David A. Brodie

A Study of the Factors Involved in the Production of Gastric Ulcers by the Restraint Technique

Summary 1.Six species of experimental animals were tested for the production of gastric ulcers by restraining the animals in wire screen for 24 hours. Mice, rats, guinea pigs, and hamsters had an incidence of gastric ulceration of 92, 86, 46, and 4 per cent, respectively. Gastric ulcers were not induced in rabbits or monkeys by the restraint technique. 2.As the time period of the restraint of the rat was increased from 6 to 24 hours, the incidence of gastric ulcer increased. Recovery of the stomach to normal after 24 hours of restraint required 72 hours. 3.The incidence of gastric ulcers in rats that were deprived of food was found to be higher than that of fed rats, when both groups were restrained for the same time period. Food deprivation also prolonged the time required for the gastric mucosa to return to normal. 4.Younger rats (50 to 185 gm.) had a higher incidence of gastric ulcers than older rats (over 250 gm.) when both groups were subjected to short periods of restraint. Weight did not seem to be an important variable when the rats were restrained for a period of 24 hours. 5.Repeated periods of restraint, 18 hours a day, increased the incidence and severity of gastric ulcers. Rumen ulcers were produced by this procedure. 6.In rats, 8 days after operation, hypophysectomy and bilateral subdiaphragmatic vagotomy did not reduce significantly the incidence of animals with ulcers. Bilateral adrenalectomy significantly increased the incidence and severity of the ulcers produced by restraint. 7.The restraint technique provides a simple, rapid, nonsurgical means of producing ulcers in the glandular portion of the stomach.

Indomethacin-induced intestinal lesions in the rat.

Abstract A single large po or sc dose of indomethacin, 80 times the antiinflammatory dose, produced a high incidence of intestinal perforations 72 hr after administration to fed rats; the perforations were confined to the mid-portion of the small intestine. When food was withheld from indomethacin-treated rats, the lesion incidence after a dose of 16 mg/kg po was reduced from 100% to zero. In a 72-hr study, it was found that food deprivation only on the day of drug administration prevented the intestinal perforations, while feeding the rats on the day of drug administration produced 100% ulcer incidence. Lesions produced by sc drug administration could also be prevented by starvation. The incidence of intestinal perforation was altered by the duration of food deprivation and the amount of food consumed. Intestinal ulcers could also be prevented, after either po or sc administration, by ligation of the bile duct. It appeared possible that there was a relationship between food intake, bile flow, and intestinal ulcers. Bile duct ligation reduced the incidence of intestinal perforation after indomethacin from 100% to zero. A time response curve indicated that bile duct ligation up to 8 hours after drug administration reduced the incidence of perforation; however, a 60% incidence of intestinal lesions was found when the bile duct was ligated 3 hours after indomethacin was given. When segments of the small intestine were isolated as Thiry loops, ulceration was prevented in the loops but occurred in the anastomosed intestine.

The mechanism of gastric hyperacidity produced by pylorus ligation in the rat

SummaryPylorus ligation significantly increased gastric acid concentration over that found in nonligated acute fistula rats. Ligating the stomach on the antrum did not change the gastric secretory pattern from that obtained by pylorus ligation. Local administration of atropine, mecamylamine, and cocaine into the lumen of a pylorus sac inhibited gastric secretion. Atropine was four times as potent and mecamylamine three times as potent locally as when given orally, indicating direct effects on nerve structures in the submucosa.Direct hormonal release as a result of ligation did not appear to have a major role in the stimulation, since neither pylorectomy, duodenectomy, nor the infusion of acid into the duodenum reduced gastric acidity. Pylorus ligation in rats wth vagally denervated gastric pouches did not stimulate pouch secretion, also suggesting a nonhormonal mechanism. The hypersecretion was postulated to be due to stimulation of pressure receptors in the antral mucosa which initiated a vagovagal reflex.

Aspirin: Intestinal Damage in Rats

Lesions induced by aspirin in the small intestine of the rat were visualized after 4 hours by the intravenous administration of a 5 percent solution of pontamine sky blue, 6 BX dye. Dose-response curves in fasted and fed rats indicated that the fed rat was about eight times more susceptible to aspirin-induced intestinal damage than was the fasted rat, while the fasted rat was about 13 times more susceptible to aspirin-induced gastric damage than was the fed rat.

Drug effects on gastric secretion and stress gastric hemorrhage in the rat

The development of a simple, rapid technic for placing drugs into the rat lateral cerebral ventricle permitted comparison of intravenous and intracerebroventricular drug administration on gastric acid secretion and cold-plus-restraint (stress) induced gastric hemorrhage. Intravenous effective dose50s (micrograms) to reduce titratable acid output in 2-hr pylorus-ligated rats were: clonidine 1.0; atropine methylbromide 1.2; atropine sulfate 2.7; chlorpromazine 20.5; imipramine 397.0; morphine 837.7; and chlordiazepoxide 3419. The intravenous ED50s for inhibition of stress-induced gastric hemorrhage were (micrograms): atropine methylbromide 64.0; atropine sulfate 902.4; clonidine >4.0; chlorpromazine >256; morphine >256; chlordiazepoxide >2048; and imipramine >256. Intracerebroventricular administration of the drugs produced a different ranking of activity for inhibition of titratable acid output (ED50 in micrograms); atropine methylbromide 0.1; atropine sulfate 0.5; clonidine 3.7; morphine 5.5; chlorpromazine 99.2; chlordiazepoxide >1024; and imipramine >4096. However, the order of activity for intracerebroventricular inhibition of stress-induced gastric hemorrhage was similar to the intravenous route in that atropine methylbromide was most active, 7.8 μg, followed by atropine sulfate, 54.8 μg, and no ED50s were obtainable for the other drugs tested. This study indicated that central nervous system control areas for gastric secretion in the rat were located in structures bordering the cerebral ventricles but that secretion inhibiting dose of drug placed in this area did not reduce the incidence of stress-induced gastric hemorrhage.

