteropancreatic endocrine system
To date 12 peptides of the GEP endocrine system have been isolated,9 of which have been sequenced in at least one species (Table 2). In addi-
338 . Ph. U. Heitz
Table I
Pancreas StomachOxyntic Pyloric
Small intestineUpper Lower
Large Function proposed orintestine ascertained
[P] P P P Bombesin-like?(EC) EC EC EC EC EC 5HT (substance P, ECI)
(motilin, EC2)(others? ECn)
DI Dl DI Dl Dl Dl (VIP-like) Disputed
PP (PP) (PP) (PP) (PP) (PP) Pancreatic polypeptide
D D D D Somatostatin
B Insulin
A [(A)l Glucagon
X (X) Unknown
ECL Unknown (H or 5HT)
[G] G G Gastrin
S S Secretin
I I Cholecystokinin
K K GIP
N Neurotensin
L L L GLI
------ - ---- ---
] = fetus or newborn, absent or only exceptional in adults
( ) = animals, not in man-~ ---- - --
Explanation to Table I: Lausanne 1977 classification of gastroenteropancreatic endo-crine cells. H: Histamine, HT: s-Hydroxytryptamine.
tion there are at least 10 "candidate hormones" which have not yet beencharacterized chemically.
3.5 Distribution of gastroenteropancreatic pep tides
Figure 3 demonstrates the distribution of GEP peptides and their cellsof origin. The widespread and overlapping distribution of many of these"hormones" is striking. It is also important to point out the demonstrationof the simultaneous occurrence of several substances in intramural nervesas well as in GEP endocrine cells. As some of the peptides appear to beparacrine substances, the triple control device of the body's functions,namely endocrine control, local control and nervous control, is especially
The Neuroendocrine System of the Gastrointestinal Tract . 339
Table 2
Peptides
• Gastrin• Cholecystokinin
SecretinGastric Inhibitory Polypeptide(GIP)Vasoactive Intestinal Polypeptide (VIP)Motilin
• Substance P• Somatostatin• Neurotensin
UrogastroneEnteroglucagon (Glycentin)InsulinGlucagonPancreatic Polypeptide (PP)
Number of amino acids
- - - - -
34 17 14+
39 33 +28 porcine
43 porcine
28 porcine22 porcineII
141353 52 +?
5329
36
Biogenic amines
5-Hydroxytryptamine (Serotonin)DopamineHistamineMelatonin
• Peptide common to nervous tissue and endocrine cells+ Several molecular formsExplanation to Table 2: Gastroenteropancreatic peptides and amines (mod. from Grossman, 1977).
well demonstrated in the gastrointestinal tract. Its analysis, therefore, is ofgreat fundamental interest.
].6 Transport of gastroenteropancreatic pep tides and amtnes to targetcells
There appear to exist three (possibly four) ways in which peptides andbiogenic amines may act.
3.6.1 HormonesBy definition, a true hormone is secreted into the blood by an endocrine cell (or organ)
and subsequently transported to the target cell (or organ) by the blood. At present, serumconcentrations of gastrin, secretin, cholecystokinin, gastric inhibitory polypeptide, motilin,enteroglucagon (or glycentin), insulin, glucagon, pancreatic polypeptide and s-hydroxytryptamine can be measured. These substances may act as hormones.
340 . Ph. U. Heitz
Fundus Antrum Duodenum Jejunum Ileum Colon Pancreas
Gastrin
Secretin
CCK
Grp
Motilin
VIP
Substance P
Enteroglucagon
Somatostaltn
NeurolenslO
Insulin
Glucagon
PP
;;g
p. h \i "Wm\B6MiMll
hi
KG· a
t& M£
Fig. 3. Distribution of gastroenteropancreatic peptides (modified from Grossman, 1977).CCK = cholecystokinin, GIP = gastric inhibitory polypeptide, VIP = vasoactive intestinal polypeptide, PP = pancreatic polypeptide.
