Gastric mucosal damage in water immersion stress: mechanism and prevention with GHRP-6.
OBJECTIVE
To investigate the mechanism of gastric mucosal demage induced by water immersion restraint stress (WRS) and its prevention by growth hormone releasing peptide-6 (GHRP-6).


METHODS
Male Wistar rats were subjected to conscious or unconscious (anesthetized) WRS, simple restraint (SR), free swimming (FS), non-water fluid immersion, immersion without water contact, or rats were placed in a cage surrounded by sand. To explore the sensitivity structures that influence the stress reaction besides skin stimuli, a group the rats had their eyes occluded. Cervical bilateral trunk vagotomy or atropine injection was performed in some rats to assess the parasympathetic role in mucosal damage. Gastric mucosal lesions, acid output and heart rate variability were measured. Plasma renin, endothelin-1 and thromboxane B2 and gastric heat shock protein 70 were also assayed. GHRP-6 was injected [intraperitoneal (IP) or intracerebroventricular (ICV)] 2 h before the onset of stress to observe its potential prevention of the mucosal lesion.


RESULTS
WRS for 6 h induced serious gastric mucosal lesion [lesion area, WRS 81.8 ± 6.4 mm² vs normal control 0.0 ± 0.0 mm², P < 0.01], decreased the heart rate, and increased the heart rate variability and gastric acid secretion, suggesting an increase in vagal nerve-carrying stimuli. The mucosal injury was inversely correlated with water temperature (lesion area, WRS at 35 °C 56.4 ± 5.2 mm² vs WRS at 23 °C 81.8 ± 6.4 mm², P < 0.01) and was consciousness-dependent. The injury could not be prevented by eye occlusion, but could be prevented by avoiding contact of the rat body with the water by dressing it in an impermeable plastic suit. When water was replaced by vegetable oil or liquid paraffin, there were gastric lesions in the same grade of water immersion. When rat were placed in a cage surrounded by sand, there were no gastric lesions. All these data point to a remarkable importance of cutenuous information transmitted to the high neural center that by vagal nerves reaching the gastric mucosa. FS alone also induced serious gastric injury, but SR could not induce gastric injury. Bilateral vagotomy or atropine prevented the WRS-induced mucosal lesion, indicating that increased outflow from the vagal center is a decisive factor in WRS-induced gastric injury. The mucosal lesions were prevented by prior injection of GHRP-6 via IP did, but not via ICV, suggesting that the protection is peripheral, although a sudden injection is not equivalent to a physiological release and uptake, which eventually may affect the vagal center.


CONCLUSIONS
From the central nervous system, vagal nerves carry the cutaneous stimuli brought about by the immersion restraint, an experimental model for inducing acute gastric erosions. GHRP-6 prevents the occurrence of these lesions.
Department of Physiology and Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
Shu
S
Guo
Qian
Q
Gao
Qing
Q
Jiao
Wei
W
Hao
Xue
X
Gao
Ji-Min
JM
Cao
D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000097:blood; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D007101:Immersion / Q000009:adverse effects*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010276:Parasympatholytics / Q000494:pharmacology; D010775:Photic Stimulation; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000097:blood; D012149:Restraint, Physical / Q000523:psychology; D012867:Skin / Q000294:innervation*; D013276:Stomach Ulcer / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D013315:Stress, Psychological / Q000097:blood / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D013929:Thromboxane B2 / Q000097:blood; D013997:Time Factors; D014110:Touch; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects / Q000503:physiopathology / Q000601:surgery; D014867:Water
D000897:Anti-Ulcer Agents; D015415:Biomarkers; D019332:Endothelin-1; D018840:HSP70 Heat-Shock Proteins; D009842:Oligopeptides; D010276:Parasympatholytics; D014867:Water; C041048:growth hormone releasing hexapeptide; D013929:Thromboxane B2; D012083:Renin