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BLACK, RICHARD M., KENT L. CONOVER, AND HARVEY P. WEINGARTEN. Accelerated gastric emptying in VMH-lesioned rats is secondary to excess weight gain. Am. J. Physiol. 259 (Regulatory Integrative Comp. Physiol 28): R658-R661, 1990.-This experiment evaluates the hypothesis that an accelerated rate of gastric emptying accounts for the hyperphagia and obesity after lesions of the ventromedial hypothalamus (VMH). Gastric emptying was measured for 16 days after the production of VMH lesions in rats maintained either ad libitum or on restricted eating. Only ad libitum VMH-lesioned rats demonstrated faster than normal rates of emptying. However, VMH rats maintained at control weights showed normal rates of gastric emptying and, even in ad libitum rats, accelerated emptying was not apparent immediately after lesions. These findings indicate that changes of emptying are not a primary effect of VMH lesions but that this dysfunction develops secondarily as a consequence of excess eating and weight gain. Measurement of stomach secretions demonstrated, however, that VMH lesions did result in an immediate and direct effect on gastric secretion. These findings mitigate the importance of gastric emptying in the etiology of the VMH syndrome. Other data consistent with this conclusion are reviewed.

Electrical stimulation of the posterior hypothalamus brought about an increase in plasma insulin accompanied by a fall in blood glucose. If glucose fell below 55 mg/100 ml, gastric secretion of HCl ensued. The same relationship between acid secretion and glucose was observed when hypoglycemia was induced by intravenous injection of insulin. Stimulation outside the posterior hypothalamus did not give either a fall in glucose or an increase in gastric acid secretion. It is concluded that posterior hypothalamic stimulation causes gastric acid secretion by inducing insulin release and a consequent hypoglycemia.

Duodenogastric reflux, gastric emptying, and gastric secretion were measured simultaneously by a double-marker technique after instillation of a liquid lipid meal (300 ml Intralipid) or a protein meal (300 ml Bactopeptone) in five trained mongrel dogs. A lipid meal was emptied slower and elicited less volume secretion than a protein meal. Duodenogastric reflux rate and intragastric accumulation of duodenal contents were similar with both meals. Intravenous infusion of atropine slowed gastric emptying and inhibited gastric volume secretion only in the case of protein meal. Atropine increased duodenogastric reflux rate and gastric accumulation of duodenal contents with both protein and lipid meals. The percentage of duodenal contents inside the stomach increased continuously during gastric emptying; it did not exceed 20% with both meals given alone and 40% with both meals given together with atropine. It is concluded that duodenogastric reflux and gastric accumulation of duodenal contents are common phenomena during gastric digestion of a meal. The degree of such accumulation does not depend on the type of meal. Intragastric accumulation of duodenal contents is increased when duodenogastric reflux rate is stimulated and when gastric emptying rate is inhibited simultaneously.

Evidence was obtained showing that in making comparative studies on gastric secretion the glands should be secreting no free acid. In the Heidenhain pouch dogs there was an optimum sized meal for an optimum secretory response during the first hour, more secretion having been obtained with a 300 gm. meal than a 900 gm. meal. The time of the occurrence of the peak of the hourly secretory output was related to the size of the meal in the Heidenhain and the transplanted (Ivy) pouch dog. A definite sigmoid dose-response curve was obtained in the dog with a transplanted pouch. In two Heidenhain pouch dogs a complete sigmoid dose-response curve was not obtained because with a large meal of 900 gm. the voluntary volumetric capacity of the main stomach was reached before the secretory capacity of the pouch was approached. A complete sigmoid curve could be obtained only with a small Heidenhain pouch. In the linear portion of the dose-response curve in both types of pouches doubling the size of the meal roughly doubled the secretory response.

The effect of administration of thyroid products on gastric acid secretion and metabolism was studied in dogs with gastric pouches and in gastric mucosa from rats and frogs. Whole thyroid, thyroxin, triiodothyronine, and iodinated casein generally reduced secretion in thyroidectomized dogs and in dogs with intact thyroids. The thyroid substances elevated BMR above euthyroid levels in normal dogs but not always in thyroidectomized dogs. In dogs with intact thyroids 2,4-dinitrophenol raised oxygen consumption but did not affect secretion. Whole thyroid elevated BMR in rats and frogs but did not change resting mucosal oxygen consumption. During spring and early summer thyroid feeding reduced histamine-stimulated acid secretion and mucosal oxygen consumption during secretion in frogs, but the acid-to-oxygen ratio was unaffected. These findings suggest that elevated tissue concentrations of thyroid hormones reduce the ability of the gastric mucosa to mobilize secretory energy in response to a stimulus. This effect of the thyroid hormones is apparently not directly correlated with their calorigenic properties.

