学位論文 The regulatory mechanism of motilin induced gastric acid and pepsinogen secretion in Suncus murinus

CHAYON, GOSWAMI

内容記述
指導教員 : 坂井貴文
ABSTRACT   IACKNOWLEDGEMENTS   IIITABLE OF CONTENTS   VLIST OF FIGURES   IXChapter 1: General Introduction and Objectives   11.1. Research background   11.1.1. Gastric acid secretion and its role in gastric acid secretion   11.1.2. Pepsinogen secretion and its role in gastric acid secretion   11.1.3. Motilin   21.1.4. Ghrelin   21.1.5. Similar properties between motilin and ghrelin   31.1.6. House musk shrew (Suncus murinus)   41.2. Hypothesis   51.3. General objectives   5Chapter 2: Motilin stimulates gastric acid secretion in co-ordination with ghrelin in Suncus murinus   62.1. Introduction   62.1.1. Gastric acid secretion mechanism   62.1.2. Motilin and ghrelin, and their functions in relation to gastric acid secretion   62.1.3. Advantages of suncus for studying gastrointestinal physiology including gastric acid experiment   72.2. Materials and Methods   92.2.1. Animals   92.2.2. Drugs   92.2.3. Determination of gastric acid output by an intragastric perfusion experimental system   102.2.4. Measurement of pH and amount of gastric acid   112.2.5. Experimental protocols   112.2.6. Statistical analyses   122.3. Results   132.3.1. Effect of ghrelin, motilin, and co-administration of motilin and ghrelin on gastric acid secretion   132.3.2. Effect of famotidine on motilin, and co-administration of motilin and ghrelin-stimulated gastric acid secretion   142.3.3. Effect of YM 022 on gastric acid secretion stimulated by motilin, and co-administration of motilin and ghrelin   152.3.4. Effect of atropine on motilin, and co-administration of motilin and ghrelin-stimulated gastric acid secretion   152.4. Discussion   172.4.1. Suncus for gastric acid secretion study   172.4.2. Motilin but not ghrelin stimulate gastric acid secretion   172.4.3. Physiological importance of motilin-induced gastric acid secretion   182.4.4. Regulatory mechanism of motilin-induced gastric acid secretion   192.5. Summary   21Chapter 3: Motilin stimulates pepsinogen secretion in Suncus murinus   223.1. Introduction   223.1.1. Regulatory mechanism of pepsinogen secretion   223.1.2. Motilin and ghrelin, and their functions in gastrointestinal tract   233.1.3. Advantages of suncus as an experimental animal for pepsinogen secretion study   233.1.4. Gastric contraction and pepsinogen secretion   243.2. Materials and Methods   253.2.1. Animals   253.2.2. Drugs   253.2.3. Determination of pepsin output using an intragastric perfusion experimental system   253.2.4. Vagotomy   263.2.5. Pepsin measurement   273.2.6. Experimental protocols   273.2.7. Statistical analyses   283.3. Results   293.3.1. Establishment of a perfusion system for pepsinogen measurement in suncus   293.3.2. Effects of motilin on pepsinogen secretion   293.3.3. Effects of ghrelin on pepsinogen secretion   293.3.4. Effect of atropine on motilin-induced pepsinogen secretion   303.3.5. Effect of vagotomy on motilin-induced pepsinogen secretion   303.3.6. Effect of motilin and histamine on both pH and pepsinogen secretion   313.3.7. Effect of co-administration of motilin and ghrelin on pepsinogen secretion   313.4. Discussion   323.4.1. Suncus as a suitable model animal for pepsinogen secretion experiments   323.4.2. Motilin-induced pepsinogen secretion and its physiological importance   323.4.3. Motilin but not ghrelin stimulates pepsinogen secretion through cholinergic pathway   343.5. Summary   35CONCLUSIONS   36ABBREVIATIONS   37REFERENCES   38FIGURES   49
Motilin and ghrelin constitute a peptide family, and these hormones are important for the regulation of gastrointestinal motility. In this study, we examined the effect of motilin and ghrelin on gastric acid secretion in anesthetized suncus (house musk shrew, Suncus murinus), a ghrelin- and motilin-producing mammal. We first established a gastric lumen-perfusion system in the suncus and confirmed that intravenous (i.v.) administration of histamine (1 mg/kg BW) stimulated acid secretion. Motilin (0.1, 1.0, and 10 μg/kg BW) stimulated the acid output in a dose-dependent manner in suncus, whereas ghrelin (0.1, 1.0, and 10 μg/kg BW) alone did not induce acid output. Furthermore, in comparison with the vehicle administration, the co-administration of low-dose (1 μg/kg BW) motilin and ghrelin significantly stimulated gastric acid secretion, whereas either motilin (1 μg/kg BW) or ghrelin (1 μg/kg BW) alone did not significantly induce gastric acid secretion. This indicates an additive role of ghrelin in motilin-induced gastric acid secretion. We then investigated the pathways of motilin/motilin and ghrelin-stimulated acid secretion using receptor antagonists. Treatment with YM 022 (a CCK-B receptor antagonist) and atropine (a muscarinic acetylcholine receptor antagonist) had no effect on motilin or motilin-ghrelin co-administration-induced acid output. In contrast, famotidine (a histamine H2 receptor antagonist) completely inhibited motilin-stimulated acid secretion and co-administration of motilin and ghrelin induced gastric acid output. This is the first report demonstrating that motilin stimulates gastric secretion in mammals. By using the above mentioned gastric lumen-perfusion system, we also found that the intravenous administration of carbachol and motilin (0.1, 1.0, and 10 μg/kg BW) stimulated pepsinogen secretion, the latter in a dose-dependent manner, whereas ghrelin had no effect. We then investigated the pathways of motilin-induced pepsinogen secretion using acetylcholine receptor antagonists. Treatment with atropine, a muscarinic acetylcholine receptor antagonist, completely inhibited both carbachol and motilin-induced pepsinogen secretion. Motilin-induced pepsinogen secretion was also observed in the vagotomized suncus. Our results suggest that motilin stimulates gastric acid secretion via the histamine-mediated pathway and also stimulates pepsinogen secretion through a cholinergic pathway in suncus.
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