Endothelin-1, interleukin-4 and nitric oxide synthase modulators of gastric mucosal injury by indomethacin: effect of antiulcer agents.
Endothelin-1 (ET-1), nitric oxide, and cytokines are recognized mediators of the inflammatory processes associated with gastric mucosal injury. In this study, we investigated mucosal expression of ET-1, interleukin-4 (IL-4), and the activity of constitutive nitric oxide synthase (cNOS) during indomethacin-induced gastric mucosal injury, and evaluated the effect of antiulcer agents on this process. The experiments were conducted with groups of rats pretreated intragastrically with ranitidine (100 mg/kg), ebrotidine (100 mg/kg), sulglycotide (200 mg/kg) or vehicle, followed 30 min later by an intragastric dose of indomethacin (60 mg/kg). The animals were killed 2 h later and their mucosal tissue subjected to macroscopic damage assessment and the measurements of epithelial cell apoptosis, ET-1, IL-4, and cNOS. In the absence of antiulcer agents, indomethacin caused multiple hemorrhagic lesions and extensive epithelial cell apoptosis, accompanied by a 20.7% reduction in IL-4, a 3.1-fold increase in mucosal expression of ET-1 and a 4.2-fold decline in cNOS. Pretreatment with H2-receptor antagonist, ranitidine produced a 15.7% reduction in the mucosal damage caused by indomethacin, 29.5% decrease in epithelial cell apoptosis and a 19.6% reduction in ET-1, while the expression of IL-4 increased by 10.8% and that of cNOS showed a 2-fold increase. The H2-blocker, ebrotidine, also known for its gastroprotective effects, reduced the indomethacin-induced lesions by 90.2%, epithelial cell apoptosis decreased by 61% and ET-1 showed a 58.2% decline, while IL-4 increased by 30.6% and that of cNOS showed a 3.1-fold increase. Pretreatment with gastroprotective agent, sulglycotide, led to a 51.2% reduction in the extent of mucosal damage caused by indomethacin, a 43.9% decrease in apoptosis, and a 63.5% decrease in ET-1, while the expression of cNOS increased by 3.4-fold and the level of IL-4 showed a 32.2% increase. The results suggest that an increase in vasoconstrictive ET-1 level combined with a decrease in regulatory cytokine, IL-4, and a loss of compensatory action by cNOS may be responsible for gastric mucosal injury caused by indomethacin. Our findings also point to a value of ebrotidine and sulglycotide in countering the untoward gastrointestinal side effects of NSAID therapy.
Slomiany
B L
BL
Research Center, University of Medicine and Dentistry of New Jersey, Newark 07103-2400, USA.
Piotrowski
J
J
Slomiany
A
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000897:Anti-Ulcer Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000627:therapeutic use; D019332:Endothelin-1 / Q000187:drug effects / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D007213:Indomethacin / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D011899:Ranitidine / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000627:therapeutic use; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy*; D013844:Thiazoles / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D001557:Benzenesulfonates; D019332:Endothelin-1; D012795:Sialoglycoproteins; D013844:Thiazoles; D015847:Interleukin-4; C009354:sulglicotide; D011899:Ranitidine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C075156:ebrotidine; D007213:Indomethacin