gastrins and geranylgeranylacetone

Recently, we have reported that several nonacid agents including phenylpentol, methanol extract of licorice root (FM 100), plaunotol, and teprenon stimulate release of endogenous secretin in humans, dogs, and rats. The latter three are antiulcer agents developed in Japan that have a protective effect on the gastric mucosa. We have clearly shown that plaunotol inhibits postprandial gastrin release and gastric acid secretion that parallel the increase in plasma secretin concentration. It has also been recently demonstrated that the secretin-induced inhibition of gastric acid secretion in rats is completely blocked by indomethacin, a potent inhibitor of prostaglandin synthesis. It appears that the inhibitory action of secretin on gastric acid secretion is mediated mainly by endogenous prostaglandins. Because the three antiulcer agents FM 100, plaunotol, and teprenon have been shown to increase the content of endogenous prostaglandins in the gastric mucosa, endogenous secretin released by these agents may play a significant role in their mucosal protective action. It is concluded that the antiulcer effect of these drugs could in part be attributable to their unique ability to release endogenous secretin, and that secretin is a potential mediator of the antiulcer actions of mucosal protective agents.

Topics: Animals; Anti-Ulcer Agents; Cimetidine; Diterpenes; Fatty Alcohols; Food; Gastric Acid; Gastrins; Humans; Prostaglandins; Ranitidine; Rats; Secretin

In the present study, we investigated the effects of MCI-727, a new anti-ulcer agent, on plasma immunoreactive secretin concentration in rats and dogs using secretin specific RIA with the ethanol extraction method. Plasma secretin levels were increased dose-dependently 10 min after oral administration of MCI-727 in rats (control: 5.5 +/- 0.6; MCI-727, 10 mg/kg: 10.4 +/- 2.6; 30 mg/kg: 15.3 +/- 1.5; 100 mg/kg: 20.7 +/- 2.6 pg/ml, n = 6). Teprenone also caused a significant increase of plasma secretin at 10 min after oral administration at the doses of 30, 100 and 300 mg/kg. Under the same conditions, MCI-727 and teprenone did not alter the plasma immunoreactive gastrin concentration in rats. From the results of the time course study, the increasing effect of MCI-727 (30 mg/kg, p.o.) on plasma secretin remained for at least 240 min after administration. On the other hand, the increasing effect of teprenone (200 mg/kg, p.o.) was only observed at 30 and 60 min after administration. Furthermore, MCI-727 had increasing effects on plasma secretin concentration in dogs, but teprenone had no effects in this species. The volume of pancreatic secretion and the pancreatic bicarbonate output increased after intra-duodenal administration of MCI-727 at 30 and 100 mg/kg in rats. Similar effects were also observed with teprenone (30-300 mg/kg, i.d.) or secretin (Secrepan, 0.1-1.0 unit/kg, i.v.).

Topics: Administration, Oral; Animals; Anti-Ulcer Agents; Bicarbonates; Diterpenes; Dogs; Female; Gastrins; Injections, Intravenous; Male; Oximes; Pancreas; Piperazines; Rats; Secretin

The effects of geranylgeranylacetone (GGA), a new acyclic polyisoprenoid with a novel antiulcer action on gastrointestinal secretion were studied in rats. Intraduodenal administration of GGA (1-30 mg/kg) dose-relatedly reduced the gastric acid secretion caused by pentagastrin, histamine or insulin. On the other hand, GGA (3-30 mg/kg i.d.) dose-relatedly increased pancreatic secretion but did not affect biliary secretion. The above-mentioned findings seem consistent with the further findings that GGA depressed a plasma gastrin level enhanced by insulin while in increased the basal level of plasma secretin. These pharmacological features found in the present studies may partially, at least, account for the mechanism of GGA antiulcer action.

Topics: Animals; Bile; Cimetidine; Digestive System; Diterpenes; Drug Interactions; Gastric Acid; Gastrins; Gefarnate; Male; Pancreatin; Rats; Rats, Inbred Strains; Secretin

The effects of various antiulcer drugs and hormones on the cell kinetics of the mouse gastric mucosa were studied using an autoradiographic technique with 3H-thymidine. The drugs or hormones were administered orally or parenterally once or twice a day for 7 consecutive days, and 3H-thymidine was injected after the last administration of the drug. The autoradiograph was prepared and then the labeling index was counted. Cimetidine (100 mg/kg X 2/day, p.o.), geranylgeranylacetone (GGA, 100 mg/kg X 2/day, p.o.) and Cu-chlorophyllin-Na (300 mg/kg X 2/day, p.o.) did not show any effect on the labeling indices in both the tissues of the fundic and pyloric glands, while carbenoxolone (100 mg/kg X 2/day), p.o.) reduced the labeling index in the pyloric glands. Tetragastrin (1 mg/kg X 1/day, i.m.) increased the labeling index in the fundic glands, whereas secretin did not affect it. Hydrocortisone (100 mg/kg X 1/day, S.C.) reduced the labeling index in the fundic glands, and this reducing effect was prevented by combining hydrocortisone with GGA. From these results, it was indicated that the labeling index in the normal mouse gastric generative zone was no influenced by the tested antiulcer drugs, except carbenoxolone; but the index was influenced by tetragastrin and hydrocortisone, especially in the fundic glands. It was also suggested that the changes in the cell kinetics of the gastric mucosa could be related to the etiology of gastric ulcer since there was a possibility that geranylgeranylacetone could control the action of hydrocortisone, an ulcerogenic agent, on the gastric mucosal cell-cycle.

Topics: Animals; Carbenoxolone; Cell Cycle; Chlorophyllides; Cimetidine; Diterpenes; Gastric Mucosa; Gastrins; Hydrocortisone; Kinetics; Male; Mice; Secretin; Stomach Ulcer