||The regulatory mechanism of motilin induced gastric acid and pepsinogen secretion in Suncus murinus
2015-9 , 埼玉大学大学院理工学研究科
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.