Effect of synthetic acyclic polyisoprenoids on the cold-restraint stress induced gastric ulcer in rats.

The antiulcer effect of a series of synthetic acyclic polyisoprenoids on cold-restraint stress induced ulcer in female rats was determined, and the relationship between their antiulcer effect and chemical structure was also investigated. As a result, the following findings were obtained: The antiulcer effect of acyclic polyisoprenoids closely correlated with the number of intramolecular isoprene units, and geranylgeranyl derivatives showed a particularly marked antiulcer effect. The terminal polar groups such as 2-oxopropyl and 2-hydroxypropyl groups in geranylgeranylacetone seemed to play an important role in the antiulcer activity of acyclic polyisoprenoids. Terminal bulky groups decreased their antiulcer activity, however. The antiulcer activity of geranylgeranylacetone correlated with the number of intramolecular double bonds. There was no significant difference in antiulcer activity between all-trans-geranylgeranylacetone, 5-cis-geranylgeranylacetone and the mixture of these isomers (1:1 and 3:2). The results of this experiment suggested that the antiulcer activity of acyclic polyisoprenoids might be governed by such factors as the number of isoprene units, terminal polar groups, and number of intramolecular double bonds.

Effects of the antiulcer drug geranylgeranylacetone on aspirin-induced gastric ulcers in rats.

Antiulcer effects of geranylgeranylacetone (GGA) on aspirin-induced gastric ulcers in rats were studied, comparing them with those of gefarnate. The oral administration of GGA prevented the development of gastric ulcer induced by a single or repeated oral administration (5 consecutive days) of aspirin. The effects of GGA were more potent and more definite than those of gefarnate. The intraduodenal administration of GGA, but not the intragastric administration, also inhibited the ulceration induced by aspirin in pylorus-ligated rats, while the intraduodenal administration of gefarnate did not. GGA prevented the reduction of the H+ concentration and the increment of Na+ concentration in the gastric juice induced by aspirin. In addition, the decrease of hexosamine content in the gastric mucosa induced by aspirin was restored to a normal level by GGA, but not by gefarnate. From these results, it was concluded that the protective actions of GGA on aspirin-induced gastric ulcers might be due to its protection from the weakening of gastric mucosal resistances.

Antiulcer effect of geranylgeranylacetone, a new acyclic polyisoprenoid on experimentally induced gastric and duodenal ulcers in rats.

Antinuclear effects of geranylgeranylacetone (GGA), new acyclic polyisoprenoid, on several types of experimental gastric and duodenal ulcers were studied in rats. The prophylactic administration of GGA (50--200 mg/kg p.o. or 12.5--50 mg/kg i.p.) reduced the gastric ulcers induced by the exposure to cold-restraint stress and by the administration of indomethacin, acetylsalicylic acid (ASA), prednisolone or reserpine and the duodenal ulcer after the administration of cysteamine, although it was not effective against Shay's ulcer. The curative treatment with GGA accelerated the healing process of the gastric ulcers induced by the topical application of acetic acid or thermocautery and by the administration of ASA with the exposure to cold-restraint stress. The antinuclear effect of GGA was more distinct than that of gefarnate in all types of experimental models studied. Carbenoxolone effectively reduced the gastric ulcer formation by cold-restraint stress when it was administered i.p. but not p.o., whereas GGA was effective either i.p. or p.o. GGA and gefarnate did not affect the gastric secretion in pylorus-ligated rats, whereas carbenoxolone definitely reduced the secretion of gastric juice and acid. Hexosamine content in the stomach was reduced by the exposure to cold-restraint stress. The pretreatment with GGA prevented the reduction in hexosamine contents in the superepithelial mucous layer and mucosal layer. These results may suggest a high possibility that GGA is useful for clinical treatment of peptic ulcers, probably through a mechanism of increasing defence force of the gastric mucosa.

[Protective effect of tocopheryl esters on pulmonary edema induced by epinephrine].

The present study was performed in order to determine protective effect of dl-alpha-tocopheryl nictonate (EN) and dl-alpha-tocopheryl acetate (EA) on pulmonary edema induced by epinephrine (Epi) in mice. The tocopheryl esters were orally administered once a day for 10 days. Epi was then infused to induce pulmonary edema 3 hr after the final dosing. One or three min infusion of 0.01% Epi at a rate of 0.1 ml/min provoked toxic syndromes as pilorection, exophthalmos and salivation. Some animals died of respiratory failure. The lung weight either wet or dry increased after the EPi infusion and diffuse hemorrhage into alveoles was microscopically recognized in untreated animals. However, these findings were of lesser degree in animals receiving NE (20, 50 and 100 mg/kg/day) and Ea (corresponding doses with EN in molecular weight basis). When comparing the effect of EN with that of EA on the increase of lung weight and death from the Epi infusion, EN was more protective than EA. Although the mechanism of protecting action of these tocopheryl esters remains obscure, the interpretation is that these compounds did not affect the pressor response to Epi.