White and Magee (1958) have reported that the continuous intravenous infusion of serotonin increased -the secretion of mucin from the pyloric mucosa. Furthermore, they demonstrated that the serotonin-effect on mucin secretion was not dependent on an increased motility of the pylorus, because the effect. was present also in the everted, gastic pouch, and was not abolished by hexamethonium which decreases gastric motility. Gaddum and Picarelli (1957) reported that there are two types of serotonin receptors, namely the M-receptor (nervous) and the D receptor (smooth muscle) in, the guinea pig ileum. The nervous receptor is blocked by morphine or atropine, while the smooth muscle receptor is blocked by dibe-nzyline or d-lysergic acid diethylamide ,(LSD).
The present study attempts first to clarify the relationship between these receptors and gastric secretion particulary mucus contents and motility, and secondly, to confirm -the. effect or role of serotonin -on dietary induced gastric secretion in dogs.
Methods
Eight healthy mongrel dogs, weighing 10 to 15 kg., were employed in these experiments. According to the technique described by DeVito and Harkins (1959). we prepared denervated (Heidenhain).,pouches´in six dogs. In two animals we made. innervated (Pavlov) pouches using the.method of Holland: and Jemerin{1938).- The dogs were maintained on a semi-fluid rice diet made of 0~0% starch and 10% protein. They were fasted for 15 hours before each experiments. Powdered whole milk was used as the standard food for the stimulation of gastric juice production. The dogs were fed portions containing :200 calories in a -solution of milk powder diluted with distilled water to a volume of 200 ml. Two grams of sodium chloride, -were added to each 200 ml. In order that the effects of calories and volume might be eliminated in these studies we used other foods in an equi-caloric and equi-volumetric basis in some of the animals. The effects of the subcutaneous injection of serotonin, histamine, and other agents on gastic secretion induced by the standard milk preparation were examined. The secretion volume and degree of -acidity. were determined at thirty minute intervals. The -free and total acidity of the gastic juice were measured in-1.0-m1. aliquots by titration of the sample with N/20 NaOH,- using Topfer´s reagent and-´phenolpht halein as indicators. Total acidity was considered to be a more accurate reflection of the parietal cell secretion than free acidity. (Shay et al., 1950). The protein content of the gastric juice (gastric mucin) was also determined by the biuret reaction.
After the dogs were anesthetized using pentobarbital, they were prepared for an acute series of testing of the effect of serotonin on the volume and acidity of the gastric secretion by inserting and fixing a Levine tube in the stomach and by ligating the pylorus.
In five dogs gastric and duodenal motility and intraluminal water pressures were determined after tubes with attached balloons were passed through a gastrostomy opening into both the stomach and the duodenum. Kymographic recordings were made over periods of several hours. Also,simultaneously, changes in blood pressure and in respiration were recorded.
Results
I . Gastric secretion:
In most experiments the Heidenhain pouch dogs showed a spontaneous fasting secretion of 0.5 to 1.0 ml. per 30 minutes of a clear, viscous fluid which contained practically no free acid, and 0.01 to 0.03 mEq of total acid. Milk stimulated the production of gastric juice. In dogs having the denervated pouch the pattern of response to milk feeding was quite consistent. Secretion lasted about 4 hours with, the peak of secretion being reached in the second half hourafter feeding. After four hours there was a negligible output of secretion.
Following the. subcutaneous administration of histamine, the peak of the gastric secretion was observed in the first half hour, and the output of secretion lasted about two hours. The pattern of response of secretion to the stimulation of milk or of histamine in the Pavlov pouch dogs was quite similar to that seen in the Heidenhain pouch dogs. However the pattern was more uniform in the Heidenhain pouch dogs.
In 15 experiments using Heidenhain dogs and 5 experiments using Pavlov dogs the single subcutaneous injection of 0.5-2.0 mg of serotonin produced little change, or even a decrease, in both the volume and degree of acid output. Furthermore, serotonin greatly inhibited the milk-induced secretion in the Heidenhain pouch dogs. This inhibition was absent when histamine was used to stimulate the gastric secretions in the same animals.
The continuous intravenous administration of serotonin, at levels of 3-10 ug per kg. per minute, wasassociated with a significant increase in the volume of gastric juice aspirated from three dogs which were anesthetized with pentobarbital. The degree of acidity varied only a little. On the contrary to the serotonin effect, histamine given at dose levels of 0.8 to 3 ug per kg. per minute caused a marked increase both in the volume and in the degree of acidity of the gastric juice in these same three animals..
. Gastric mucin secretion:
There was aa significant. increase in the mucin content of gastric juice obtained from the Heidenhain, pouch following a´ single subcutaneous injection of 1.0 mg of serotonin. However, following the administration of 0.2 mg´ histamine or of histamine plus. l:0 mg of serotonin, the mucin content was not relatiyely-~_ increased. There was an increase in the total amount of mucin secondary to the increased total volume of the gastric juice. This increase in the total mucin :.production and in the degree of acid output paralleled the increase in the total gastric secretion -volume secondary to the histamine stimulation.
In the Heidenhain pouch dogs the stimulation of mucin production following the administration of serotonin was strikingly inhibited by the subcutaneous injection of 1.0 mg of LSD, of 20 mg of 2-bromo-dlysergic acid diethylamide (BOL) or of 50 mg of dibenzyline. The subcutaneous . injection of 25 mg of morphine produced a mild inhibition of the serotonin effect of stimulation of mucinn production in the gastric juice. 1.0 mg of atropine or. 10 mg of hexamethonium did not block the increased production of mucin -following serotonin injections. Nevertheless,-dibenzyline, LSD,_ BOL, morphine atropine or hexamethonium alone, did not affect on gastric mucus production.
Gastric ´motility:
The single administration ..of, 0.5. mg of serotonin produced an immediate increase in gastric and duod-, anal- tonus and motility in the anesthetized dogs. The arterial blood pressure also rapidly increased. A period of apnea was followed by a transient hyperpnea. The increased motility, elicited by the serotonin, usually ceased within 10 minutes, and gastrointestinal motility returned to normal.
The effect of several pharmacologic agents in modifying the gastrointestinal response to serotonin was examined. The intravenous administration of 1.0 mg of atropine did not inhibit the serotonin response. Intravenous administration of 10 mg of hexamethonium, or 20 mg of morphine stimulated duodenal motility but had no effect on gastric motility. However, the response of duodenal motility to serotonin was not inhibited by hexamethonium or morphine. A single intravenous injection of 1.0 mg of LSD caused no response in gastroduodenal motility. Further-more, there was no inhibitory action to serotonin induced motility. The intravenous administration of 0.2 mg of histamine did not affect on increased duodenal motility caused by serotonin. However, administration histamine and serotonin, raised arterial blood pressure. (Author´s abstract)
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