The effect of insulin hypoglycemia on acid output of gastric secretion over 5-hour periods was studied in eighteen patients with duodenal ulcer, five patients before and after vagotomy and two patients before and after bilateral total adrenalectomy. Results of this study show three components of the mechanism of action of insulin hypoglycemia on gastric secretion, an initial inhibitory effect on basal gastric secretion, a stimulating effect mediated through the vagus nerve responsible for the early phase of secretion (1st and 2nd hr.) and. a gastric secretory response mediated through the adrenal glands manifested in the late phase of secretion (3rd–5th hr.). However, the magnitude of this late phase of gastric secretion was considerably less pronounced after vagotomy. It appears that a maximal response of this phase of gastric secretion following insulin hypoglycemia dependent on the adrenal gland is also dependent upon an intact vagal mechanism. A significant hypoglycemia of 40 mg % or less was necessary to produce the late phase of gastric secretion. The adrenal phase can contribute to the potential for ulcer occurrence or reactivation, not so much through the increase in secretion it alone might induce, since this is small, but of greater importance in its synergistic action with the vagal mechanism. Submitted on December 9, 1959

Since the derivatives of histamine metabolism are quite well known, those which have been synthesized were tested for gastric secretory activity in Heidenhain pouch dogs. All were inactive in a single total dose of 20 mg or 1.7 mg/kg. N-acetylhistamine is 1000 times less active than histamine. 1-Methyl-4-(aminoethyl) imidazole, the first derivative produced by the methylation of histamine in the liver, was inactive. Imidazole-4-acetaldehyde, the first derivative of the oxidative deamination of histamine has not been synthesized, but the next derivative, imidazole-4-acetic acid, was inactive. Among the five histamine diamine oxidase inhibitors studied in relation to gastric secretion to date, aminoguanidine is the most ideal. It has the additional advantage of not inhibiting histidine decarboxylase.

Nineteen sham-feeding tests were performed on eleven rats with a chronic gastric and esophageal fistula. As compared with man and the dog, a slight increase in acid output occurred in 17 tests, the increase being quite definite in 13 tests. Sham feeding had no effect on gastric secretion in 16 tests on rats when performed from 1 to 14 days after bilateral vagotomy. The vagotomy had a profound depressing effect on the interdigestive secretion, no free acid being found in the fasting secretion in any of the rats during the period of these tests. The vagi exert a marked secretory tone on the gastric glands, but the conditioned secretion of gastric juice is probably not of much physiological significance in the rats studied in these tests.

Gastric secretion in response to graded doses of histamine was obtained from the whole stomach in five trained dogs, and the animals were sacrificed to determine the total number of parietal cells in the stomach. Histamine was administered by single s.c. injection (Hsc) and continuous i.v. infusion (Hiv). Maximal histamine response (MHR) was determined, and studies permitting the construction of dose-response curves were carried out in three of the five dogs. Dose-response curves for acidity and for acid output and volume during the entire duration of secretory response to Hsc were also established. The MHR was found to be a linear function of both the total number of parietal cells ( P < .01) and the fundic mucosal volume ( P < .05). The magnitude of the MHR and the PCM in the five dogs was within the respective ranges reported in man, but the mean MHR per billion cells (9.8 ± 0.44 mEq/30 min.) and the mean MHR per 100 cc fundic mucosal volume (58.2 ± 5.12 mEq/30 min.) were both about 30% less than the respective ratios in man.

In dogs prepared with both a vagus denervated Heidenhain pouch and a total pancreatic fistula, the intravenous injection of pancreatic secretin (Lilly) produced a profuse secretion of pancreatic juice and a simultaneous marked inhibition of gastric secretion. In dogs prepared with an isolated antrum pouch and a Heidenhain pouch the gastric secretion induced by the instillation of food in the antrum pouch was completely inhibited by the intravenous injection of pancreatic secretin. On the other hand, the intravenous injection of pancreatic secretin had little or no effect on the secretion of gastric juice produced by insulin hypoglycemia or by the injection of histamine. It is suggested that pancreatic secretin may represent the mechanism by means of which acid food in the duodenum inhibits gastric secretion. It is probable that this inhibition is caused by prevention of gastrin release from the antrum rather than to a depressant effect on the parietal cells.

