Transforming growth factor alpha-mediated gastroprotection against stress ulceration in the rat: involvement of capsaicin-sensitive sensory neurons.
Exogenously administered TGF alpha has been shown to protect rodent gastric mucosa against injury caused by acid-dependent and acid-independent injury. The present study examined whether the gastroprotective effects of TGF alpha on stress-induced gastric ulceration in the rat involves activation of capsaicin-sensitive sensory neurons. Fasted male SD rats were subjected to water restraint stress (WRS) for four hours. Thereafter, rats were euthanized; the stomach opened and macroscopic areas of gastric ulceration quantitated (mm(2)). Gastric tissue contents of TGF alpha and the sensory neuropeptide, calcitonin gene-related peptide (CGRP) were determined by radioimmunoassay. Prior to stress rats received TGF alpha 50, 100 or 200 microg/kg by intraperitoneal injection. Sensory denervation was accomplished by high dose capsaicin treatment. WRS caused severe ulceration in the gastric corpus; 46.1 + 6.6 mm(2). Parenteral administration of TGF alpha caused dose-dependent reduction in gastric injury: 34.7 + 4.9 mm(2) with 50 microg/kg (p < 0.05); 25.4 + 3.6 mm(2) with 100 microg/kg (p < 0.001) and 9.4 + 0.8 mm(2) with 200 microg/kg (p < 0.001). The gastroprotective action of TGF alpha (200 microg/kg, i.p.) was abolished by capsaicin-induced sensory denervation. In addition, WRS ulceration was associated with significant reduction in gastric CGRP (-42%) and TGF alpha (-48%) content. Reduction in CGRP content was prevented by TGF alpha pretreatment. We conclude that: 1) TGF alpha caused dose-dependent gastroprotection against WRS ulceration, 2) TGF alpha-mediated gastric mucosal protection was prevented by capsaicin-induced sensory denervation and, 3) stress-induced injury was associated with significant reduction in gastric content of both TGF alpha and CGRP.
Vongthavaravat
Verapan
V
Department of Medicine, Division of Gastroenterology, University of Oklahoma Health Sciences Center, PO Box 26901, ET NP526, Oklahoma City, OK 73190, USA.
Mesiya
Sikandar
S
Saymeh
Layth
L
Xia
Yang
Y
Ward
Angela
A
Harty
Richard F
RF
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000294:innervation* / Q000378:metabolism; D007101:Immersion; D007103:Immobilization; D007274:Injections, Intraperitoneal; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects / Q000294:innervation / Q000473:pathology; D013276:Stomach Ulcer / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013315:Stress, Psychological; D013563:Sympathectomy, Chemical; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000627:therapeutic use*
D016211:Transforming Growth Factor alpha; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin