A role for calcitonin gene-related peptide in protection against gastric ulceration.

OBJECTIVE: The goal of this investigation was to determine the role of calcitonin gene-related peptide (CGRP) in gastric mucosal resistance to ulceration. SUMMARY BACKGROUND DATA: CGRP is a 37-amino acid peptide found in the peripheral ends of afferent gastric neurons. CGRP is known to inhibit acid secretion, stimulate mucosal blood flow, and stimulate release of somatostatin. METHODS: The release of CGRP in response to intragastric and intra-arterial administration of capsaicin in the isolated, vascularly perfused rat stomach was measured by radioimmunoassay. The molecular forms of CGRP released were analyzed by gel filtration chromatography. The effect of intravenous CGRP or intragastric capsaicin on gastric ulceration induced by 100 mmol/L HCl and indomethacin was studied in intact and endogenous CGRP-depleted rats. RESULTS: Intra-arterial capsaicin (concentration range, 10(-7) to 10(-5) mol/L) stimulated a prompt and sustained release of immunoreactive CGRP, of which 84% coeluted with rat 1-37 CGRP I by gel filtration. Intragastric capsaicin (range, 10(-5) to 10(-4) mol/L) failed to release CGRP into the vascular perfusate. In intact rats, intragastric capsaicin (10(-6) mol/L) or intravenous CGRP I (10 micrograms/kg/hr) reduced the number and area of mucosal lesions caused by HCl and indomethacin compared with the findings in control rats. Rats depleted of endogenous CGRP were more susceptible to gastric ulceration than were normal rats. Intragastric capsaicin failed to protect the mucosa of CGRP-depleted rats, whereas exogenous intravenous CGRP was effective. CONCLUSIONS: These data support the hypothesis that CGRP released from gastric enteric neurons mediates gastric mucosal resistance to ulceration by noxious agents.     

The effect of somatostatin on experimental intestinal obstruction.

The effect of somatostatin (SS-14) was tested in an anesthetized rabbit model of closed-loop ileal obstruction. Experimental groups included (1) immediate treatment (N = 6) receiving SS-14 2,000 pmol X kg-1 X h-1 intravenously (I.V.) beginning at the time of ileal obstruction, (2) delayed treatment (N = 5) receiving SS-14 beginning 6 hours following ileal obstruction, and (3) control (N = 6) receiving only hydration. After 24 hours, all rabbits were killed. Significantly decreased intestinal luminal volume and sodium and potassium output was observed with both immediate and delayed SS-14 treatment when compared to control. Additionally, the gross and microscopic pathologic features of intestinal distension, inflammation, and necrosis seen in control rabbits were absent in rabbits treated with SS-14. The known broad spectrum of physiologic activity of SS-14 on the gastrointestinal tract appeared beneficial in this rabbit model of intestinal obstruction.     

Peripheral acid inhibitory action of corticotropin releasing factor: mediation by nongastric mechanisms

Corticotropin releasing factor (CRF) inhibits gastric acid secretion via both central neural and peripheral mechanisms. We examined whether local gastric factors may mediate the peripheral action of CRF. In pylorus-ligated anesthetized rats, CRF infusion (15 nmol/kg X h) produced roughly 60% inhibition of pentagastrin (16 micrograms/kg X h)-stimulated acid secretion. Similarly, in the gastric fistula dog, CRF (1 nmol/kg X h) inhibited pentagastrin-induced acid secretion by 74%. This action of CRF did not result from direct inhibition of gastric parietal cells, as concentrations of the peptide ranging from 10(-11) to 10(-6) M had no effect on the activity of isolated parietal cells in the unstimulated state or after stimulation with pentagastrin (10(-8) M), histamine (10(-5) M), or carbachol (10(-5) M), against a background of isobutylmethylxanthine (10(-4) M). To determine whether local hormones may mediate CRF-induced acid inhibition, we examined the peptide's effect on the release of somatostatin and gastrin from cultured canine gastric D and G cells and from isolated perfused rat stomachs. Corticotropin releasing factor in doses ranging from 10(-11) to 10(-6) M had no influence on release of either gastric peptide under basal conditions or after stimulation of gastrin with carbachol (10(-6) M) and somatostatin with isoproterenol (10(-8) M). These data suggest that the peripheral acid inhibitory action of CFR is mediated by nongastric mechanisms.     

Postprandial neurohormonal control of gastric emptying

The delay in gastric emptying after a meal is thought to result from nutrient distention-induced release of peptides and neurotransmitters in the gut. The potential contribution of the brain and central neuropeptides to the postprandial regulation of gastric emptying has not been studied adequately. The purpose of this study was twofold: to examine the relative importance and pure central stimulation (sham feeding) or pure peripheral stimulation (duodenal feeding) on gastric emptying, and to determine whether relevant neuropeptides act in the brain to slow gastric emptying of a meal. Six mongrel dogs were prepared with esophageal fistulas, gastric fistulas, duodenal fistulas, and chronic lateral cerebroventricular guides. Gastric emptying of a 300 ml saline solution meal was measured by a phenol red dye dilution technique. Sham feeding of a blenderized meal through the esophageal fistula was used as a central cephalic stimulus. Intraduodenal oleic acid was used as a peripheral stimulus. Both sham feeding and intraduodenal oleic acid inhibited gastric emptying by 59 +/- 12 percent, 73 +/- 5 percent, respectively. In separate studies, we examined the effect on gastric emptying of a bolus injection into the lateral cerebral ventricle of graded doses of corticotropin-releasing factor (110 to 440 pmol/kg), cholecystokinin (16 to 128 pmol/kg), somatostatin-14 (55 pmol/kg), human calcitonin gene-related peptide (230 pmol/kg), and neuropeptide Y (62 to 250 pmol/kg). These peptides are known to affect satiety, gastric emptying, and gastric acid secretion. Of these, only neuropeptide Y and cholecystokinin had an effect on gastric emptying when administered into the lateral cerebral ventricle. Neuropeptide Y inhibited emptying by 28 +/- 8 percent and cholecystokinin accelerated emptying by 32 +/- 12 percent (p less than 0.05). Sham feeding inhibits gastric emptying to a similar degree as intraduodenal feeding, and of the neuropeptides tested, only neuropeptide Y inhibited gastric emptying when given into the brain. The central release of neuropeptides such as neuropeptide Y during a meal may trigger neural pathways that promote postprandial delay in gastric emptying. Central signals may be as important as peripheral signals in the postprandial control of gastric emptying. Further studies are needed to determine the mechanism by which sham feeding inhibits gastric emptying and whether central release of neuropeptide Y is involved.