adrenomedullin and Stomach-Ulcer

The role of central nervous system (CNS) in regulation of gastric function has long been known. The dorsal vagal complex (DVC) has an important role in regulation of gastric mucosal integrity; it is involved both in mucosal protection and in ulcer formation. Neuropeptides have been identified in DVC, the origin of these peptides are both intrinsic and extrinsic. Neuropeptides are localized also in the periphery, in afferent neurons. The afferent neurons also have efferent-like function in the gastroinetestinal tract, and neuropeptides released from the peripheral nerve endings of primary afferent neurons can induce gastric mucosal protection. Centrally and /or peripherally injected neuropeptides, such as amylin, adrenomedullin, bombesin, cholecystokinin, neurotensin, opioid peptides, thyreotropin releasing hormone and vasoactive intestinal peptide, influence both the acid secretion and the gastric mucosal lesions induced by different ulcerogens. The centrally induced gastroprotective effect of neuropeptides may be partly due to a vagal dependent increase of gastric mucosal resistance to injury; activation of vagal cholinergic pathway is resulted in stimulation of the release of mucosal prostaglandin and nitric oxide. Furthermore, release of sensory neuropeptides (calcitonin gene-related peptide, tachykinins) from capsaicin sensitive afferent fibers are also involved in the centrally induced gastroprotective effect of neuropeptides.

Topics: Adrenomedullin; Amyloid; Animals; Bombesin; Calcitonin Gene-Related Peptide; Disease Models, Animal; Gastric Acid; Gastric Mucosa; Homeostasis; Humans; Islet Amyloid Polypeptide; Neurons, Afferent; Neuropeptides; Neuroprotective Agents; Peptides; Stomach Ulcer; Tachykinins; Vagus Nerve

Topics: Adrenomedullin; Amylases; Animals; Cell Division; Cyclic AMP-Dependent Protein Kinases; Depression, Chemical; Gastric Acid; Gastric Mucosa; Gastrointestinal Motility; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Pancreas; Peptides; Stomach Ulcer; Vascular Resistance

Here, we show an increase in c-Met receptor expression during reserpine-induced gastric damage in the rat, as assessed by immunohistochemistry. Pretreatment of animals with adrenomedullin prevented this increase in c-Met expression. c-Met immunoreactivity was localized in gastric glands. c-Met immunoreactivity was associated with increased phosphorylation of c-Met receptor and extracellular signal-regulated kinase (ERK(1/2)). Our results suggest that both adrenomedullin and c-Met act as parallel defence mechanisms during pharmacologically induced gastric mucosa injury.

Topics: Adrenomedullin; Animals; Anti-Ulcer Agents; Blotting, Western; Immunohistochemistry; Immunoprecipitation; Male; Mitogen-Activated Protein Kinases; Peptides; Phosphorylation; Proteins; Proto-Oncogene Proteins c-met; Rats; Rats, Sprague-Dawley; Reserpine; Signal Transduction; Stomach Ulcer; Tubulin

Adrenomedullin (100 ng/kg, s.c.) prevents reserpine-induced damage of gastric mucosa. In the model of in vitro gastric arteries from reserpine-treated rats, adrenomedullin pre-treatment resulted in a decrease of the vasoconstriction in response to 5-hydroxytryptamine. In contrast, adrenomedullin pre-treatment of rat with intact gastric mucosa did not affect the vasoconstriction to 5-hydroxytryptamine. In the presence of the NOS inhibitor N(G)-nitro-L-arginine, the responsiveness to 5-hydroxytryptamine in gastric arteries from rats treated with reserpine + adrenomedullin was enhanced to the same level of rats treated with reserpine alone. The anti-ulcer effect of adrenomedullin could therefore be related, at least in part, to an increase of blood flow at the gastric mucosa, by a mechanism involving nitric oxide.

Topics: Adrenomedullin; Animals; Arteries; Male; Muscle Contraction; Peptides; Rats; Rats, Sprague-Dawley; Reserpine; Stomach; Stomach Ulcer

Adrenomedullin prevents damage of gastric mucosa in either reserpine-treated or pylorus-ligated rats. Pre-treatment with CGRP(8-37) resulted in a decrease of the gastro-protective effect of adrenomedullin in both models and reversed the inhibitory effect of adrenomedullin on gastric acid output in the pylorus-ligated rats. These adrenomedullin actions were less effectively modified by pre-treatment with adrenomedullin(22-52). These data suggest that the anti-ulcer effect of adrenomedullin is mainly related to its anti-secretory action, presumably mediated through CGRP-receptors.

