Satoru Takahashi, Jun-ichi Shigeta, Makoto Ishikawa, Norihiro Kobayashi
and Susumu Okabe
Department of Applied Pharmacology, Kyoto Pharmaceutical University,
Misasagi, Yamashina, Kyoto 607-8414, Japan
Abstract: We investigated the role of thromboxane (TX) A2
in gastric ulcer healing in rats. Acetic acid ulcers were produced in male
Donryu rats. TXA2 synthesis in the stomachs with ulcers was significantly
elevated in ulcerated tissue, but not in intact tissue, compared with that
in the gastric mucosa of normal rats. Indomethacin inhibited both TXA2
and prostaglandin E2 (PGE2) synthesis in ulcerated
tissue, while NS-398 (selective cyclooxygenase-2 inhibitor) reduced only
PGE2 synthesis. OKY-046 (TXA2 synthase inhibitor)
dose-relatedly inhibited only TXA2 synthesis. The maximal effect
of OKY-046 (80% inhibition) was found at more than 30 mg/kg. When OKY-046
was administered for 14 days, the drug at more than 30 mg/kg significantly
accelerated ulcer healing without affecting acid secretion. The maximal
reduction of ulcerated area by OKY-046 was about 3O%, compared with the
area in the control. Histological studies revealed that regeneration of
the mucosa was significantly promoted by OKY-046, but neither maturation
of the ulcer base nor angiogenesis in the base were affected. OKY-046 and
TXB2 had no effect on proliferation of cultured rat gastric epithelial
cells, but U-46619 (TXA2 mimetic) dose-relatedly prevented the
proliferation without reducing cell viability. These results indicate that
the increased TXA2, probably derived from cyclooxygenase-1 in
ulcerated tissue, exerts a weak inhibitory effect on ulcer healing in rats.
The effect of TXA2 might be due partly to prevention of gastric
epithelial cell proliferation at the ulcer margin.
Keywords: Acetic acid ulcer, Healing, Thromboxane A2, OKY-046,
Mucosal regeneration