Effects of a transplantable insulinoma upon regulatory peptide concentrations in the gastrointestinal tract of the rat

Summary The rapid growth (0.8±0.3 g/day) of a transplantable insulinoma, which also contained substance P (2.9±2.3 pmol/g) and gastrin-releasing peptide (3.2± 2.1 pmoll/g), resulted in the development of hyperphagia, hyperinsulinaeinia and hypoglycaemia in rats (n=8). After a 14-day growth period, the insulinoma-bearing rats showed an increase (49%; p<0.01) in the weight of the small intestine but no significant change in stomach weight compared with control animals. The content (pmol/organ) of somatostatin, substance P, neurokinin A and vasoactive intestinal peptide in the stomachs of the tumour rats was unchanged. A depletion in the content (53% p<0.01) and concentration (57%; p<0.01) of gastrin-releasing peptide, however, suggested either hypersecretion, possibly mediated through hypoglycaemia-induced vagal stimulation, or inhibition of synthesis. The concentration and content of glucagon-like immunoreactivity (enteroglucagon) in the small intestine of the insulinoma rats increased markedly (47%; p<0.01 and 120%; p<0.01). This increase is consistent with a proposed role of this peptide as a factor trophic to the intestinal mucosa. No significant changes in the concentrations of somatostatin, substance P, neurokinin A, vasoactive intestinal peptide and gastrin-releasing peptide in the small intestine were observed. However, the increase in gut weight resulted in a greater content of vasoactive intestinal peptide (40%; p<0.01) and substance P (37%; p<0.05) in the insulinoma rats.     

The effect of pancreatic acinar atrophy upon the concentration of vasoactive intestinal polypeptide, substance P, somatostatin and glucagon in the pancreas and gastrointestinal tract of the rat

Atrophy of the exocrine pancreas was induced in rats by feeding a copper-deficient diet combined with penicillamine. The treatment resulted in significant decreases in the weights of pancreas and stomach but an increase in the weight of the small intestine compared with control animals receiving the same amount of food. Despite almost total destruction of acinar cells, the content of vasoactive intestinal polypeptide, (VIP) and substance P in the pancreas was not different from controls but the total somatostatin increased by 258% and the glucagon content by 370%. Significant decreases (p less than 0.05) in the concentrations (pmol/g) of VIP, substance P and somatostatin in the small intestine were observed but the total amount (pmol/organ) of the peptides was unchanged. Similarly, an increase (59%) in the concentration of gastric somatostatin in exocrine atrophy was not reflected in a significant difference in the total amount. The content of enteroglucagon in the small intestine was not different in the two groups suggesting that this material was not the trophic influence leading to increased intestinal weight.     

Neuropeptides and Nerve Growth in Inflammatory Bowel Diseases: A Quantitative Immunohistochemical Study

Many studies have indicated changes in neuropeptides in inflammatory bowel disease (IBD), but with contradictory results. Nerve growth factor also has a potential role in the maintenance of enteric nerves and may be associated with IBD. A quantitative immunohistochemical method was used to measure area density of immunoreactive nerves in the colonic mucosa of surgical specimens. No significant differences in immunoreactivity for substance P, vasoactive intestinal polypeptide, growth associated protein 43, and the neurotrophin receptor p75 were seen in the control, Crohn's, and ulcerative colitis groups. Compared to age-matched normal colon (N = 18), there was an increase in neutrophil number in Crohn's (P < 0.05) and ulcerative colitis (P < 0.01) (both N = 9). There were positive correlations (P < 0.05) between neutrophil number and growth associated protein, between p75 and substance P immunoreactive nerves in ulcerative colitis, and between p75 and vasoactive intestinal polypeptide in Crohn's specimens. These data indicate a link between the immunologic and nervous systems in IBD.     

Neuroendocrine peptides of the gastrointestinal tract of an animal model of human type 2 diabetes mellitus

We studied ten obese diabetic mice (Umeå/ Bom-ob) and 10 homozygous lean controls aged 21 weeks. The concentration of several neuroendocrine peptides was determined by radioimmunoassay of tissue extracts of antrum, duodenum and distal colon. The neuroendocrine peptides that we investigated were: secretin, gastric inhibitory polypeptide (GIP), gastrin, motilin, peptide YY (PYY), somatostatin, vasoactive intestinal polypeptide (VIP), substance P, neurotensin, neuropeptide Y (NPY) and galanin. In the antrum, gastrin, somatostatin, VIP, substance P and NPY concentrations were significantly lower in obese diabetic mice than in the lean controls. There was no statistical difference between the obese mice and lean controls for neurotensin and galanin content. In the duodenum, the concentration of substance P was lower in the obese diabetic mice than in lean mice. There was no statistical difference between obese diabetic mice and lean controls regarding the concentration of secretin, GIP, motilin, gastrin, somatostatin, VIP, neurotensin, NPY or galanin. In the colon, the levels of PYY, somatostatin, VIP, substance P, NPY and galanin were significantly lower in the obese diabetic mice than the lean controls. The concentration of neurotensin in the obese mice did not differ from that in the lean controls. The present study showed that the neuroendocrine system is disturbed in an animal model of human type 2 diabetes and that this disturbance differs from that observed in other animal models of human type 1 diabetes. The present findings may have some implications for the gastrointestinal dysfunction observed in patients with type 2 diabetes.     

Vasoactive intestinal peptide

Dose—response characteristics of feline corpus circular muscle were studiedin vitro for three neuropeptides individually and with vasoactive intestinal peptide. Bombesin, substance P, and cholecystokinin-octapeptide each elicited concentration-dependent isometric contractions that were reduced by 10^–8 M or 10^–7 M vasoactive intestinal peptide (P<0.01). The concentration of each neuropeptide producing a half-maximal response was increased more than one logfold to 10^–6 M by vasoactive intestinal peptide. Tetrodotoxin blocked responses to bombesin (P<0.001) and reduced responses to substance P (P<0.05), but had no effect on responses to cholecystokinin-octapeptide (P>0.1). These results demonstrate inhibition of neuropeptide responses of gastric smooth muscle and support vasoactive intestinal peptide as an inhibitory regulator of gastric motor function.     

Vasoactive intestinal polypeptide levels in sigmoid colon in idiopathic constipation and diverticular disease.

The distribution in the bowel wall of vasoactive intestinal polypeptide-, neuropeptide Y-, and substance P-containing nerve cell bodies and nerve fibers has been described in human sigmoid colon by immunohistochemical examination. In patients with chronic idiopathic constipation, diverticular disease, and in controls (of tissue taken from patients with carcinoma, from a site distant from the tumor that appeared macroscopically normal), the concentrations of vasoactive intestinal polypeptide, neuropeptide Y, and substance P have been measured by immunoassay in the following preparations of sigmoid colon: mucosa, whole colonic wall with mucosa dissected away, circular muscle, and taenia coli. In idiopathic constipation, the vasoactive intestinal polypeptide content of the whole wall minus mucosa was reduced when compared with controls (P less than 0.05) but was unaltered in the mucosa, circular muscle, and taenia coli. In diverticular disease, the vasoactive intestinal polypeptide content of the mucosa and whole wall minus the mucosal layer was increased when compared with control tissue (P less than 0.05 and P less than 0.02, respectively) but was unaltered in the circular muscle and taenia coli. Substance P and neuropeptide Y levels in all layers of colonic wall were unaltered in these two diseases. The disturbances in the normal neural content of vasoactive intestinal polypeptide in the bowel wall in idiopathic constipation and diverticular disease may initiate or contribute to the functional changes seen in these disorders.     

