James E. Nezamis

Inhibition of gastric secretion by prostaglandins

p ROSTAGLANDINS (PGs) are a group of long-chain, unsaturated, oxygenated fatty acids, first discovered in 1935 by Goldbla t t 1 and Von Euler 2 in semen and seminal vesicles. Since then, these substances have been identified in several other tissuesfi including the gastrointestinal tract of the frog, 4, ~ the rat, 6, 7 the guinea pig, and the rabbit , s and have been found to st imulate smooth muscles (e.g., gastric and intestinal strips) in vitro. 6 These findings suggest a possible role for PGs in gastrointestinal function. In this paper we repor t the effect of four PGs on gastric secretion in the dog.

Gastric Antisecretory and Antiulcer Properties of PGE2, 15-Methyl PGE2, and 16,16-Dimethyl PGE2: Intravenous, oral and intrajejunal administration

15-Methyl PGE2 and 16,16-dimethyl PGE2 were found (1) to be 40 and 100 times, respectively, more potent than PGE2 after intravenous administration in inhibiting histamine-stimulated gastric secretion in dogs with a denervated (Heidenhain) gastric pouch, (2) to be active orally and intrajejunally, whereas PGE2 was inactive, and (3) to exert antisecretory activity for longer duration than PGE2. 16,16-Dimethyl PGE2 was about 2.5 times more potent than 15-methyl PGE2. Volume, acid concentration, and output, and pepsin output (but not concentration) were reduced in a dose-dependent manner. In the rat, 16,16-dimethyl PGE2 also inhibited gastric secretion and prevented the formation of ulcers produced by various methods: gastric ulcers (Shay, and steroid induced) and duodenal ulcers (secretogogue induced). In this species, 1l816-dimethyl PGE2 was 2 to 50 times more potent than PGE2, depending on the endpoint, and was active orally. These prostaglandins appear to inhibit gastric acid secretion by acting directly on the parietal cells, and making these unresponsive to most stimulants. Vomiting was a side effect of the prostaglandin analogues in the dog, but almost exclusively when these were given orally. After intravenous or intrajejunal administration at doses inhibiting gastric secretion by 80%, vomiting was seen only once. These results suggest that 15-methyl PGE2 and 16,16-dimethyl PGE2 may be of value in the treatment of peptic ulcer.

Cysteamine-Induced Duodenal Ulcers: A New Model to Test Antiulcer Agents

Cysteamine, administered as a single subcutaneous or oral dose, produced duodenal ulcers in rats within 24 h. At least 50% of the ulcers perforated at a dose of 425 mg/kg subcutaneously. Cysteamine-in

Ulcerogenic property of steroids.

Summary An assay for the ulcerogenic property of steroids is described. The test compound is administered subcutaneously once a day for 4 days during which the animals are fasted in individual cages. At autopsy, the incidence of animals showing ulcers is noted, severity is estimated, and number of ulcers per rat is counted. These 3 values are combined and expressed in terms of ulcer index ranging from 0 to 20. It was shown that response is directly related to dose and that Δ1-cortisol is 2 to 3 times as ulcerogenic as cortisol. Hypotheses to explain this effect of steroids are mentioned, namely, increased secretion of gastric juice, antiphlogistic property of steroids favoring necrosis of the mucosa, and decrease of mucus formation in steroid-treated animals.

Comparison of prostacyclin and prostaglandin E2 on gastric secretion, gastrin release, and mucosal blood flow in dogs.

In dogs with gastric fistulae (GF) and Heidenhain pouches (HP), intravenous graded doses of prostacyclin (PGI2) (dose range: 2.5–20 μg/kg/hr), and prostaglandin E2 (PGE2) (dose range: 10–80 μg/kg/hr) produced a dose-dependent inhibition of acid and pepsin secretion stimulated by pentagastrin (3 μg/kg/hr). The ID50 (dose inhibiting acid output by 50%) were 6 μg/kg/hr for PGI2 and 26 μg/kg/hr for PGE2 for the GF, and 7 μg/kg/hr for PGI2 and 22 μg/kg/hr for PGE2 for the HP. Acid secretion from the GF stimulated by histamine (20 μg/kg/hr) was also inhibited by both prostaglandins: the ID50 were 16 μg/kg/hr for PGI2 and 22 μg/kg/hr for PGE2 For the HP, the ID50 were about 20 and 40 μg/kg/hr for PGI2 and PGE2, respectively. Meal-induced acid secretion from the GF reached a level similar to that observed in tests with pentagastrin and was inhibited by both prostaglandins. The ID50 were 5 and 20 μg/kg/hr for PGI2 and PGE2, respectively. PGI2 significantly increased serum gastrin above that obtained with meal alone whereas PGE2 did not affect postprandial serum gastrin. The inhibition of pentagastrin and meal-induced acid secretion was accompanied by a marked reduction in gastric mucosal blood flow (MBF) measured by the [14C]aminopyrine method, without significant change in the ratio of gastric blood flow to gastric secretion. The MBF in the resting HP mucosa was significantly increased by PGI2 but reduced by PGE2. This study shows that PGI2 is about 3–4 times more potent than PGE2 in inhibiting pentagastrin and meal-induced gastric secretion and MBF; PGI2, unlike PGE2, increases the postprandial serum gastrin and raises the MBF of the resting mucosa. Therefore, both PGI2 and PGE2 are antisecretory, but their effects on gastrin release and resting MBF are qualitatively different.