Four dogs with Thomas gastric pouches and one dog with a Heidenhain pouch were stimulated to secrete gastric juice by feeding 100 gm of lean beef. Feeding whole desiccated thyroid ordinarily caused a significant fall in volume of gastric juice and in the total quantity of HCl secreted. Crystalline thyroxine yielded erratic results and one trial with triiodothyronine produced a significant increase in gastric secretion. Thyroidectomy in one dog resulted in a gradual decline in secretion, but hypothyroidism produced by administration of mercaptoimidazole in another animal lead to a significant increase in secretion.

This study was done to determine whether, after a meat meal, the outputs of acid in gastric juice and free histamine in urine are related and whether the output of free urinary histamine is increased after transplantation of the gastric antrum to the colon. Dogs with separated gastric pouches (Heidenhain) were used. Gastric juice and urine were collected at hourly intervals before and after the ingestion of the meal and for 24-hour periods before and after transplantation of the gastric antrum to the colon. Similar collections were made when histamine was injected intravenously at different rates. A rough temporal correlation was found between the outputs of HCl in gastric juice and free histamine in the urine after the meal of meat. There was not a significant increase in the 24-hour output of free histamine in the urine of the dogs in which a modest hypersecretion developed following transplantation of the gastric antrum to the colon.

The present investigation is an attempt to confirm and amplify in vivo the observation of Davenport that HCl secretion by mouse stomachs in vitro is blocked ‘nearly to zero’ by the irreversible enzyme inhibitors iodo acetamide (IAA) and N-ethyl maleimide (NEM). Aqueous solutions of the inhibitor, in various concentrations, were applied topically to canine Heidenhain pouches for a half-hour. In each such experiment, secretory capacity was measured directly before and after such treatment in terms of the output of free HCl ( Qhcl, expressed as mEq/2 hr.) following subcutaneous injection of histamine (0.1 mg/kg). In 13 such experiments, the posttreatment Qhcl was zero for at least 4 hours, thus demonstrating inhibition of acid formation in the living pouch dog. Contrary to the results in vitro, secretory response to histamine was complete; also, it recovered markedly within 24 hours, and probably completely within 48 hours following withdrawal of the inhibitor. In these experiments, and also in others in which histamine administration was withheld following application of the inhibitor to the mucosa, there was formed a nonacid viscous fluid (ph above 7.0) which contains hexosamine, other reducing substances, and much protein, and which has a variable buffering power. This material is suspected of being a mixture of gastric mucus, the still hypothetical ‘mucoid secretion’ and serous transudate formed in response to mucosal initiation.

An isotonic solution containing 55 mEq/liter hydrogen, 100 mEq/liter sodium, and 155 mEq/liter chloride was instilled into pylorus- and cardia-ligated stomachs of intact and vagotomized anesthetized rats for 2-hr periods. Two patterns of change were observed in the solution. In all vagotomized rats and some intact animals, there was a modest increase in volume with reduction in acidity, decrease in chloride concentration and osmolality, rise in sodium concentration, and increase in potassium concentration. In some animals with intact vagi there was a larger increase in volume, an increase in acidity, rise in chloride concentration and osmolality, fall in sodium concentration, and increase in potassium concentration. Changes are compared with those previously observed in human stomachs and differences interpreted in terms of possible persistent vagal activity in the rat. Appreciable volumes of fluid were added to the gastric contents. Net gain of sodium greatly exceeded net loss of hydrogen during most periods. Both dilution-neutralization and diffusion mechanisms may operate when there is reduction in acidity of instilled acid solutions.

Previous work indicated that K concentration ([K]) of gastric juice rises abruptly after histamine injection, concomitantly with acid efflux. Using Heidenhain and vagal pouch dogs, these experiments (26 in all) were repeated with mecholyl and histamine. The concentration-time curves for K were similar for both stimuli with early rise in [K], its late fall below preinjection level, and eventual recovery. The initial rise tended to be smaller and occurred less often with mecholyl. Its occurrence after histamine was also inconsistent. [K] was poorly correlated with both acidity and volume-rate. Time curves for K output likewise were similar with both stimuli, but correlation with acid output was high. Exogenous histamine is not essential to this K efflux, which may represent a basic process associated with glandular, neural, or muscular stimulation in general.