Distributions of neuropeptides in the human esophagus

The distributions of nerve cells and fibers with immunoreactivity for the peptides substance P, somatostatin, enkephalin, vasoactive intestinal peptide, gastrin-releasing peptide, and neuropeptide Y and the enzyme tyrosine hydroxylase were examined in 25 samples of human esophagus. These were compared with samples of stomach and intestine. In the smooth muscle of the muscularis externa, the muscularis mucosae, and beneath the epithelium, the most abundant nerve fibers contained vasoactive intestinal peptide and neuropeptide Y, in contrast to the scarcity of substance P, enkephalin, somatostatin, and gastrin-releasing peptide. Gastric and intestinal samples contained dense populations of fibers containing vasoactive intestinal peptide, neuropeptide Y, substance P, and enkephalin in the equivalent layers, but somatostatin- and gastrin-releasing peptide-immunoreactive fibers were scarce. Complete coexistence of vasoactive intestinal peptide and neuropeptide Y in nerve fibers within the muscle layers was demonstrated in the esophagus, but not in gastric and intestinal samples. The myenteric plexus along the length of the esophagus contained cell bodies and fibers reactive for vasoactive intestinal peptide, neuropeptide Y, enkephalin, and substance P. Somatostatin-immunoreactive cell bodies were very rare in the myenteric plexus, no gastrin-releasing peptide-immunoreactive cell bodies were seen, and both somatostatin and gastrin-releasing peptide-immunoreactive fibers were rare. In the upper esophagus, striated muscle bundles did not contain nerve fibers reactive for these peptides but immunoreactive fibers were seen in the muscularis mucosae and subepithelium. It is concluded that the esophagus has a different pattern of innervation by peptide-containing neurons than the stomach and intestines. Esophageal neurons can be classified into separate classes on the basis of their peptide content.     

Role of vasoactive intestinal peptide (VIP) in pathogenesis of ethanol-induced gastric mucosal damage in rats

To elucidate the possible role of vasoactive intestinal peptide (VIP) in the pathogenesis of acute gastric mucosal damage, rats were treated intragastrically with 1.0 ml 96% ethanol with or without intravenous or intraperitoneal coadministration of VIP (1 nmol/liter to 1 mol/liter/100 g). VIP was found to double the mean lesion area when compared with that induced by ethanol alone (P<0.05), an effect that was prevented by VIP antagonist (1 mol/liter/100 g). A substance P antagonist (1 mol/liter/100 g) also reduced the extent of gastric damage induced by coadministration of VIP and ethanol. VIP antagonist or substance P antagonist significantly reduced ethanol-induced gastric mucosal damage. Gastric mucosal levels of LTB₄, LTC₄, VIP, and substance P were significantly increased in ethanol-treated rats as compared with saline-treated animals (P<0.05). The augmentation of ethanol-induced damage by VIP was associated with increased gastric mucosal levels of LTB₄. In VIP-treated rats, gastric mucosal levels of substance P were found to be significantly increased compared with control rats (P<0.05). Administration of VIP to pyloric-ligated rats significantly increased gastric acid output and blood pepsinogen A levels as compared with saline treated rats (P<0.05). Ketotifen, a mast cell stabilizer (100 g/100 g), administered orally 30 min before damage induction by ethanol, with or without VIP, totally abolished the damage of the surface epithelium of the entire gastric mucosa and significantly reduced the mucosal levels of LTC₄ and LTB₄ (P<0.05). It is suggested that VIP is involved in the pathogenesis of acute ethanol-induced gastric mucosal damage. The effective mucosal protection by ketotifen suggests a role for mast cells and their mediators in the pathogenesis of acute gastric mucosal damage.     

Enteric nerves in diabetic rats: increase in vasoactive intestinal polypeptide but not substance P

The distribution of vasoactive intestinal polypeptide (VIP) and substance P-like immunoreactivities was studied by immunohistochemistry in the myenteric plexus and circular muscle layer of the ileum and proximal colon of rats 8 wk after induction of diabetes with streptozotocin. A consistent increase was observed in fluorescence intensity of VIP-like immunoreactivity in the nerve fibers, and intensely stained cell bodies were significantly more frequent in the myenteric plexus of the ileum (p less than 0.001) from diabetic animals. Some varicosities of VIP-like immunoreactive fibers in the myenteric plexus appeared to be enlarged. Vasoactive intestinal polypeptide-like immunoreactivity was increased and VIP-like immunoreactive nerves appeared thicker in the circular muscle layer of both diabetic ileum and proximal colon. The VIP levels were measured biochemically in tissue consisting of the smooth muscle layers and myenteric plexus. A significant increase in the VIP content per centimeter of intestine was found in both the ileum (p less than and proximal colon (p less than 0.01) from diabetic rats. In contrast, no apparent change in substance P innervation was observed immunohistochemically in the myenteric plexus and circular muscle layer of either diabetic ileum or proximal colon when compared with controls. The results are discussed in relation to the symptoms of autonomic neuropathy of the gut in diabetes.     

