Intragastric administration of heparin enhances gastric ulcer healing through a nitric oxide-dependent mechanism in rats.
Our preliminary finding indicated that intravenous (i.v.) injection of heparin increased gastric ulcer healing in rats. However, the anticoagulant action of i.v. heparin could produce complications in ulcer patients if the drug was used as an anti-ulcer agent. The present study aimed to investigate whether intragastric (i.g.) administration of heparin, known to have no anticoagulant activity, would have the similar ulcer healing effect and the relationship of this effect, if any, with nitric oxide (NO), a substance suggested to be important for ulcer healing. Heparin (100, 500, 1000 U/kg, i.g. ) administered once daily for 4 days accelerated the healing of gastric ulcer induced by acetic acid in Sprague-Dawley rats, which was accompanied by an increase in mucosal proliferation and regeneration at the ulcer margin, microvessel number both at the ulcer margin and base, and the thickness of mucus layer. Both activity and content, but not the mRNA of constitutive nitric oxide synthase (cNOS) in the gastric mucosa were enhanced. L-N(G)-nitroarginine methyl ester (L-NAME), an inhibitor of NOS activity blocked the cNOS activity activated by heparin and reversed the beneficial effects of heparin on ulcer healing. The bleeding time was not altered by i.g. heparin. These findings demonstrate that i.g. heparin promotes the healing processes of gastric ulcer. Such effect is suggested to act through the stimulation of mucosal cNOS activity. In addition, i.g. heparin is better than i.v. heparin without the potential anticoagulation effect.
Li
Y
Y
Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, 5 Sassoon Road, Hong Kong, People's Republic of China.
Wang
W P
WP
Wang
H Y
HY
Cho
C H
CH
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000188:drug therapy* / Q000473:pathology
D000925:Anticoagulants; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D009569:Nitric Oxide; D006493:Heparin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019331:NG-Nitroarginine Methyl Ester