Phosphodiesterase type IV inhibitors prevent ischemia-reperfusion-induced gastric injury in rats.
The effects of selective inhibitors of phosphodiesterase type IV (PDE4) on ischemia-reperfusion-induced gastric injuries were investigated in rats. Gastric ischemia was induced by applying a small clamp to the celiac artery, and reoxygenation was performed by removal of the clamp. Ischemia-reperfusion produced gastric hemorrhagic injuries and increased the content of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and myeloperoxidase (MPO) activity in gastric mucosa. Rolipram (0.03-0.3 mg/kg, s.c.) and Ro-20-1724 (0.3-3 mg/kg, s.c.) prevented the development of gastric injury in a dose-dependent manner, and it also inhibited the increase in mucosal TNF-alpha content and MPO activity induced by ischemia-reperfusion. The anti-ulcer drug irsogladine (1-10 mg/kg, p.o.), which is known to possess a PDE4 inhibitory action, also inhibited the gastric injury produced by ischemia-reperfusion, as well as the increase in TNF-alpha levels and MPO activity. It is concluded that the ability of PDE4 inhibitors to inhibit cytokine TNF-alpha synthesis and the infiltration of polymorphonuclear leukocytes underlies their gastroprotective effects in ischemia-reperfusion-induced gastric injury. Our experiments suggest that drugs that inhibit PDE4 isoenzyme, such as the anti-ulcer drug irsogladine, may be a useful adjunct therapy for the treatment of the gastric damage that follows ischemia-reperfusion.
Kyoi
Takashi
T
Research Laboratories, Nippon Shinyaku Co., Ltd., Kisshoin, Minami, Kyoto 601-8550, Japan. t.kyoi@po.nippon-shinyaku.co.jp
Kitazawa
Satoru
S
Tajima
Koyuki
K
Zhang
Xin
X
Ukai
Yojiro
Y
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009853:Omeprazole / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D020889:Rolipram / Q000494:pharmacology; D013276:Stomach Ulcer / Q000517:prevention & control*; D014227:Triazines / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D000897:Anti-Ulcer Agents; D010726:Phosphodiesterase Inhibitors; D014227:Triazines; D014409:Tumor Necrosis Factor-alpha; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D009195:Peroxidase; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D009853:Omeprazole; C041836:irsogladine