Immunohistochemical measurements of nerves and neuropeptides in diabetic skin: relationship to tests of neurological function

Summary Image-analysis was used to measure nerves immunoreactive to the general neuronal marker protein gene product 9.5 (PGP 9.5-IR) and the neuropeptides calcitonin gene-related peptide and vasoactive intestinal polypeptide in standardised leg skin biopsies of three age-matched groups of young subjects: non-diabetic (n=14), diabetic patients with normal small fibre function (non-neuropathic, (n=11) and diabetic patients with abnormal small fibre function (neuropathic, n=11). Depletion of nerves and neuropeptides was most marked in the epidermis, where calcitonin gene-related peptide-immunoreactivity was more frequently absent than PGP 9.5-IR in diabetic patients. Epidermal PGP 9.5-IR nerve area and counts were reduced in neuropathic compared with normal subjects (p<0.001), as were epidermal calcitonin gene-related peptide nerve counts (p=0.003). Sweat gland PGP 9.5 and vasoactive intestinal polypeptide, which may be involved in sweat production, showed no diminution in diabetic patients (area: p=0.160, p=0.372 by ANOVA). Two diabetic patients showed elevated sweat gland PGP 9.5-IR and three had increased sweat gland vasoactive intestinal polypeptide; this may represent nerve proliferation. In local sweat tests, acetylcholine-stimulated sweat output was associated with increased immunoreactivity, while the sympathetic skin response showed inverse correlations with immunoreactivity. There were no consistent changes with other commonly-used neurophysiological tests. HbA₁ correlated negatively with immunohistochemical measurements. Neuropeptide changes were seen in the absence of macro- and microvascular disease, and epidermal nerve depletion occurred in patients with normal thermal thresholds and cardiac autonomic function. Immunohistochemical measurement of cutaneous nerves in skin biopsies is a practical method for assessing peripheral small fibres in diabetes, and one which could be repeated in longitudinal studies.     

Ultrastructural localization of four different neuropeptides within separate populations of p-type nerves in the guinea pig colon

The ultrastructural localization of four neuropeptides, substance P, vasoactive intestinal polypeptide, Met-enkephalin, and somatostatin, in the guinea pig colon was investigated using electron immunocytochemistry. Each peptide was localized to the large granular vesicles in separate subpopulations of p-type nerves. These nerves could often be distinguished by the size and appearance of their immunostained granular vesicle cores. Thus, vasoactive intestinal polypeptide- and somatostatin-immunoreactive vesicles contained cores that were significantly larger (p less than 0.005) than those of substance P- or Met-enkephalin-positive vesicles. In addition, vasoactive intestinal polypeptide-immunoreactive vesicle cores were less well defined and more variable in shape than those of somatostatin-positive vesicles. Substance P- and Met-enkephalin-immunoreactive vesicle cores, however, were very similar in size (p greater than 0.05) and appearance and could only be differentiated using immunocytochemistry. This study demonstrates that the four neuropeptides under investigation are present within separate, often ultrastructurally distinct, neuronal systems in the gut. The distribution of these nerves within the colon is also described.     

Substance P,vasoactive intestinal polypeptide,and gastrin catabolism in canine liver and kidney

No reports have described the catabolic mechanism of substance Pin vivo. We studied the effects of hepatic or renal transit on substance P, vasoactive intestinal polypeptide, and gastrin in anesthetized dogs. It was found that the liver plays a more important role in vasoactive intestinal polypeptide catabolism than the kidney and the kidney is more important in gastrin catabolism than the liver. Substance P was more rapidly degraded than the other two peptides in both organs. The transrenal substance P loss measured byC-terminal antiserum differed from that measured byN-terminal antiserum, although there was no difference in the liver. This suggested that there were different patterns of cleavage of substance P between the liver and the kidney, and that itsC terminal was degraded more strongly than itsN terminal in the kidney.     