Effects of route of administration on the production of gastric hemorrhage in the rat by aspirin and sodium salicylate

Dose response curves were obtained in food-deprived rats for aspirin-induced incidence of gastric hemorrhage by four routes of administration: oral (ED50=18 mg/kg); intravenous (ED50=36 mg/kg); small intestinal (ED50=34 mg/kg); and colonic (ED50=12 mg/kg). A similar study with sodium salicylate gave a dose response curve after oral administration (ED50=33 mg/kg), but no incidence of gastric hemorrhage was produced when sodium salicylate was given by the other three routes, even at toxic dose levels. The data indicate that aspirin can produce gastric hemorrhage in the rat by parenteral as well as by oral route, but that sodium salicylate causes gastric hemorrhage in the rat only on direct contact with the gastric mucosa.Dose response curves were obtained in food-deprived rats for aspirin-induced incidence of gastric hemorrhage by four routes of administration: oral (ED50=18 mg/kg); intravenous (ED50=36 mg/kg); small intestinal (ED50=34 mg/kg); and colonic (ED50=12 mg/kg). A similar study with sodium salicylate gave a dose response curve after oral administration (ED50=33 mg/kg), but no incidence of gastric hemorrhage was produced when sodium salicylate was given by the other three routes, even at toxic dose levels. The data indicate that aspirin can produce gastric hemorrhage in the rat by parenteral as well as by oral route, but that sodium salicylate causes gastric hemorrhage in the rat only on direct contact with the gastric mucosa.

Evaluation of Gastric Acid as a Factor in Drug-Induced Gastric Hemorrhage in the Rat

Studies on six drugs at maximal gastric hemorrhage producing dose in the rat indicate that there is no common mechanism of drug-induced gastric hemorrhage. Vagotomy significantly reduced hemorrhage incidence after administration of aspirin, phenylbutazone, 2-deoxyglucose, and reserpine, but not after serotonin or histamine. Acid infusion (0.075 m) in vagotomized rats treated with aspirin and reserpine returned hemorrhage incidence to control values, but acid infusion after phenylbutazone or 2-deoxyglucose did not. Studies on gastric secretion in the acute fistula rat indicated that, of the drugs studied, only 2-deoxyglucose increased any parameter of gastric secretion above control values while the most common effect was an inhibition of titratable acid output. The use of glycine infusion to trap spontaneously secreted hydrochloric acid demonstrated that the decrease in gastric secretion seen with aspirin, serotonin, and histamine was not due to a loss of secreted HCl through the damaged gastric mucosa.

The Mechanism of the Inhibition of Gastric Secretion Produced by Esophageal Ligation in the Pylorus-Ligated Rat

Esophageal ligation in the pylorus-ligated rat significantly inhibited volume, titratable acidity, and titratable acid output and reduced the incidence of ulcers, perforations, and death of 18-hr pylorus-ligated rats. Draining the saliva outside the body of the rat by esophageal cannulation produced a significant increase in volume and gastric acidity over the esophagus-ligated preparation. A method for collection of saliva in the unanesthetized unstimulated rat was developed, and basal salivary flow was found to be 0.84 ml/4 hr. Administration of 1.0 ml of freshly collected saliva to esophagus + pylorus-ligated rats increased titratable acidity, but not volume of secretion, to the level found in the pylorus-ligated rat. A similar effect was obtained with administration of 1.0 ml of a phosphate buffer. Removal of the salivary glands had no significant effect on gastric acidity in the pylorus-ligated rat and the reduction in volume could be accounted for by the lack of saliva. Gastric secretion in the esophagus + pylorus-ligated rat was stimulated by histamine, carbachol, insulin, and 2-deoxyglucose. When the vagus nerves were cut, stimulation was still obtained with carbachol but not with insulin or 2-deoxyglucose. The data indicated that rat saliva did not contain a specific gastric stimulant material, and esophageal ligation depressed gastric secretion in the pylorus-ligated rat by inhibition of the central vagal activity.

Rewarding Properties of Intracranial Stimulation

Monkeys can be trained to press a lever to obtain intracranial brain stimulation on a large fixed-ratio schedule as well as on a continuous reinforcement schedule. A long extinction curve appears to be indicative of a future high fixed-ratio performance.

A Comparison of Anticholinergic Drugs on Gastric Secretion, Gastric Emptying, and Pupil Diameter in the Rat

Summary The effects of five anticholinergic drugs were compared on gastric secretion, gastric emptying, and pupil diameter in the rat. Gastric secretion was obtained from the acute gastric fistula rat preparation while gastric emptying was measured by the passage of amberlite resin pellets out of the stomach. On oral administration, atropine sulfate and dicyclomine affected pupil size before the other parameters. Atropine depressed acid output and gastric emptying at the same dose, while dicyclomine depressed gastric emptying before gastric acid output. Atropine methyl bromide, scopolamine methyl iodide, and propantheline bromide first inhibited acid output, next changed pupil size, and then depressed gastric emptying. Propantheline, although not the most potent drug, had the highest ratios of acid output inhibition to pupil diameter and gastric emptying. Comparison of the drugs after subcutaneous administration showed that all drugs studied increased pupil diameter before affecting acid output or gastric emptying. Atropine sulfate and scopolamine methyl iodide depressed acid output before gastric emptying while the reverse was true with atropine methyl bromide and propantheline. Gastric acid output and gastric emptying were depressed at essentially equal doses by dicyclomine. The study suggested that relationship of secondary drug actions (pupil size and gastric emptying) to the desired action of gastric acid inhibition is more important than the absolute potency of the drugs.