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Receptor-mediated inhibition of small bowel migrating complex by GLP-1 analog ROSE-010 delivered via pulmonary and systemic routes in the conscious rat
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
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2012 (English)In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 179, no 1-3, 71-76 p.Article in journal (Refereed) Published
Abstract [en]

Background: ROSE-010, a Glucagon-Like Peptide-1 (GLP-1) analog, reduces gastrointestinal motility and relieves acute pain in patients with irritable bowel syndrome (IBS). The rat small bowel migrating myoelectric complex (MMC) is a reliable model of pharmacological effects on gastrointestinal motility. Accordingly, we investigated whether ROSE-010 works through GLP-1 receptors in gut musculature and its effectiveness when administered by pulmonary inhalation. Materials and methods: Rats were implanted with bipolar electrodes at 5, 15 and 25 cm distal to pylorus and myoelectric activity was recorded. First, intravenous or subcutaneous injections of ROSE-010 or GLP-1 (1, 10, 100 mu g/kg) with or without the GLP-1 receptor blocker exendin(9-39)amide (300 mu g/kg.h), were studied. Second, ROSE-010 (100, 200 mu g/kg) Technosphere (R) powder was studied by inhalation. Results: The baseline MMC cycle length was 17.5 +/- 0.8 min. GLP-1 and ROSE-010. administered intravenously or subcutaneously, significantly inhibited myoelectric activity and prolonged MMC cycling; 100 mu g/kg completely inhibited spiking activity for 49.1 +/- 4.2 and 73.3 +/- 7.7 min, while the MMC cycle length increased to 131.1 +/- 11.4 and 149.3 +/- 15.5 min, respectively. Effects of both drugs were inhibited by exendin(9-39) amide. Insufflation of ROSE-010 (100, 200 mu g/kg) powder formulation totally inhibited myoelectric spiking for 52.6 +/- 5.8 and 70.1 +/- 5.4 min, and increased MMC cycle length to 102.6 +/- 18.3 and 105.9 +/- 9.5 min, respectively. Conclusions: Pulmonary delivery of ROSE-010 inhibits gut motility through the GLP-1R similar to natural GLP-1. ROSE-010 causes receptor-mediated inhibition of MMC comparable to that of intravenous or subcutaneous administration. This suggests that ROSE-010 administered as a Technosphere (R) inhalation powder has potential in IBS pain management and treatment.

Place, publisher, year, edition, pages
2012. Vol. 179, no 1-3, 71-76 p.
Keyword [en]
Gastrointestinal motility, IBS, Irritable bowel syndrome, Glucagon, Pulmonary delivery
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-188421DOI: 10.1016/j.regpep.2012.08.009ISI: 000311186000013OAI: oai:DiVA.org:uu-188421DiVA: diva2:577953
Available from: 2012-12-17 Created: 2012-12-17 Last updated: 2012-12-17Bibliographically approved

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