Inhibition by prostaglandin E1 of gastric secretion in the dog

1. The effect of prostaglandin E1 (PGE1) on gastric secretion was studied in dogs equipped with gastric fundic pouches, either innervated (Pavlov) or denervated (Heidenhain).

Prevention of Duodenal Ulcers by Administration of Prostaglandin E2 (PGE2)

Duodenal ulcers were produced by constant subcutaneous infusion for 24 h of two gastric secretogogues mixed together. The agents were cither histamine + carbachol, pentagastrin + carbachol, or pentagastrin + histamine. The ulcers were localized only in the duodenum (the stomach was not involved); they were usually multiple, and duodenal perforations occurred in many instances. When prostaglandin E2 (PGE2) was infused subcutaneously to animals treated simultaneously with duodenoulcerogenic doses of secretogogues, and for the same time interval, the ulcers were prevented, and the degree of inhibition was dose-dependent. It is concluded that PGE2 prevents formation of duodenal ulcers in the rat. Since prostaglandins were previously shown to reduce gastric secretion in dogs and rats, the anti-ulcer effect of PGE2 may be due to its antisecretory activity.

Effect of Prednisolone on Gastric Mucus Content and on Ulcer Formation

Summary Prednisolone, administered subcutaneously to rats, produced gastric ulcers and reduced the mucus of gastric juice and tissue. Determination of hexosamine was used as a measure of mucus. Ulcers were limited to the corpus and never appeared in the antrum. The antrum was found to contain twice as much mucus as the corpus. Gastric juice acidity was markedly reduced. These data favor a hypothesis ascribing a protecting role to mucus in the natural defense of the gastric mucosa against ulcerogenic agents. Steroid ulcers may be explained by a diminution of gastric mucus.

Exertion ulcers in the rat.

Gastric ulcers were produced in rats by forced muscular exercise (“exertion ulcers”). These ulcers were multiple, bleeding, located in the corpus, consisted of hemorrhagic necrosis of the mucosa, and could easily be counted. The animals were fasted overnight prior to exertion. Female rats were more sensitive than males to this type of ulcer. Agents known to reduce gastric acidity (anti-cholinergics, antacids, mercuric acetate) prevented their formation, as did prednisolone. Neither adrenalectomy nor administration of desoxycorticosterone affected these ulcers. During exertion, volume and acidity of gastric juice were reduced. Although the pathogenesis of these ulcers remains to be elucidated, the following chain of events is offered as a hypothesis: Exertion (severe stress) → vascular shock → impairment of gastric circulation → gastric anoxia → decreased resistance to autodigestion → ulcers. Since exertion ulcers can be graded quantitatively (incidence, severity, and number of ulcers are expressed as such, and also are combined as an “ulcer index”), and are prevented by antiulcer drugs on a dose-dependent basis, this technic is proposed as an assay for antiulcer agents. Its main advantages are rapidity (2 hr and 45 min), simplicity, reproducibility and quantitation.Gastric ulcers were produced in rats by forced muscular exercise (“exertion ulcers”). These ulcers were multiple, bleeding, located in the corpus, consisted of hemorrhagic necrosis of the mucosa, and could easily be counted. The animals were fasted overnight prior to exertion. Female rats were more sensitive than males to this type of ulcer. Agents known to reduce gastric acidity (anti-cholinergics, antacids, mercuric acetate) prevented their formation, as did prednisolone. Neither adrenalectomy nor administration of desoxycorticosterone affected these ulcers. During exertion, volume and acidity of gastric juice were reduced. Although the pathogenesis of these ulcers remains to be elucidated, the following chain of events is offered as a hypothesis: Exertion (severe stress) → vascular shock → impairment of gastric circulation → gastric anoxia → decreased resistance to autodigestion → ulcers.Since exertion ulcers can be graded quantitatively (incidence, severity, and number of ulcers are expressed as such, and also are combined as an “ulcer index”), and are prevented by antiulcer drugs on a dose-dependent basis, this technic is proposed as an assay for antiulcer agents. Its main advantages are rapidity (2 hr and 45 min), simplicity, reproducibility and quantitation.

Duodenal ulcers produced in rats by propionitrile: Factors inhibiting and aggravating such ulcers

Abstract Propionitrile (PPN), administered either sc or orally to female rats, produced within 2 days severe duodenal ulcers that often perforated. Such ulcers were prevented by methscopolamine bromide (an anticholinergic agent) and by 16,16-dimethyl prostaglandin E 2 (a gastric antisecretory agent). Overnight fasting and administration of prednisolone increased the toxicity of PPN, as shown by a high mortality rate, whereas desoxycorticosterone and ACTH did not influence the effects of PPN on ulcer formation and on toxicity. Male rats were found to be relatively resistant to PPN-induced duodenal ulcers. PPN had little effect on gastric secretion other than a moderate inhibition of pepsin secretion, but PPN retarded gastric emptying. Although the mode of action of PPN is unknown, the duodenal ulcers produced by this compound can be used as an assay for antiulcer agents.