The effect of short-term dietary supplementation with glucose on gastric emptying of glucose and fructose and oral glucose tolerance in normal subjects

Summary Recent observations indicate that gastric emptying may be influenced by patterns of previous nutrient intake. The aims of this study were to determine the effects of a high glucose diet on gastric emptying of glucose and fructose, and the impact of any changes in gastric emptying on plasma concentrations of glucose, insulin and gastric inhibitory polypeptide in response to glucose and fructose loads. Gastric emptying of glucose and fructose (both 75 g dissolved in 350 ml water) were measured in seven normal volunteers on separate days while each was on a standard diet and an identical diet supplemented with 440 g/day of glucose for 4–7 days. Venous blood samples for measurement of plasma glucose, insulin and gastric inhibitory polypeptide levels were taken immediately before and for 180 min after ingestion of glucose and fructose loads. Dietary glucose supplementation accelerated gastric emptying of glucose (50% emptying time 82±8 vs 106±10 min, p=0.004) and fructose (73±9 vs 106±9 min, p=0.001). After ingestion of glucose, plasma concentrations of insulin (p<0.05) and gastric inhibitory polypeptide (p<0.05) were higher during the glucose-supplemented diet. In contrast, plasma glucose concentrations at 60 min and 75 min were lower (p<0.05) on the glucose-supplemented diet. We conclude that short-term supplementation of the diet with glucose accelerates gastric emptying of glucose and fructose, presumably as a result of reduced feedback inhibition of gastric emptying from small intestinal luminal receptors. More rapid gastric emptying of glucose has a significant impact on glucose tolerance.Abbreviations GIP Gastric inhibitory polypeptide - T50 50% gastric emptying time     

Effect of immunisation against vasoactive intestinal polypeptide on gastric corpus tone and motility in the ferret.

The role of vasoactive intestinal polypeptide in the control of gastric corpus tone and motility was investigated using auto-antibodies to neutralise endogenous vasoactive intestinal polypeptide. Six ferrets were immunised with vasoactive intestinal polypeptide thyroglobulin conjugate in Freund's complete adjuvant which resulted in a significant increase in plasma vasoactive intestinal polypeptide binding activity compared with unimmunised control animals. In acute experiments the level of spontaneous motility in the period immediately after completion of the surgical preparation was 15 times higher in immunised v control animals (p < 0.02). Surprisingly, however, there was no deficit in the ability of the corpus to accommodate fluid. Peak pressure at the end of a 20 ml ramp distension was not different in immunised animals (5.7 (0.6) cm H2O) compared with controls (4.8 (0.3) cm H2O). It is concluded that the non-adrenergic non-cholinergic inhibitory mechanisms regulating corpus tone and motility are different and that vasoactive intestinal polypeptide acts primarily to regulate phasic contractile activity. Alternatively, because of plasticity in the mechanisms controlling corpus tone, the effect of vasoactive intestinal polypeptide may have been superceded during the timecourse of the immunisation procedure.     

Regulatory peptide distribution in separated layers of the human jejunum

The distribution of regulatory peptides was studied in the separated epithelium, lamina propria, submucosa and muscularis externa of the human jejunum. Gastrin, secretin, gastric inhibitory polypeptide, enteroglucagon and neurotensin immunoreactivity were almost confined to the endocrine cell-containing mucosal epithelium (greater than 98% of the total content), only minor amounts of motilin being detected in non-epithelial layers (3.6 +/- 0.7%, mean +/- SEM, n = 7). Conversely, vasoactive intestinal polypeptide, substance P and mammalian bombesin were virtually limited to non-epithelial layers (greater than 99%). Only somatostatin was found in all layers (44 +/- 6.7% in the epithelium, 34 +/- 5.2% in the lamina propria, 13 +/- 2.9% in the submucosa, and 7.9 +/- 2.8% in the muscularis). Substance P was found in higher concentrations in the mucosa, compared to submucosa and muscle (56 +/- 10, 30 +/- 4.0 and 29 +/- 4.0 pmol/g, respectively), while vasoactive intestinal polypeptide was more abundant in the muscle (411 +/- 52 pmol/g) compared to mucosa and submucosa (228 +/- 64 and 219 +/- 31 pmol/g, respectively). Only low levels of mammalian bombesin were measured, mainly in the muscle (6.9 +/- 1.5 pmol/g, or 89 +/- 3.6% of total content).     