3.6.2 Paracrine peptidesThe term "paracrine", coined by Feyrter, means "acting locally", and is used here to
mean acting on cells in the immediate vicinity of the source of the peptide.Paracrinesubstances might reach their target cells via the extracellular fluid or via a local portalsystem of blood vessels (e.g. similar to the portal system of the hypothalamus-pituitaryaxis). At present, it is difficult to demonstrate the paracrine action of peptidesunequivocally, but there is considerable evidence of its existence. Some peptides have extremely short half-lives (often less than 1 minute) when injected. Moreover, they exertmultiple actions in a large number of organs. Thus these peptides appear unlikely toact through the circulation.
This situation is best demonstrated by somatostatin (or growth hormone inhibitinghormone, GHIH). This peptide is produced not only by cells of the hypothalamus butalso by cells of the gastric and duodenal mucosa and of the endocrine pancreas (Table I ).Its effects are inhibitory in all these organs, e.g. it inhibits the secretion of growth hormoneby the pituitary gland, the secretion of acid by the oxyntic gland of the stomach, and thesecretion of gastrin, cholecystokinin, insulin, glucagon , and possibly pancreatic polypeptide. It is difficult to conceive a control system inhibiting so man y different systemsat once.
Further candidates for paracrine action are substance P, vasoactive intestinal polypeptide, and neurotensin.
3.6.3 NeurotransmittersA neurotransmitter is released from nerve endings following axonal depolarization.
It then crosses the synaptic cleft, averaging 20-30 nm in width. Its half-life is extremelyshort (e.g, a few seconds). In addition to the classical neurotransmittrs such as catecbolamine s and acetylcholine, s-hydioxytryptamine and several peptides such as substance
The Neuroendocrine System of the Gastrointestinal Tract . 34 1
P, vasoactive intestinal polypeptide, neurotensin, gastrin, cholecystokinin, and possiblyendorphins (substances derived from a larger precursor molecule, lipotropin, acting asendogenous opiates ) have been localized in ner ves as well as in GEP endocrine cells.These substances may act as aminergic or peptidergic neurotransmitters. It is interestingthat the molecular form es) of a given peptide occurring in nerves may diff er from thatpresent in GEP endocrine cells.
3.6.4 Luminal releaseIt has recently been demonstrated that gastrin and somatostatin are released into the
lumen of the gastrointestinal tract by endocrine cells. It is not yet known whether thesepeptides exert any effect by this route. It is difficult to conceive such an effect,because of the presence of potent proteolytic enzymes in the lumen which probablydestroy these peptides rapidly.
Urogastrone might be an exception, as it has been shown to be produced by Brunner's glands and by the submandibular gland. On the other hand, urogastrone has beenshown to be stable to proteolytic enzymes such as trypsin, chymotrypsin, and pepsin.Urog astrone is present in the blood and is excreted in the urine. It is conceivable thaturogastrone exerts a dual action as a hormone and as a protective factor secreted intothe duodenal lumen.
Additional information is needed to establish luminal release as a fourth type oftransport of GEP endocrine pept ides.
) .7 Effects on the target cell
The specificity of action of a hormone, neurotransmitter, or paracrinepeptide is essential to the subtle regulation of a large number of activities.Peptides as well as catecholamines interact reversibly with the outer surface of the cell membrane. The information content of the amino acidsequence of the peptide is then transduced to the inside of the target cellthrough the action of receptors , which are integral lipoproteins of the cellmembrane. This information-transduction leads to short-term metabolic orphysical effects of the target cell. By contrast, peptide hormones probablyexert long-term effects on cellular growth and metabolism by entering thetarget cell.
).8 Physiologic versus pharmacologic effects
The purpose of every investigation must be to determine the effects of agiven substance under physiologic conditions. The stimulus for release of asubstance under investigation must be physiologic (e.g, a meal may beconsidered as a physiologic stimulus for the gastrointestinal tract). Theeffects of the peptide must be tested in the intact organism. The effectsexerted by the agonists and antagonists of the substance must be takeninto account. Therefore, only the simultaneous determination of therelease, the cell of origin , the transport to the target cell(s), the response of the latter, the half-life, the metabolism, and the dose-response
34 2 • Ph. U. He itz
Table 3
Gastrin Cholecystokinin Secretin Gastri cInhibitoryPolypeptide
Secretion
Gastric acidBicarbonateEnzymesInsulin
Motility
FundusAntrumSmall intestineLarge intestine
t
t
+
t
tt
t+
t
Trophic action
Acid secret ing mucosa tPancreat ic acinar tissue t
-t+
+ = augments the action of another hormoneExplanation to Table 3: Physiologic actions of gastroenteropancreatic peptides (Grossman, 1977).
relationship of all substances involved will give useful information on thecontrol of a physiologic function . Such investigations are extremel y complex and only possible through interdisciplinary collaboration among manyscientists. It is not surprising that only a few effects of the large number ofGEP peptides and amines can be considered as physiologic at present (Table 3).
On the other hand, some physiologic actions of insulin and glucagonare well known. Both hormones are involved in control of the flow ofmetabolic fuels after intake of a meal and during fasting or starvation. Thecontrol is exerted in common with the peripheral nervous system and withhormones of the pituitary, thyroid, and adrenal glands.
In sulin is a very important anabolic hormone which stimulates appropriate storage of fuels, e.g. it stimulates the synthesis of glycogen in thehepatocyte, the uptake of amino acids, and the synthesis of proteins inmany tissues (e.g. liver and muscle) and, most important, it increases glucoseupt ake into adipose tissue and thereby stimulates lipogenesis (sec above).
Thc Neuroendocrine System of the Gastrointestinal Tract . 343
liver
Pyruvate
°2
609
Brain 02
~C02
<449 LliP;o
Glucose ErythrocytesIll:> 9 leukocytes
1------'" tn-;el369 I
tKetone lat1ate
Glycogen
°2 G H20-, V,,/--_.....:::_~..._---Fatty acid 409
160 9
Glycerol169
Triglyceride
160 9
Adipose tissue
Muscle
§-ote;nAmino acids-
~g "
GluconeogenesIsI
I
Ii!! 9
I
: CO2
~----e- H:O
MuscleKidneyHeart
Fig. 4. Estimation of the flow of metabolic fuels in normal man fasted for 24 hours,utilizing 7>536 k] (r,800 kcal) (from Cahill, r974).
Glucagon is involved in the control of the flow of metabolic fuel duringfasting (e.g. overnight-fast) or during starvation (Fig. 4). In the fastedstate, the glucose level in the blood and thus glucose uptake by the brainmust be maintained, because the glycogen reserves of the latter are small.This is achieved by stimulating glycogenolysis or gluconeogenesis in thehepatocyte after depletion of its glycogen stores.
Both insulin and glucagon are important trophic factors of the liver inthat they are involved in the maintenance of liver mass and in the regulation of liver cell regeneration.
In contrast to the restricted number of known physiologic actions ofGEP peptides and amines, a large number of pharmacologic effects areknown. They can be tested by the administration of large doses of a substance by infusion or intravenous injection. In general, pharmacologic andphysiologic effects are clearly different. However, testing of the former isimportant in order to elucidate the adverse effects of GEP peptides indisease and to test therapeutic implications.
].9 Evolutionary aspects
A number of authors argue that some of the increasingly large numberof peptides discovered in the gastrointestinal tract may have no physic-
344 . Ph. U. Heitz
logic role. In fact, the rate of discovery of new peptides is bewildering.However, any substance or control system which is not essential for survival of a species will be gradually eliminated by natural selection. At presentthere is no evidence for the disappearance of any of the known peptides.On the contrary, peptides immunologically cross-reacting with mammalianpeptides have been discovered in the most primitive vertebrates, the agnatha. During a period of evolution lasting 200-S00 X 106 years, relativelyfew amino acids have been substituted in some molecules (e.g. insulin:2S%; glucagon: 3-7%; vasoactive intestinal polypeptide: r6% of aminoacid residues). The substitution of these amino acid residues occurred atpositions in the molecules which are not of importance to their tertiarystructure.