Topics: Adrenomedullin; Animals; Humans; Male; Peptides; Rats; Receptors, Adrenomedullin; Receptors, Calcitonin Gene-Related Peptide; Receptors, Peptide; Serotonin; Stomach Ulcer

Adrenomedullin (AM) is a potent vasodilatory peptide. While its growth-regulating action in some cultured cells has been recognized, expression of AM and its receptor during gastric ulcer healing has not been explored. Specimens of gastric walls from control rats or gastric ulcers were obtained at 1, 3, 7, and 14 days after gastric ulcer induction. AM and its receptor mRNAs expression were determined by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization. By RT-PCR, AM mRNA was increased by 167% at three days, while AM receptor mRNA was increased by 234% at seven days (both P < 0.05). By in situ hybridization, AM and AM receptor mRNAs were increased at ulcer margin from three days after ulcer induction. By immunohistochemistry, AM was increased in the ulcer margin at three and seven days. In separate in vitro studies using a rat gastric epithelial (RGM1) cell line, AM treatment significantly increased transforming growth factor-alpha mRNA expression and cell proliferation.

Topics: Adrenomedullin; Animals; Immunohistochemistry; In Situ Hybridization; Male; Peptides; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Receptors, Adrenomedullin; Receptors, Peptide; RNA, Messenger; Stomach Ulcer; Transforming Growth Factor alpha; Wound Healing

In order to study the roles of vasoactive peptides during tissue repair of gastric ulcers, we compared concentrations in tissue surrounding gastric ulcers of endothelin-1(ET-1), adrenomedullin (AM), and transforming growth factor-beta (TGF-beta) among different stages of ulcer development. A total of 82 cases were studied. Ulcers were located in the gastric angulus in 51 cases. All cases were positive for Helicobacter pylori (Hp). Ten cases were in the active stage (GA), 18 were in the healing stage (GH), and 28 were in the scarring stage (GS). As control, 17 cases of Hp-positive gastritis (gast+) and 14 of Hp-negative gastritis (gast-) were studied. The concentrations of endothelin (ET) and TGF-beta were in the order of GH> GA> GS, and those of AM were in the order of GS > GH > GA. On immunostaining, ET stained positively in endothelial cells and vascular smooth muscle cells (VSMCs) during the GH and GS stages, and AM stained positively in histiocytes during GA, GH and GS, and also stained positively in glandular epithelia and smooth muscle fibers during GH and GS. When our results were reviewed with respect to the regulation of vascular tonus and the proliferation of VSMCs, ET and AM were considered to have roles in the regulation of proliferation.

Topics: Adrenomedullin; Endothelin-1; Gastric Mucosa; Humans; Immunoenzyme Techniques; Peptides; Stomach Ulcer; Transforming Growth Factor beta; Wound Healing

Adrenomedullin intracerebroventricularly administered (0.1 to 20 ng/rat i.c.v.), showed significant gastroprotective activity in a dose-dependent manner. When the peptide was intravenously administered (1 to 1000 ng/kg i.v.) it did not show significant gastroprotective activity in the same test. The gastroprotective effect of the peptide (10 ng/rat) was abolished by bilateral adrenalectomy, by pretreatment with the beta-adrenoceptor antagonist, propranolol (1 mg/kg i.p.), or by a calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP-(8-37) fragment (1 or 10 ng/rat i.c.v.). This study showed that adrenomedullin is protective against reserpine-induced gastric lesions, that the action involves sympathetic nerve activity, and moreover interferes with CGRP receptors.

Topics: Adrenalectomy; Adrenomedullin; Animals; Anti-Ulcer Agents; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Dose-Response Relationship, Drug; Drug Administration Routes; Gastric Mucosa; Injections, Intravenous; Injections, Intraventricular; Male; Peptide Fragments; Peptides; Phentolamine; Propranolol; Rats; Rats, Sprague-Dawley; Reserpine; Stomach Ulcer; Sympatholytics; Vasodilator Agents