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Gastric motor effects of ghrelin and growth hormone releasing peptide 6 in diabetic mice with gastroparesis

World Journal of Gastroenterology 2008年第9期14卷 1419-1424页

作者： Wen-Cai Qiu Zhi-Gang Wang Wei-Gang Wang Jun Yan Qi Zheng The Affiliated Sixth Hospital of Medical School Shanghai Jiaotong University Shanghai 200233 China

AIM:To investigate the potential therapeutic significance of ghrelin and growth hormone releasing peptide 6 (GHRP-6) in diabetic mice with gastric motility disorders. METHODS: A diabetic mouse model was established by intraperitoneal (ip) injection of alloxan. Diabetic mice were injected ip with ghrelin or GHRP-6 (20-200 μg/kg), and the effects on gastric emptying were measured after intragastric application of pheno. red. The effect of atropine, NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) or D-Lys3-GHRP-6 (a growth hormone secretagogue receptor (GHS-R) antagonist) on the gastroprokinetic effect of ghrelin or GHRP-6 (100 μg/kg) was also investigated. The effects of ghrelin or GHRP-6 (0.01-10 μmol/L) on spontaneous or carbachol-induced contractile amplitude were also investigated in vitro, in gastric fundic circular strips taken from diabetic mice. The presence of growth hormone secretagogue receptor 1a transcripts in the fundic strips of diabetic mice was detected by reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: We established a diabetic mouse model with delayed gastric emptying. Ghrelin and GHRP-6 accelerated gastric emptying in diabetic mice with gastroparesis. In the presence of atropine or L-NAME, which delayed gastric emptying, ghrelin and GHRP-6 (100 μg/kg) failed to accelerate gastric emptying. D-Lys3-GHRP-6 also delayed gastric emptying induced by the GHS-R agonist. Ghrelin and GHRP-6 increased the carbachol-induced contractile amplitude in gastric fundicstrips taken from diabetic mice. RT-PCR confirmed the presence of GHS-R mRNA in the strip preparations. CONCLUSION: Ghrelin and GHRP-6 increase gastric emptying in diabetic mice with gastroparesis, perhaps by activating peripheral cholinergic pathways in the enteric nervous system.

关键词： Gastric emptying Ghrelin Growth hormone releasing peptide 6 Growth hormone secretagogue receptor Diabetic mice

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Ghrelin improves delayed gastrointestinal transit in alloxan-induced diabetic mice

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World Journal of Gastroenterology 2008年第16期14卷 2572-2577页

作者： Wen-Cai Qiu Zhi-Gang Wang Ran Lv Wei-Gang Wang Xiao-Dong Han Jun Yan Yu Wang Qi Zheng Kai-Xing Ai Department of General Surgery The Aflihated Sixth Hospital of Medical School Shanghai Jiaotong University Shanghai 200233 China Department of Anesthesiology Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 Zhejiang Province China

AIM: To investigate the effects of ghrelin on delayed gastrointestinal transit in alloxan-induced diabetic mice. METHODS: A diabetic mouse model was established by intraperitoneal injection with alloxan. Mice were randomized into two main groups: no.mal mice group and diabetic mice group treated with ghrelin at doses of 0, 20, 50, 100 and 200 μg/kg ip. Gastric emptying (GE), intestinal transit (IT), and colonic transit (CT) were studied in mice after they had a pheno. red meal following injection of ghrelin. Based on the most effective ghrelin dosage, atropine was given at 1 mg/kg 15 min before the ghrelin injection for each measurement. The mice in each group were sacrificed 20 min later and their stomachs, intestines, and colons were harvested immediately. The amount of pheno. red was measured. Percentages of GE, IT, and CT were calculated. RESULTS: Percentages of GE, IT, and CT were significantly decreased in diabetic mice as compared to control mice (22.9 ± 1.4 vs 28.1 ± 1.3, 33.5 ± 1.2 vs 43.2 ± 1.9, 29.5 ± 1.9 vs 36.3 ± 1.6, P no. CT. The most effective dose of ghrelin was 100 μg/kg and atropine blocked the prokinetic effects of ghrelin on GE and ***: Ghrelin accelerates delayed GE and IT but has no.effect on CT in diabetic mice. Ghrelin may exert its prokinetic effects via the cholinergic pathway in the enteric nervous system, and therefore has therapeutic potential for diabetic patients with delayed upper gastrointestinal transit.

关键词： Ghrelin Diabetes mellitus Gastric emptying Intestinal transit Colonic transit

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Prokinetic effects of a ghrelin receptor agonist GHRP-6 in diabetic mice

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World Journal of Gastroenterology 2008年第30期14卷 4795-4799页

作者： Qi Zheng Wen-Cai Qiu Jun Yan Wei-Gang Wang Song Yu Zhi-Gang Wang Kai-Xing Ai Department of General Surgery The Affiliated Sixth Hospital of Medical School Shanghai Jiaotong University Shanghai 200233 China

AIM： To investigate the effects of a ghrelin receptor agonist GHRP-6 on delayed gastrointestinal transit in alloxan-induced diabetic mice. METHODS： A diabetic mouse model was established by intraperitoneal injection with alloxan. Mice were randomized into two main groups： no.mal mice and diabetic mice treated with GHRP-6 at doses of 0, 20, 50, 100 and 200 μg/kg ip. Gastric emptying （GE）, intestinal transit （IT）, and colonic transit （CT） were studied in mice after they had a pheno. red meal following injection of GHRP-6. Based on the most effective GHRP-6 dosage, atropine was given at 1 mg/kg for 15 rain before the GHRP-6 injection for each measurement. The mice in each group were sacrificed 20 min later and the percentages of GE, IT, and CT were calculated. RESULTS： Percentages of GE, IT, and CT were significantly decreased in diabetic mice as compared to control mice. In the diabetic mice, GHRP-6 improved both GE and IT, but no. CT. The most effective dose of GHRP-6 was 200 μg/kg and atropine blocked the prokinetic effects of GHRP-6 on GE and IT. CONCLUSION： GHRP-6 accelerates delayed GE and IT, but has no.effect on CT in diabetic mice. GHRP-6 may exert its prokinetic effects via the cholinergic pathway in the enteric nervous system, and therefore, has therapeutic potential for diabetic patients with delayed upper gastrointestinal transit.

关键词： GHRP-6 Diabetes mellitus Gastric emptying Intestinal transit Colonic transit

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Therapeutic effects of ghrelin and growth hormone releasing peptide 6 on gastroparesis in streptozotocin-induced diabetic guinea pigs in vivo and in vitro

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Chinese Medical Journal 2008年第13期121卷 1183-1188页

作者： QIU Wen-cai WANG Zhi-gang WANG Wei-gang YAN Jun ZHENG Qi Department of General Surgery Sixth Hospital Affiliated to Shanghai Jiao Tong University Shanghai 200233 China

Background Diabetic gastroparesis is a disabling condition with no.consistently effective treatment. In no.mal animals, both ghrelin and its synthetic peptide, growth hormone releasing peptide 6 （GHRP-6）, increase gastric emptying. Thus, we investigated the potential therapeutic significance of ghrelin and GHRP-6 in diabetic guinea pigs with gastric motility disorders. Methods A diabetic guinea pig model was produced by intraperitoneal （i.p.） injection of streptozotocin （STZ, 280 mg/kg）. Diabetic guinea pigs were injected i.p. with ghrelin or GHRP-6 （10-100 μg/kg）, and the effects on gastric emptying were measured after intragastric application of pheno. red. The effect of atropine or a growth hormone secretagogue receptor （GHS-R） antagonist, D-Lys^3-GHRP-6, on the gastroprokinetic effects of ghrelin or GHRP-6 （100 μg/kg） was also investigated. Further, the in vitro effects of ghrelin or GHRP-6 （0.01-10 μmol/L） on spontaneous or carbachol-induced contractile amplitude in gastric fundic circular strips taken from diabetic guinea pigs were examined. Growth hormone secretagogue receptor transcripts in the fundic strips of diabetic guinea pigs were detected by reverse transcriptase polymerase chain reaction （RT-PCR）. Results We established a guinea pig model of delayed gastric emptying. Ghrelin （20, 50, or 100 μg/kg） and GHRP-6 （20, 50, or 100 μg/kg） accelerated gastric emptying in diabetic guinea pigs with gastroparesis （n=6, P 〈0.05）. In the presence of atropine, which delayed gastric emptying, ghrelin and GHRP-6 （100 μg/kg） failed to accelerate gastric emptying （n=6, P 〈0.05）. D-Lys^3-GHRP-6 also delayed gastric emptying induced by the GHS-R agonist （n=6, P 〈0.05）. Ghrelin and GHRP-6 increased the carbachol-induced contractile amplitude in gastric fundic strips taken from diabetic guinea pigs （n=6, P〈0.05）. RT-PCR confirmed the presence of GHS-R mRNA in the strip preparations. Conclusions Ghrelin and GHRP-6 increased gastric emptying in diabetic guinea pigs wit

关键词： gastric emptying smooth muscle strips ghrelin growth hormone releasing peptide 6 growth hormone secretagogue receptor

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