Very similar molecules possibly appeared during molecular evolution byduplication of a gene coding a common precursor molecule. Increasinglydivergent molecules were perhaps coded by subsequent independent mutations of the duplicated gene. This is a possible explanation for the appearance of so-called hormone families, e.g. the secretin family (secretin, glucagon, vasoactive intestinal polypeptide, gastric inhibitory polypeptide)and the gastrin family (gastrin, cholecystokinin, cerulein).
4. Control of Food Intake, Digestion, and IntermediateMetabolism
The widespread distribution of the GEP peptides produces an integratedresponse to diffuse and discontinuous stimuli involved in the intake of food,its transport along the gastrointestinal tract, its digestion, and its resorptIOn.
The sequence of digestion and flow of metabolic fuels may be dividedschematically into four phases: r , cephalic phase, 2. gastric phase, ]. intestinal phase, 4. pancreatic phase. This classification, although very schematic, is helpful for demonstrating the multiple steps involved in digestionand intermediate metabolism regulated by the control system of the gut.The various phases are interdependent and overlapping.
The first stimulus is probably entirely neural. A meal presented to one ina fasted state will immediately stimulate the secretion of saliva, gastric, andpancreatic juice (cephalic phase). After food intake, the activity of the gut(including the exocrine pancreas) is largely controlled by the volume ofnutrients and their chemical constituents, the pH of the luminal contents,and the transport of food along the gastrointestinal tract (gastric and intestinal phases). Food intake stimulates the release of hormones, neurotransmitters, and paracrine substances (and possibly substances secreted
The Neuroendocrine System of the Gastrointestinal Tract . 345
Table 4
Stimulus
Gastrin
Cholecystokinin
Secretin
Gastric InhibitoryPolypeptide
Enteroglucagon
Vagusnerve
+
Protein
++
Fat
+
++
Carbohydrate
++
Gastricacid
+
+ = Stimulation- = Inhibition
Explanation to Table 4: Stimuli regulating release of gast roenreropancreatic peptides(Grossman, 1977).
into the lumen), which control (r) the contraction of gastrointestinal wallmuscles, (2) secretion by the gut mucosa and exocrine pancreas, and (3)bile flow (Table 4). Distention of the gastrointestinal wall is thought tobe important to the stimulation of nerves. Direct contact of the microvilliof GEP endocrine cells with the luminal contents (Fig. 5) probably regulatesthe secretion of their products. Inactivation of secretion is probably causedby transport and resorption of nutrients. It is possible, however, thatinactivation is induced by the secretion of hormones by cells located inmore distal parts of the gastrointestinal tract.
The secretion of pancreatic hormones (pancreatic phase) is induced byneural stimuli and duodenal hormones, the most important of which appears to be gastric inhibitory polypeptide. In a later phase, their secretionis largely controlled by serum levels of glucose, amino acids, lipoproteins,and fatty acids.
The complex control of every phase of digestion and food assimilationmay be demonstrated by the control of gastric acid output, which is one ofthe best known processes of gastrointestinal physiology (Table 5).
ConclusionHumans readily adapt to nutritional and environmental changes. Homeo
stasis is finely regulated and maintained during phases of fasting, foodintake, exercise, and stress. The subtle regulation of every activity of the
346 . Ph. U. H eitz
Fig. 5. Microvilli of an endocrine cell of the human duoden um in contact with theduodenal lumen. Glut araldehyde-osmium tetro xide, uranyl acetate, and lead citrate; X2 0 , 5 0 0 .
gastrointestinal tract and the many enzymatic pathways of intermediatemetabolism is effected by a highly complex control system, the signals ofwhich are mediated by hormones, neurotransmitters, paracrine substances,and possibly by secretion of substances into the lumen.
Research into the activities of this system using highly sophisticatedtechniques of biochemistry , molecular biology, cell biology, immunology,and morphology is extremel y complex. It is to be expected that in the nearfuture this research will result in significant advances in the field of physiology and pathology of the neuroendocrine regulatory system, which integrates every activity of the organism.
