Receptor-mediated inhibition of small bowel migrating complex by GLP-1 analog ROSE-010 delivered via pulmonary and systemic routes in the conscious rat

Regul Pept. 2012 Nov 10;179(1-3):71-6. doi: 10.1016/j.regpep.2012.08.009. Epub 2012 Sep 4.

Abstract

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 μg/kg) with or without the GLP-1 receptor blocker exendin(9-39)amide (300 μg/kg·h), were studied. Second, ROSE-010 (100, 200 μg/kg) Technosphere® 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 μg/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 μg/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® inhalation powder has potential in IBS pain management and treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Administration, Intravenous
  • Animals
  • Consciousness
  • Drug Evaluation, Preclinical
  • Electrodes, Implanted
  • Gastrointestinal Motility / drug effects
  • Glucagon-Like Peptide 1 / administration & dosage
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide-1 Receptor
  • Injections, Subcutaneous
  • Intestine, Small / drug effects
  • Intestine, Small / metabolism
  • Irritable Bowel Syndrome / metabolism
  • Male
  • Myoelectric Complex, Migrating / drug effects*
  • Peptide Fragments / administration & dosage*
  • Peptide Fragments / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glucagon / antagonists & inhibitors*
  • Receptors, Glucagon / metabolism
  • Statistics, Nonparametric
  • Time Factors

Substances

  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Peptide Fragments
  • Receptors, Glucagon
  • glucagon-like peptide (7-37), valyl(10)-
  • exendin (9-39)
  • Glucagon-Like Peptide 1