Nitric Oxide Control of Migrating Motor Complex: L-NMMA Effects in Relation to Receptor Blockades (LNMMA)

Nitric Oxide Control of the Migrating Motor Complex in Man: L-NMMA Effects in Relation to Muscarinic and Serotonergic Receptor Blockade

The aim is to elucidate how NO works in conjunction with other neurotransmitters to regulate the migrating motility complex (MMC). Twenty-two healthy volunteers should undergo water-perfused antroduodenojejunal manometry during a control period of 4 h, followed by another 4h after a bolus injection of either saline or the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 10 mg/kg intravenously) with or without atropine (1 mg) or ondansetron (8 mg). Effects on the MMC pattern are determined. Exhaled and rectal NO is monitored throughout the experiments. Effects of L-NMMA on the MMC pattern are analyzed against a background of atropine or ondansetron. Blood samples are drawn for analysis of simultaneous peptide hormone release into the bloodstream. Peptide hormone release will be correlated to the respective motility pattern elicited by LNMMA.

Study Overview

• Status: Completed
• Conditions: Gastrointestinal Motility Disorder; Disturbance of Salivary Secretion
• Intervention / Treatment: Biological: L-Nitro-Monomethyl-Arginine (LNMMA) 10 mg/kg IV; Biological: saline

Detailed Description

Dysregulation of the cyclic motility pattern controlling propulsion during fasting, the migrating motor complex (MMC), can result in small intestinal bacterial overgrowth and symptoms of intestinal obstruction. Nitric oxide (NO) acts as an inhibitory neurotransmitter by relaxation of smooth muscle cells. Little is known on how NO works in conjunction with other neurotransmitters to regulate the MMC.

Methods: Twenty-two healthy volunteers (22-38 years) should undergo antroduodenojejunal manometry recordings for 8h, 4h of which as a control period with basal motility recording and 4h after a bolus injection of either saline or the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 10 mg/kg intravenously) with or without atropine (1 mg) or ondansetron (8 mg). The effects of L-NMMA on the MMC pattern are to be determined. Exhaled and rectal NO was monitored throughout the experiments as a means to secure efficient NO synthase inhibition.

Expected results: L-NMMA is expected to increase the intestinal motor activity, either as a direct effect on the small muscle cells, or through the release of some motility-stimulating gut peptide hormone (motility, ghrelin, somatostatin).

Expected conclusions: A NO donor, such as nitrite or nitrate which is converted to NO in an acidic milieu in the stomach may act as an inhibitor of motility. Thus, swallowed nitrite and nitrate from the saliva may contribute to the regulation of gastric emptying and gastrointestinal motility.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Uppsala county
    • Uppsala, Uppsala county, Sweden, 75185
      • Uppsala University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy volunteers 18-50 years of age

Exclusion Criteria:

• Age < 18, or > 50 years
• Any disease
• Any medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nitric oxide synthase (NOS) inhibition; After a control period of 4 hours, intervention with L-NMMA (10 mg/kg IV) is done and recording continued for 4 hours.	Biological: L-Nitro-Monomethyl-Arginine (LNMMA) 10 mg/kg IV; Other Names: L-NMMA
Sham Comparator: Saline; After a control period of 4 hours, intervention with saline is done and recording continued for 4 hours.	Biological: saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect on phases I-III of the migrating motor complex	NO is considered to be of importance for gastrointestinal motility. The MMC is measured as a biomarker of regulatory functions of gastrointestinal motility. Inhibition of the elaboration of NO by use of LNMMA is used to draw conclusions about the importance of NO for regulation of gastrointestinal motility.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduced exhaled NO after administration of NO synthase inhibitor LNMMA	After administration of a Nitric oxide synthase (NOS) inhibitor exhaled NO is used as a marker of reduced NOS activity.	1 year

Collaborators and Investigators

• Sponsor: Uppsala University
• Collaborators: The Swedish Society of Medicine; Bengt Ihre Foundation
• Investigators: Principal Investigator: Per M Hellstrom, MD, prof, Uppsala University

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: May 5, 2014
• First Submitted That Met QC Criteria: September 16, 2014
• First Posted (Estimate): September 19, 2014

Study Record Updates

• Last Update Posted (Estimate): September 19, 2014
• Last Update Submitted That Met QC Criteria: September 16, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: Nitric oxide; Gastrointestinal motility; Nitric oxide synthase; Gut peptide hormones
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; omega-N-Methylarginine
• Other Study ID Numbers: LNMMA-UU-02 (Other Grant/Funding Number: Uppsala Univ, Bengt Ihre Fund, Swedish Soc of Medicine)