Th e Ne uroendocrine System of the Gastroint est inal Tract . 347
Table 5
LuminalNutrient spH
Neura lVagus ner veLocal peptidergicSymp athetic
Ho rmon alGastrinCholecystokininGastric Inhibitory PolypeptideSecretinBulbo gastrone (Urogastrone?)
Paracrin eSomatostat inHistamine5-HydroxytryptamineProstaglandinsNeurot ensin? Enkephalin?
Gast ric Empty ingRate of emptyingPyloric reflux
Expl an ati on to Table 5: Control of gastric ac id secretion (Bloom and Polak, 1978).
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York (1978)Bloom , S. R. , and Polak, J. M.: Gut Hormone Ove rview. In: Gut Hormones, Bloom, S.
R. , ed., pp. 3-1 7. Churchill Livin gstone, Edinburgh-London-New York (1978)Bonfils, S., Fromageot , P., an d Rosselin, G. (ed.) : Hormonal Receptors in Digest ive Tract
Ph ysiology. North-Holland , Amster dam-N ew York-Oxford (1977)Cahill jr., G. F. : Intermediat e Meta bolism of Protein, Fat and Carbohydrate. In: Harri
son's principle s of internal medici ne, Wintrobe, M. M., G. W. Thorn, R. D. Adams,E. Braun wald, K . ]. Isselb acher, R. G. Perersdorf, ed., pp. 396-408. McGraw-Hill,N ew York (1974)
Coupland, R. E., and Fujita , T . (cd.) : Chromaff in, Enterochr omaffin and Related Cells .Elsevier, Amsterdam-Oxford-New Yor k (1976)
Davenport, H. W.: Physiology of the Di gestive Tract, 4th ed. Year Book Medical Pu-blishers, Inc., Chicago (1977)
Dhom, G. (ed.): Verh. Drsch. Ges. Path. 6r (1977)Fujita, T.: Endocrine Gut and Pancreas. Elsevier, Amsterdam-New York (1976)Glass, G. B. ]. (ed. ) : Progress in Gastr oent erology. Grune and Stratton, New York-San
Fr an cisco-London (1977)Grossman , M. L : Th e Gast roint est inal Hormones: An Ov erview. In : Endocrinology, Vol.
1 , pp. 1- 6, Ja mes, V. H . T., ed. Exce rpta Med ica, Amsterdam-Oxford (1977)Pearse, A. G. E., Pol ak , J. M., and Bloom, S. R.: Th e N ewer Gut H ormones. Cellular
source , physiology, path ology and clinica l aspects. Gastr oent erology 72, 746-7 61(1977)
Singh, M., and Webster , P. D. : N eurohormonal Con trol of Pancreatic Secretion. AReview. Gastroenterology 74, 294- 3°9 (197 8)
348 . Ph. U. H eitz
Solcia, E., Polak , J. M., Pearse, A. G. E., Forssmann, W. G., Larsson, LA., Sundler, F.,Lediago, ]. , Grimelius, L., Fujita, T., Creutzfeldt, W., Geprs, W., Falkmer, S., Lefranc,G., Hei tz, Ph., Hage, E., Buchan, A. M. J., Bloom, S. R., Grossman, M. I.: Lausanne1977 classification of gastroenreropancreatic endocrine cells. In : Gut Hormones,Bloom, S. R., ed., pp. 40-48 . Churchill Livingstone, Edinburgh-London-New York(1978)
Sternb erger, L. A. : Immunocytochemistry . Prentice-Hall, Inc., Englewood Cliffs N. ] .(1974)
Williamson, R. C. N.: Intestinal adaptation. 1. Structural, functional and cytokineticmanges. New Engl. J. Med. 298, 1393-1 402 (1978). 2. Mechanisms of Control. NewEngl. ] . Med. 298, 1444-1 450 (1978)
Received November 2, 1978 . Accepted November 30, 1978
Key words: Neuroendocrine System - Gastrointestinal tract - Digestion-Intermediate metabolism
Ph. U. Heitz, M. D., Department of Pathology, University of Basle, Schonbeinstr. 40,CH-4 056 Basic, Switzerland