Effects of substance P and vasoactive intestinal polypeptide on contractile activity and epithelial transport in the ferret jejunum.

Previous studies in the ferret demonstrated that vagal nerve stimulation induced an atropine-resistant water secretion. Substance P and vasoactive intestinal polypeptide are possible mediators of this secretory response. The objectives of this study were to investigate the in vivo effects of substance P and vasoactive intestinal polypeptide on the jejunal musculature and epithelium. Substance P caused an increase in jejunal motility, water secretion, and transmural potential difference. Cholinergic blockade did not affect the substance P-induced contractions, but did reduce the increase in transmural potential difference, suggesting an inhibition of water secretion. Vasoactive intestinal polypeptide abolished motor activity; however, it induced an increase in transmural potential difference that was atropine and tetrodotoxin resistant. By immunohistochemical methods, immunoreactive vasoactive intestinal polypeptide and immunoreactive substance P were localized to both nerve cell bodies and nerve fibers in the ferret intestine. Determination of intestinal concentrations of vasoactive intestinal polypeptide and substance P in the ferret showed concentrations of these two neuropeptides that were similar to those in human intestine and demonstrated much higher concentrations of these substances in the muscular layer than in the epithelial layer. Our data demonstrate that in the ferret substance P excites and vasoactive intestinal polypeptide inhibits jejunal motor activity. However, both peptides increase water secretion. Our results suggest that in response to vagal stimulation, neuronally released substance P or vasoactive intestinal polypeptide may participate in the atropine-resistant water secretion.     

Density of substance P, vasoactive intestinal polypeptide and somatostatin-containing nerve fibers in the ageing small intestine of the rats

Immunoelectron microscopic investigations were carried out to study the substance P, vasoactive intestinal polypeptide (VIP) and somatostatin immunoreactive nerve elements in the wall of the small intestine. In young and old animals a large number of immunoreactive nerve fibers were found in all layers of the small intestine. They were observed closely to the epithelial cells, to the blood vessel basement membrane and to the smooth muscle cells and in some cases they were observed in a synapse with other unlabelled nerve fibers. On the other hand, in the senile animals very few immunoreactive nerve fibers were observed, calculated for a 100 micron2 tissue area. In the senile animals the overall number of nerve fibers was decreased in comparison to the young and old animals and most of them were in degeneration. This change could be the cause of the changes in the senescence-related epithelial transport processes and furthermore, of the modifications of the overall intestinal motility of the gastrointestinal tract, resulting in the age-dependent transit rates.     

Stress-induced changes in gastric emptying, postprandial motility, and plasma gut hormone levels in dogs

The influence of acoustic stress on postprandial gastrointestinal motility, gastric emptying, and plasma gastrin, pancreatic polypeptide, motilin, and somatostatin was evaluated in conscious dogs. Six dogs were equipped with strain-gauge transducers and were exposed from 1-3 h after the meal to prerecorded music (80-90 dB broad frequency noise), which produced a significant (p less than or equal to 0.05) lengthening of the gastric (31.2%) and jejunal (37.0%) postprandial pattern. In 4 other dogs with gastric cannula, a 2-h session of acoustic stress beginning just after eating a radiolabeled standard meal induced a slowing of gastric emptying of both liquid (45.7%) and solid (47.1%) phases of the test meal when measured 0.5 h after feeding. In contrast, when measured 2 h after feeding, similar values of gastric emptying of liquids and solids were observed in stressed and control animals. Compared with controls, the postprandial increases of plasma gastrin and pancreatic polypeptide levels were significantly enhanced in stressed animals and occurred early (15 min after the meal). Although postprandial decrease in plasma motilin was unchanged by acoustic stress, the rise in plasma somatostatin level was significantly (p less than or equal to 0.05) prolonged in stressed dogs. These results indicate that acoustic stress affects gastric and intestinal postprandial motility in dogs, delaying the recovery of the migrating motor complex pattern, inducing a transient slowing of gastric emptying, and enhancing the feeding-induced release of gastrin, pancreatic polypeptide, and somatostatin. Such hormonal changes might be due to a direct effect of stress rather than being the consequence of acoustic stress-induced slowing of gastric emptying.     

