thromboxane-a2 and ecabet

The gastroprotective agent ecabet sodium (ecabet, 12-sulfodehydroabietic acid monosodium salt) increases the formation of prostaglandin (PG) E2 and I2 by gastric mucosa. In the present study, we examined the effect of ecabet on metabolism of arachidonic acid (AA) in rat gastric mucosal cells. Ecabet (0.1-10 mM) concentration- and time-dependently potentiated the release of [14C]AA from gastric mucosal cells prelabeled with [14C]AA and simultaneously increased the production of PGE2 and PGI2. The ecabet-mediated increases in [14C]AA release and PGE2 production were both partly depressed by mepacrine (30 and 100microM) and Ca2+ chelation. Ecabet, however, showed no effect on gastric phospholipase A2 (PLA2) activity and [Ca2+]i in the gastric mucosal cells. Ecabet and other dehydroabietic acid derivatives, 12-carboxydehydroabietic acid monosodium salt and mono[16-(12-sulfodehydroabietyl)]succinic acid monosodium salt, which potentiated the liberation of [14C]AA, increased the membrane fluidity of gastric mucosal cells assessed by using diphenylhexatrienepropionic acid (DPH-PA) as the probe, while 12-sulfamoyldehydroabietic acid showed no effect on either the AA liberation or the membrane fluidity. Ecabet (0.1-10 mM) increased the membrane fluidity concentration- and time-dependently in accordance with its facilitating effect on AA release. In conclusion, ecabet increases the synthesis of PGE2 and PGI2 by gastric mucosal cells through promoting the release of AA, which is partly dependent on PLA2 and Ca2+. The ecabet-induced increase in membrane fluidity may be involved in part in the liberation of AA from the gastric mucosal cells.

Topics: Abietanes; Animals; Anti-Ulcer Agents; Arachidonic Acid; Calcium; Dinoprostone; Diterpenes; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epoprostenol; Gastric Mucosa; Hydroxyprostaglandin Dehydrogenases; In Vitro Techniques; Male; Membrane Fluidity; Phospholipases A; Phospholipases A2; Quinacrine; Rats; Rats, Sprague-Dawley; Thromboxane A2

Effects of ecabet sodium (TA-2711), a locally acting antiulcer agent, on prostanoid production and the morphology of the rat gastrointestinal mucosa were studied in comparison with sucralfate. Ecabet, at therapeutic doses (25 and 100 mg/kg, p.o.), dose-dependently increased the gastric mucosal level of prostaglandin E2 (PGE2): sucralfate (100 mg/kg, p.o.) showed a tendency to increase the PGE2 level. In an ex vivo study, ecabet (25 and 100 mg/kg, p.o.) dose-dependently increased the capacity of the gastric mucosa to synthesize PGE2 and PGI2 without modifying tromboxane A2 (TXA2) synthesis, and the 100 mg/kg dose persisted for up to 3 h. Ecabet (400 mg/kg, p.o.) also significantly increased PGE2 synthesis and there was a tendency to increase PGI2 synthesis by the duodenal mucosa, without affecting TXA2 synthesis. PGE2 synthesis by the colonic mucosa was not affected, even at a high dose of ecabet (1000 mg/kg, p.o.). When the rat gastric mucosa was examined by light microscopy and scanning electron microscopy, ecabet (100 and 400 mg/kg, p.o.) had caused no morphological change to the gastric mucosa, while sucralfate (100 and 400 mg/kg, p.o.) produced apical rupture of the epithelial cells and subepithelial edema. The present study indicates that ecabet locally stimulates PGE2 and PGI2 production in the gastroduodenal mucosa and this effect is not attributable to a local irritant action accompanied by superficial epithelium damage.

Topics: Abietanes; Animals; Anti-Ulcer Agents; Dinoprostone; Diterpenes; Epoprostenol; Gastric Mucosa; Intestinal Mucosa; Male; Microscopy, Electron, Scanning; Prostaglandins; Rats; Rats, Sprague-Dawley; Thromboxane A2