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Chapter 9 (page 37)
It was suggested that VIP functioned as the mediator of
actions in the gastrointestinal tract known to be elicited via non-cholinergic, non-
adrenergic vagal fibres (Fahrenkrug et al. l977).
VIP may participate in the regulation of gastrointestinal tone, motility and secretion (Said
l978). It has been proposed as a possible neurotransmitter of inhibitory nerves of the gut
(Fahrenkrug et al. l977, l978) and it appears likely that it is involved in sphincter
relaxation (Alumets et al. l978). It is a strong candidate as a neurotransmitter responsible
for relaxation of the lower oesophageal sphincter (Goyal et al. l980) and the internal anal
sphincter in some vertebrates (Biancani et al. l985). It inhibits the amplitude of smooth
muscle contractions of the gastric "antrum" in canines (Morgan et al. l978); its usual
effect on gastrointestinal smooth muscle is relaxation (Walsh l983).
VIP appears to be an important mediator of paraneoplastic syndromes associated with
islet-cell tumors of the pancreas, especially the watery diarrhoea hypokalaemia
achlorhydria (WDHA or Verner-Morrison) syndrome. Although disputed by some
authors, the findings of Welbourn et al (l978) left little doubt that a WDHA syndrome
could occur in association with a pancreatic or certain neural tumors. Other tumors
which may secrete large amounts of VIP or VIP-like peptides are neuroblastoma,
ganglioneuroma, pheochromocytoma, medullary thyroid carcinoma and bronchogenic
carcinoma (Said l978).
While studying the biological effects of extracts of intestinal wall on isolated jejunum
preparations, Von Euler and Gaddum (l930) described contractions occurring as a result
of a "novel" or unknown substance. Its effects were two fold: it lowered arterial pressure
(presumably as a result of vasodilatation), and it caused contraction of smooth muscle in
various organs. Fourty years later Chang and Leeman (l970) isolated and identified the
unknown factor as an 11-amino-acid peptide called substance P. It was shown to be
present in various tissues, including the central nervous system; particularly high
concentrations occurred in the posterior horns of the spinal cord.
In the gastrointestinal tract, substance P containing nerve fibres and cell bodies are
encountered along its entire length; they are least prominent in the oesophagus and upper
part of the stomach (Polak and Bloom l98l). According to Walsh (l983) the highest
concentrations occur in the duodenum. Substance P neuronal cell bodies are mainly
located in the myenteric plexuses; their nerve fibres richly innervate the circular
musculature, whereas the longitudinal muscle contains only a sparse network of fibres.
Substance P nerve fibres are also in close contact with the blood vessels (Polak and
In the human gastric mucosa Ferri et al. (l984) demonstrated substance P
immunoreactivity in the oxyntic zone in a few, thin fibres only. Fibres containing this
peptide were more numerous and interconnecting in the "antrum" 3.0cm above the
pyloric aperture. In the duodenum substance P (and VIP) were present in striking nerve
networks in the villi as well as in the muscularis mucosae and around blood vessels. The
peptide was also immunostained in nerve fibres in the submucosa, in neuronal perikarya
between the lobules of Brunner's glands and in Meissner's plexus.
Substance P has been found to cause contraction of the muscularis mucosae; it is also a
well-known vasodilator (Ferri et al. l984).
Hughes et al (l975) isolated two endogenous opiate-like compounds from pig brain. The
two pentapeptides, endorphin and enkephalin, were subsequently demonstrated in other
mammalian species (Polak et al. l977).
The distribution of endorphins and enkephalins in man was studied by a combination of
immunocytochemistry and radioimmunoassay (Polak et al l977, l978). Endorphin
immuno-reactivity was found to be confined to the intermediate and anterior lobes of the
pituitary. Enkephalins on the other hand, were found to have a much wider distribution,
being present in many areas of the central nervous sytem, spinal cord and peripheral
nerves and being widely distributed in the gastrointestinal tract (Polak et al. l977; Skov
Olsen et al. l98l). It was of interest that enkephalins were absent from the pituitary.
In the gastrointestinal tract enkephalin was found in most areas, the highest concentration
being in the "antrum" (i.e. the pyloric mucosal zone) with lesser amounts in the
duodenum and jejunum and even less in the colon; it was not present in the gastric
fornix. The "antrum" contained 31 to 103 ng/gm wet weight, the duodenum l7 to 93
ng/gm, and the colon 6 to 15 ng/gm; the gall bladder and pancreas contained smaller
amounts (Polak et al. l977, l978). Distribution of enkephalin cells closely paralleled the
localization as determined by radioimmunoassay. According to Polak et al (l977)
enkephalin was found in endocrine cells of the "antrum" and duodenum similar to G
cells; it was presumed that the peptide could be stored either within gastrin containing
granules or in different granules, as several granule types might occur in the same cell.
However, the exact intracellular localization of these peptides was not clear; according to
Skov Olsen (l98l) enkephalins were localized to specific endocrine-paracrine cells (other
than G cells) of the APUD series, as well as to nerve fibres of the myenteric plexuses.
In the human gastric mucosa Ferri et al (l984) found metenkephalin immunoreactivity in
a few scattered nerve bundles in the basal parts of the mucosa and in the muscularis
mucosae. Enkephalins were rapidly degraded by blood and were unlikely to have a
hormonal function; a paracrine function was more probable (Skov Olsen l98l).
The localization of enkephalins in neural tissue parallels that of opiate receptor sites
(Polak et al. l978). Both are found in high concentrations in areas associated with
sensory input of pain signals; the small molecular size and short half-life of this peptide
suggest a neurotransmittive function.
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