Richard F. Harty

Cholinergic Mediation of γ-Aminobutyric Acid-Induced Gastrin and Somatostatin Release From Rat Antrum

Addition of gamma-aminobutyric acid (GABA) to antral mucosal fragments in short-term incubation results in dose-dependent and bicuculline-sensitive stimulation of gastrin release and inhibition of somatostatin release, respectively. These effects of GABA on antral gastrin and somatostatin release closely resembled the actions of cholinergic agonists on G- and D-cell function. The present study examines the possibility that the effects of GABA on antral peptide release may be mediated, in part, through stimulation of antral cholinergic neurons. Inclusion of either atropine or pirenzepine in incubation medium prevented GABA-induced stimulation of gastrin release and inhibition of somatostatin release. Addition of the acetylcholinesterase inhibitor, physostigmine, caused a leftward shift in the GABA dose-response curve and increased by 10-fold the sensitivity of the antral preparation to GABA stimulation. Studies with tetrodotoxin suggest that GABA-stimulated gastrin release is mediated through activation of neurons contained within the antral mucosal/submucosal fragments. Hexamethonium, the ganglionic nicotinic receptor antagonist, did not affect GABA-induced gastrin release. These results indicate that GABA affects antral gastrin and somatostatin release through stimulation of antral postganglionic cholinergic neurons.

Cholecystokinin, vasoactive intestinal peptide and peptide histidine methionine responses to feeding in anorexia nervosa

Anorexia nervosa (AN) is a syndrome of unknown cause characterized by voluntary starvation. Cholecystokinin has been implicated as a neuroendocrine regulatory factor in control of satiety. Relatively little information is known about gastrointestinal hormone responses to feeding in subjects with anorexia nervosa. In the present studies, we examine fasting and postprandial levels of cholecystokinin (CCK), vasoactive intestinal peptide (VIP) and peptide histidine methionine (PHM) in anorexia nervosa subjects and in control individuals. Results of these studies indicate that plasma CCK response to a liquid meal (Ensure Plus) in untreated AN subjects was distinctly different from that observed in healthy controls, both in terms of temporal pattern of peptide released and the amount of CCK secreted into the circulation. Peak levels of CCK release occurred at 30 min following meal ingestion in AN patients and at 60 min in control subjects. Integrated CCK release in untreated AN patients was approximately twice that measured in control individuals. Renutrition therapy was associated with reversion of the pattern of CCK release to that observed in control subjects. Plasma VIP levels were unchanged following meal ingestion in both control and anorexic subjects. In contrast, PHM levels in AN subjects were significantly greater than that observed in control individuals. The pattern of PHM release following liquid meal ingestion was similar to that observed with plasma CCK; namely, peak release of peptide was observed at 30 min which was significantly greater than corresponding control values (P less than 0.05). In conclusion, these results demonstrate distinctive differences in plasma CCK and PHM levels in response to feeding in AN subjects when compared to control individuals. These findings suggest that the earlier and greater rise in plasma CCK levels in AN subjects following meal ingestion may contribute to the abnormal sensation of satiety in this condition.

γ-Aminobutyric acid localization and function as modulator of cholinergic neurotransmission in rat antral mucosal/submucosal fragments

gamma-Aminobutyric acid, a neurotransmitter in the central nervous system, has been shown to be present in and synthesized and secreted by rodent and feline myenteric plexus neurons. The aims of the present studies were to measure gamma-aminobutyric acid concentrations and synthesis and to establish cellular localization and uptake of gamma-aminobutyric acid by immunocytochemistry and autoradiography, respectively, within mucosal and submucosal tissues of the rat antrum. Direct demonstration of [3H]gamma-aminobutyric acid release and the effects of exogenous gamma-aminobutyric acid and muscimol, a GABA alpha agonist, on [3H]acetylcholine release from antral mucosal/submucosal fragments were examined in perifusion experiments. gamma-Aminobutyric acid content and synthesis, as reflected by glutamic acid decarboxylase activity, were present within antral mucosa at levels two to three times that of the body and muscular layers of both the gastric body and antrum. gamma-Aminobutyric acid was identified immunocytochemically, principally in mucosal epithelial cells of the antrum. Exogenous gamma-aminobutyric acid and muscimol were capable of stimulating acetylcholine release through a GABA alpha receptor-mediated mechanism that was abolished by tetrodotoxin. These results indicate that gamma-aminobutyric acid is present in and taken up by epithelial cells of the gastric antrum and that gamma-aminobutyric acid is capable of being synthesized by antral mucosal/submucosal tissues. Furthermore, these studies suggest that a peripheral gamma-aminobutyric acid mechanism that may modulate cholinergic neurotransmission and endocrine cell function exists within the antrum.

Endoscopy in the diagnosis of gastrointestinal mycobacterium avium-intracellulare infection

Two cases of mycobacterium avium-intracellulare (MAI) infection in association with acquired immunodeficiency syndrome (AIDS) are presented to highlight the distinctive upper gastrointestinal endoscopic appearances: 2 X 4 mm diameter, white nodules with intervening erythema and hemorrhagic erosions covered the mucosa of the second part of the duodenum. Histological evaluation of these nodules revealed diffuse expansion of the lamina propria by macrophages that contained numerous intracellular and extracellular acid-fast organisms. We conclude that endoscopy with endoscopic biopsy may represent the most rapid and sensitive diagnostic tool available in this disease.

Stimulation of Rat Antral CGRP Release by Intraluminal Peptone

Calcitonin gene-related peptide (CGRP) is a neuropeptide that has wide distribution within the mammalian gastrointestinal tract. I CGRP-containing nerves in the rat stomach are derived exclusively from extrinsic capsaicin-sensitive primary sensory afferent nerves of splanchnic and vagal origin.?,3 In vivo studies indicate that exogenously administered CGRP inhibits gastric acid secretion and stimulates gastric somatostatin release.4 Furthermore, in uirro studies with rat antral fragments have shown that capsaicin stimulated endogenous CGRP and somatostatin release and inhibited gastrin and acetylcholine release.s These effects were prevented by the CGRP receptor antagonist CGRP8.,, .6 Results of these studies suggest that endogenous CGRP may participate in the regulation of antral neuroendocrine function. The role of luminal factors in controlling antral CGRP release from sensory neurons has not been examined. In the present studies, we sought to study the effects of luminal peptone and acid on CGRP and gastrin release from isolated rat antrum. The hypothesis addressed in the present study was that CGRP is released from peripheral primary sensory afferent nerve endings in response to luminal nutrients, such as peptone, and an acidic environment. Adult nonfasted Sprague-Dawley rats were sacrificed, and the antrum was transected at the proximal margin and pylorus. The antrum was everted and placed on a rotatable conical rubber stopper assembly. Circumferential dissection of the mucosa : submucosa from the muscularis propria resulted in a continuous intact sleeve. The antral sleeve was reverted with the mucosa luminally oriented. The ends of the antral sleeve were then secured to plastic tubing, and the assembly was mounted in a perfusion chamber that permitted separate perfusion of mucosal and submucosal surfaces with oxygenated Krebs-Henseleit bicarbonate buffer (0.5 ml/min, 37 C). Perfusate samples were assayed for CGRP and gastrin by radioimmunoassay . Initial experiments examined the effects of luminal peptone on antral gastrin and CGRP release into the submucosal compartment. Peptone (5%) evoked significant gastrin release within 6-10 minutes after the initiation of perfusion. Gastrin release achieved peak levels that were 210% above control values: 384 f 106 vs. 124 t 14 pg/ml, p < 0.02 (FIG. IA). Antral CGRP release was also stimulated significantly by intraluminal peptone; peak levels of CGRP release were above nonstimulated control values: 92 ? 33 vs. 35 * 10 pg/ml, p < 0.05 (FIG. 1B). In separate experiments, the antral lumen was perfused with acidified medium (pH 3.0) for 30 minutes. Luminal acid evoked a significant increase in antral CGRP release that was more than 3.5-fold greater than control values: 340 ? 128 vs. 73 & 18, p < 0.05 (FIG. 2B). In contrast, simultaneously measured gastrin release

Psoriasis, dysphagia, and esophageal webs or rings

Esophageal webs and rings may have a congenital origin and have been associated with iron-deficiency states and esophageal mucosal inflammation. Cutaneous diseases associated with esophageal webs and rings include benign mucosal pemphigoid and epidermolysis bullosa dystrophica. We report three cases of patients with psoriasis and associated single or multiple esophageal webs. Two of the three patients experienced a significant degree of dysphagia requiring periodic esophageal dilatation. Esophageal abnormalities did not seem to correlate directly with the extent or activity of psoriasis. The cause of esophageal webs or rings in these patients with psoriasis is not known. This report suggests, but does not prove, that there may be an association between these conditions.

Immune Disorders of the Gastrointestinal Tract and Liver

Immune disorders of the gastrointestinal tract and hepatobiliary systems comprise a diverse group of illnesses which share in common certain overlapping and yet distinctive expressions of cellular and humoral immunity. As is evident from material contained in this article, controversy and disparate results frequently characterize the study of immune mechanisms in a given disease process. Nonetheless, advances in quantitation of specific immunocyte function and phenotypic expression have greatly facilitated the depth of understanding of the immune process related to these disorders. Challenges for future clinical investigation of these disorders are to characterize cell-specific target antigens to which immunologic attack is directed and to unravel the immunogenetic mechanisms that trigger and direct immune-mediated injury to host tissues. It is anticipated that continued investigation of immune disorders of the gastrointestinal tract and liver will clarify pathogenetic mechanisms and thus permit formulation of rational and effective therapies.

Validation of the antral mucosal/submucosal sleeve preparation: Studies of gastrin and acetylcholine release in response to luminal stimulation

In the present study we developed an experimental model for direct assessment of antral endocrine cell and cholinergic neural responses to luminal stimulation. A sleeve of antral mucosal/submucosal tissue was prepared from rat antrum, mounted in perfusion chamber, and perfused in both luminal and submucosal compartments. Morphological and functional integrity of the antral sleeve were confirmed by histological examination and measurement of protein synthesis. Antral gastrin release was assessed in response to luminal stimulation with acid, peptone and distension. Luminal acid (pH3) inhibited basal gastrin release by -70.4% and luminal peptone stimulated gastrin release to 210% above control (p < 0.02). Distention of the antral sleeve by hydrostatic pressure (3-25cm H2O) caused stepwise and significant increase in gastrin release that was reversible. 3H-acetylcholine was stimulated significantly by KCl (56mM) to values twice control. In summary, these results establish the integrity and responsiveness of the antral sleeve to pharmacological and luminal stimulation. The antral sleeve may be a useful model in assessing antral function in response to luminal stimulation.