Elsevier

Regulatory Peptides

Volume 120, Issues 1–3, 15 August 2004, Pages 39-51
Regulatory Peptides

Exogenous and endogenous ghrelin in gastroprotection against stress-induced gastric damage

https://doi.org/10.1016/j.regpep.2004.02.010Get rights and content

Abstract

Ghrelin, identified in the gastric mucosa has been involved in control of food intake and growth hormone (GH) release but little is known about its influence on gastric secretion and mucosal integrity. The effects of ghrelin on gastric secretion, plasma gastrin and gastric lesions induced in rats by 75% ethanol or 3.5 h of water immersion and restraint stress (WRS) were determined. Exogenous ghrelin (5, 10, 20, 40 and 80 μg/kg i.p.) increased gastric acid secretion and attenuated gastric lesions induced by ethanol and WRS and this was accompanied by the significant rise in plasma ghrelin level, gastric mucosal blood flow (GBF) and luminal NO concentrations. Ghrelin-induced protection was abolished by vagotomy and attenuated by suppression of COX, deactivation of afferent nerves with neurotoxic dose of capsaicin or CGRP8–37 and by inhibition of NOS with l-NNA but not influenced by medullectomy and administration of 6-hydroxydopamine. We conclude that ghrelin exerts a potent protective action on the stomach of rats exposed to ethanol and WRS, and these effects depend upon vagal activity, sensory nerves and hyperemia mediated by NOS-NO and COX-PG systems.

Introduction

Ghrelin is a novel 28-amino acid peptide with an n-octanoyl ester in the serine 3 that has recently been discovered in rat and human gastrointestinal tract, particularly gastric mucosa, as an endogenous ligand for growth hormone (GH) secretagogue receptor (GHS-R) [1], [2]. Recent studies revealed that ghrelin is produced by the special neuroendocrine cells located mainly in oxyntic mucosa but not in ECL, EC or D cells [3], [4]. Ghrelin has no relevant homology with any known gastrointestinal peptides but potently stimulates the release of GH and acts as a natural ligand for the GHS-R which is the endogenous counter of the family of synthetic peptidyl and nonpeptidyl GH secretagogues [5], [6]. Recent studies revealed that the functions of this novel hormone are related to the stimulation of food intake, GH secretion and modulation of. energy expenditure [7], [8]. This peptide was also shown to affect gastric motility and gastric secretion [9], [10]. Although previous study have demonstrated that feeding, food intake and obesity decrease circulating ghrelin levels in humans and rodents [11], [12], little is known about other factors that might affect ghrelin secretion in the stomach. A recent study in humans revealed that gastrectomy produced dramatic fall in the plasma ghrelin levels, whereas fasting and anorexia nervosa was accompanied by an elevated plasma ghrelin concentration supporting the notion that the gastrointestinal tract, primarily the stomach, is a major source of circulating ghrelin that could be considered as a starvation-related hormone [2], [13], [14].

The role of peripheral ghrelin in the mechanism of gastric secretion, mucosal defense and gastroprotection has been little investigated, but Sibilia et al. [15] showed recently that central administration of ghrelin exerts a potent protection against the lesions induced by ethanol, while subcutaneous application of this peptide reduced only the depth of ethanol lesions. This gastroprotective effect of central ghrelin was attenuated by the blockade of NOS activity with l-NAME and by the functional ablation of sensory afferent nerves with capsaicin, suggesting that NO and neuropeptides released from sensory nerves may play an important role in this protection [15]. The effects of this peptide applied intraperitoneally on gastric mucosal integrity and gastroprotection as well as the identity of the neural and humoral pathways that are activated by peripheral ghrelin have not been not fully elucidated. The question remains whether ghrelin protects only against ethanol-induced gastric lesions or whether this protection extends also against natural ulcerogens such as stress and what is the role for the cyclooxygenase (COX)-prostaglandin (PG), nitric oxide (NO) synthase (NOS)-NO systems, vagal and afferent nerves and adrenergic system in the possible gastroprotective effects of this peptide.

This study was designed; (1) to confirm the protective effects of ghrelin in rats against ethanol-induced gastric lesions and to determine the effects of peripheral (intraperitoneal) administration of ghrelin on the gastric lesions induced by water immersion and restraint stress (WRS) and the gastric mucosal blood flow (GBF); (2) to examine the involvement of COX-PG and NOS-NO systems, gastrin, vagal and sensory innervation as well as adrenal medulla-adrenergic system in ghrelin-induced gastroprotection against WRS damage and (3) to determine the plasma levels of ghrelin and gastric mucosal gene expression of ghrelin, cNOS- and iNOSmRNAs in the gastric mucosa of intact animals and in those pretreated with ghrelin with and without exposure to WRS.

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Material and methods

Male Wistar rats, weighing 190–230 g and fasted for 24 h, were used in gastric secretory tests and in studies on gastroprotection. This study was approved by the Institutional Animal Care and Use Committee of Jagiellonian University Medical College in Cracow and run in accordance to the statements of European Union regarding handling of experimental animals.

Effects of exogenous ghrelin applied i.p. on gastric acid and pepsin secretions

The effects of vehicle (1 ml of saline) or ghrelin dissolved in 1 ml of saline and applied i.p. in different doses (5, 10, 20, 40 or 80 μg/kg ) on basal gastric acid and pepsin secretions from the GF in conscious rats are shown in Table 1. In control vehicle-treated rats, basal acid output averaged 115±11 μmol/30 min, while pepsin output reached the value of 0.77±0.03 mg/30 min. Ghrelin given i.p. raised dose-dependently gastric acid and pepsin secretions with the highest outputs of gastric

Discussion

This study demonstrates for the first time that exogenous ghrelin administered intraperitoneally exhibits dose-dependent gastroprotection against the stress-induced gastric lesions and shows that the rats exposed to stress exhibit an increased expression of ghrelin in their gastric mucosa. Furthermore, it confirmed [15] that ghrelin is also an effective inhibitor of gastric mucosal injury induced by a corrosive substance such as ethanol.

The results of secretory studies performed on conscious,

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