Distribution and development of peptidergic nerves and gut endocrine cells in mice with congenital aganglionic colon, and their normal littermates

Studies were made of the distribution of gut hormones and neuropeptides in the gastrointestinal tract of mice with hereditary aganglionic colon (s1/s1) and their normal littermates. Antisera to substance P, vasoactive intestinal polypeptide, and enkephalins demonstrated markedly diminished numbers of immunofluorescent nerve fibers in the aganglionic segment of colon; in contrast, in proximal colon and small intestine the distribution of peptidergic nerve fibers was essentially normal. Mucosal endocrine cells were demonstrated in the colon by antisera to substance P, somatostatin, glucagon, and cholecystokinin; in each case there were similar numbers of cells in s1/s1 and normal mice. Radioimmunoassays for vasoactive intestinal polypeptide and bombesin showed diminished concentrations of immunoreactive material in the aganglionic segment of colon of 16-17-day-old animals. However, assays for CCK--which is predominantly located in endocrine cells--showed similar concentrations of immunoreactive material throughout the gut of s1/s1 and normal mice. It was of interest that the concentrations of immunoreactive substance P were lower than normal not only in the aganglionic segment of colon, but also in proximal colon and distal small intestine, and that at all ages the development of substance P in the intestine was delayed in the s1/s1 mice. The results are consistent with the idea that the constriction of the aganglionic segment of colon develops as a consequence of lack of intrinsic inhibitory neurons, possibly those containing vasoactive intestinal polypeptide. The presence of an aganglionic segment is attributable to delayed migration of the neuroblasts from the neural crest. Thus the findings of normal populations of gut endocrine cells in the aganglionic segment is further support for the view that the embryologic origin of gut endocrine cells is different to that of gut neurons.     

Somatostatin effectively prevents ethanol-and NSAID-induced gastric mucosal damage in rats

The interrelationship between somatostatin and its synthetic analog, sandostatin, with neuropeptides and inflammatory mediators, as well as their protection of gastric mucosal damage, were tested in rats. Rats were treated intragastrically with 1.0 ml of 96% ethanol with or without intravenous or intraperitoneal coadministration of somatostatin (1.0 µM/kg). Mucosal damage was also induced by the administration of either indomethacin (30 mg/kg subcutaneously) with or without intravenous sandostatin (10 µg/rat), given 30 min prior to damage induction. Somatostatin levels in ethanol-damaged gastric mucosa were significantly lower than in control rats. Substance P and vasoactive intestinal peptide (VIP) levels were significantly higher in the damaged mucosa in rats treated with ethanol, as was the mucosal generation of leukotriene B₄ (LTB₄) and cysteinyl-containing leukotrienes. The coadministration of somatostatin with ethanol significantly reduced gastric mucosal injury induced by ethanol alone. The protection of the mucosa was accompanied by reduction of mucosal substance P and VIP levels, as well as the generation of leukotrienes, an effect that was reversed by intraperitoneal or intravenous coadministration of somatostatin antagonist, cyclo-(7-aminoheptanoyl-PH-E-d-Trp-Lys-THR), 1.0 µM/100 g, with somatostatin (1.0 µM/kg) and ethanol. When given by itself somatostatin significantly reduced mucosal leukotriene generation compared with their generation in saline-treated rats. Sandostatin completely abolished gastric mucosal damage induced by indomethacin administration. In rats treated with somatostatin and indomethacin, this effect was accompanied by reduction of mucosal leukotriene generation. Administration of sandostatin to pylorus-ligated rats significantly reduced gastric acid output. It is suggested that somatostatin may be involved in the pathogenesis of acute ethanol- and NSAID-induced gastric mucosal injury and that part of its protective effect involves interrelationships with the neuropeptides, substance P and VIP, as well as inhibition of mucosal leukotriene production.