Association of heparin with basic fibroblast growth factor, epidermal growth factor, and constitutive nitric oxide synthase on healing of gastric ulcer in rats.
The healing effect of heparin on gastric ulcer and its underlying mechanisms were studied. The influences of protamine on these effects were also investigated. Gastric ulcer was induced by acetic acid in rats. Heparin (100-1000 U/kg i.v.) was given once daily for 4 or 7 days. Ulcer area was measured; gastric mucosal regeneration, proliferation, and angiogenesis were determined by histological or immunohistochemical methods. Gastric mucosal basic fibroblast growth factor (bFGF) level was assessed by an enzyme-linked immunosorbent assay, and the mucosal epidermal growth factor (EGF) level and nitric oxide synthase (NOS) activity were measured by radioimmunoassay. The anticoagulant action of heparin was determined by the duration of bleeding time. The results showed that heparin given for 4 or 7 days significantly accelerated gastric ulcer healing in a dose-dependent manner. The three doses of heparin significantly stimulated mucosal regeneration and proliferation as well as angiogenesis but not the contraction of ulcer base. Similar effects were observed in gastric mucosal bFGF and EGF levels and constitutive NOS activity. Protamine not only abolished the anticoagulant action of heparin but also significantly potentiated its effects on ulcer healing, gastric mucosal proliferation, angiogenesis, and constitutive NOS activity. These findings indicate that heparin can accelerate gastric ulcer healing, which is associated with mucosal regeneration, proliferation, and angiogenesis. These actions are likely to be stimulated by bFGF, EGF, and constitutive NOS activity in the gastric mucosa. Protamine potentiates the ulcer-healing effect of heparin, which is probably acting through constitutive NOS activation.
Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
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D000085:Acetates; D000818:Animals; D000897:Anti-Ulcer Agents / Q000627:therapeutic use*; D000925:Anticoagulants / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000502:physiology*; D004847:Epithelial Cells / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000502:physiology*; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006493:Heparin / Q000627:therapeutic use*; D006494:Heparin Antagonists / Q000494:pharmacology; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D011479:Protamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000097:blood / Q000139:chemically induced / Q000473:pathology*
D000085:Acetates; D000897:Anti-Ulcer Agents; D000925:Anticoagulants; D006494:Heparin Antagonists; D011479:Protamines; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D006493:Heparin; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat