Effects of citrulline on intestinal function during physical exercise

Introduction: The gastrointestinal (GI) system plays an important role in the
human body. The wall of the GI system regulates digestion and absorption of
nutrients and it also has a very important function as a barrier between the
internal and external environment. The penetration of harmful substances and
microbiota of the GI lumen (external environment) into the systemic circulation
(internal environment) depends on the barrier.
Previous studies have shown that exercise in healthy subjects leads to
splanchnic hypoperfusion, resulting in intestinal damage, increased intestinal
permeability and liver damage. The same splanchnic hypoperfusion occurs in
patients with compromised circulation, but then with more harmful effects.

Rationale: During episodes of splanchnic hypoperfusion is the de novo synthesis
of nitric oxide (nitric oxide, NO) from the amino acid arginine compromised. It
is possible that this disturbed NO synthesis plays a role in the development of
organ dysfunction function during exercise. By administration of L-citrulline,
a precursor of arginine and consequently of NO, NO production may possibly be
increased, resulting in less or no organ dysfunction.

Specific research objectives:

Investigate the effect of orally administered citrulline at:
- Circulation of gastrointestinal (GI) system
- The occurrence of GI damage, liver and kidneys
- The GIpermeability
- Production of amino acids
- Endothelial function (glycocalyx)
- The release of endotoxins and inflammatory markers

Crossover dubbelblinded

Oral intake of citrulline or placebo alanine

Intensive exercise is intense, but for these subjects a weekly if not daily
activity.

To take the acid inhibitor, ranitidine, has contraindications. Adverse
reactions are: hypersensitivity reactions, however, the overall incidence of
adverse reactions is very low (<0.01-0.1%)

Placing a nasogastric (tonometry) catheter is not without risk for the subject.
The placement of the catheter may be painful and the subject may vomit.
Moreover, 'minor' complications such as nasal bleeding, transient sinusitis and
sore throats, may occur. 'Major' complications have been reported, including
stembandparalysis due to incorrect positioning of the catheter, erosion of
adjacent mucosa and perforation. Sequelae of a nasogastric catheter are rare
and are mainly reported for patients who have abnormalities of the GI system
and in whom the catheter tube (five days on average) remains in situ. There are
no good studies on the incidence of perforations associated with nasogastric
catheters. An estimate could be based on the morbidity and mortality numbers
known for diagnostic endoscopy of the upper GI system, in which the overall
complication rate for endoscopy (including biopsy) was 0.13% and the associated
mortality is 0.004%. In theory, a possible perforation is possible if the video
capsule would open and the tiny elements damage the gut wall. Such a
complication has not been described in the literature. The nasogastric catheter
will be placed by a skilled medical doctor. Nasoduodenal and naso-ileal
intubation, have been approved in MEC 08-1-008, 07-1-006 and 09-3-005.

The blood drawing will be performed by a skilled medical doctor. A venous
catheter is placed in a dorsal hand vein. The puncture can be painful.
Potential risk is the development of a bruise at the site of injection of the
needle. This will disappear spontaneously after a few days.

Risks sublingual circulation filming: none.
Risks citrulline intake / alanine: none.

See pages 19 and 20 protocol.