David D. Reeder

Dynamic Characteristics of Gastrin Release

Abstract Much of the current knowledge regarding the characteristics of mechanisms responsible for the release of endogenous gastrin has come from studies in dogs with isolated gastric pouches. By direct measurement of gastrin rising solely from the antum, our study delineates many phenomena that have been previously accepted on indirect evidence. We have found that: 1. 1. Acetylcholine, instilled into the isolated antral pouch, effects an immediate release of gastrin into the antral vein which is accompanied by fundic acid secretion. 2. 2. Subsequent acidification of the antrum suppresses the secretion of both gastrin and acid to basal levels. 3. 3. Acidification of acetylcholine only partially blocks its stimulatory effect on gastrin release. 4. 4. Acidification of the resting antrum decreases the secretion of background gastrin. 5. 5. In the absence of acid suppression, brief stimulation of the antrum produces an immediate elevation of the concentration of antral venous gastrin which persists for at least eight hours.

Inhibition of gastrin release and gastric secretion by calcitonin in patients with peptic ulcer

Abstract We studied the effect of an intravenous infusion of calcitonin (2 MRCU/kg) on gastric secretion and serum gastrin and serum calcium levels in eight normal subjects, six patients with duodenal ulcer disease, three patients with primary hyperparathyroidism, six patients with histologically proved Zollinger-Ellison syndrome, and three patients with the Zollinger-Ellison syndrome and hyperparathyroidism. Gastric secretion was greatly inhibited in all groups of patients. Serum calcium was significantly diminished only in patients with hypercalcemia. Serum gastrin levels were depressed in all patients with elevated basal gastrin levels (DU, HPT, Z-E, and ZE + HPT). In normal subjects calcitonin inhibited strongly the serum gastrin response to food. These findings suggest that calcitonin may have a regulatory function in the release or catabolism of the hormone gastrin.

Gastrin release by ethanol in man and in dogs.

In man, oral or intravenous administration of ethanol caused a small but definite increase in peripheral serum gastrin concentration (measured by radioimmunoassay). In dogs, perfusion of the antrum with 10% ethanol caused an immediate increase in gastrin levels in the antral venous outflow. Acidification of the perfusate did not totally block the gastrin release from the antrum. Intravenous infusion of ethanol in dogs caused release of gastrin from the antrum.

Clinical role of serum gastrin measurements in the Zollinger-Ellison syndrome

Abstract Radioimmunoassay technics provide an opportunity for making serial measurements of serum gastrin concentrations in patients with the Zollinger-Ellison syndrome. The usefulness and limitations of these measurements are discussed in case presentations of three patients with variations of the syndrome. In the first case, early definitive diagnosis was possible in an elderly woman who presented with symptoms of diarrhea only. The second patient presented with duodenal ulcer, massive hepatic tumor, and previous obstruction of the common duct by extrinsic tumor in the region of the head of the pancreas. Measurements of serum gastrin allowed a definitive preoperative diagnosis of the Zollinger-Ellison syndrome to be made, and total gastrectomy was performed in hopeful expectancy of long survival despite metastatic disease. The third patient presented with a previous parathyroid adenoma and duodenal ulcer and a family history of multiple endocrine adenomas. Measurements of serum gastrin afforded an early diagnosis, and total gastrectomy was performed, even though the only tumor found was a small, easily resectable pancreatic nodule. Postoperative elevation of the serum gastrin levels suggests that the tumor was multiple or metastatic. Serum gastrin measurements may be critical in deciding on the management of patients with atypical manifestations of the Zollinger-Ellison syndrome and in patients with metastatic hepatic tumors. Hypergastrinemia per se does not seem to cause symptoms in patients after total gastrectomy. At present, we do not know the prognostic value of serum gastrin measurements in postoperative patients. In patients in whom there is no possibility of excluded antral mucosa, the coexistence of hypersecretion of gastric acid and elevated levels of serum gastrin (either basal levels or those in response to the infusion of calcium) is diagnostic of the Zollinger-Ellison syndrome.

The Effect of Changes in Antral pH on the Basal Release of Gastrin

Summary Gastrin concentrations in the blood draining the gastric antrum were measured by radioimmunoassay during changes in the antral pH. Neutralization of the antrum (raising the basal ambient pH of 3.5-5 to 7 or 8) resulted in a significant increase of antral venous gastrin concentration. Acidification of the antrum significantly lowered, but did not abolish, the basal release of gastrin. These studies demonstrated, by direct measurement of gastrin, the presence of a very sensitive feedback mechanism between antral pH and gastrin release, and that gastrin may be released by simply raising the basal antral pH to 7.

Effect of nephrectomy on the rate and pattern of the disappearance of exogenous gastrin in dogs

Studies of gastrin metabolism were performed in four dogs before and after nephrectomy. Synthetic human gastrin I was infused for two hours and serum samples were obtained at various times during and after infusion. Serum concentrations of gastrin were measured by radioimmunoassay. A two-compartment model was employed to calculate half-lives under each of four experimental conditions, low and high infusion rates, used both before and after nephrectomy. The model half-life was greatly prolonged after nephrectomy at both infusion rates (from 2·54 min to 5·15 min at the low rate, and from 2·85 min to 7·88 min at the high rate). The metabolic clearance rate, an expression of the rate of catabolism during infusion, decreased significantly after nephrectomy at both infusion rates. These observations indicate that the kidney is an important organ for the catabolism of exogenous gastrin.

Depletion of antral gastrin after food in rats.

The results of these studies indicate that in fasting rats, there is an abrupt and prolonged rise in circulating gastrin after feeding. This increase in serum gastrin is accompanied by an early (five minutes) diminution in antral gastrin which is followed by slightly higher and more variable antral gastrin values. These findings suggest that feeding triggers the release of gastrin with early depletion of antral gastrin and that, subsequently, gastrin syhthesis and release interact cyclically to maintain antral and serum concentrations of gastrin. Antral, fundic, and duodenal gastrin values in rats are similar to those reported in dogs and cats. The jejunum of the rat contains little, if any, gastrin.

Extraction of circulating endogenous gastrin by the gastric fundus

The effect of circulatory transit of the gastric fundus on serum levels of endogenous gastrin measured directly by radioimmunoassay has been studied in 14 dogs. Gastrin was measured in samples obtained simultaneously from the arterial inflow and venous outflow of the gastric fundus. During basal conditions, transit of the gastric fundus resulted in no change in gastrin concentration. During periods of stimulated gastrin release from the antrum, nine of the 14 dogs demonstrated a significant gastric acid secretory response. In these dogs there was a significant arteriovenous difference (approximately 30%) in circulating gastrin values. In the remaining five dogs, which did not demonstrate a significant gastric acid secretory response, there was no arteriovenous difference in circulating gastrin values. It is concluded that the gastric fundus is an important site for the inactivation of stimulated levels of circulating gastrin.

Effect of antrectomy and subsequent vagotomy on the serum gastrin response to food in dogs.

The effect of food on serum gastrin and gastric acid secretion has been studied in dogs with denervated pouches before and after antrectomy and subsequent vagotomy. A Billroth I anastomosis was used in one group of dogs and a Billroth II in the other. Serum gastrin was measured by radioimmunoassay. In both groups of dogs antrectomy significantly depressed mean basal levels of serum gastrin and abolished the rise in serum gastrin in response to a meat meal. Meal-induced pouch acid secretion was considerably lowered by antrectomy after either Billroth I or Billroth II anastomosis. Vagotomy after antrectomy increased basal levels of gastrin, but did not restore the serum gastrin response to a meat meal in either group of dogs. It is suggested that biologically active forms of gastrin are released from the antrum in response to a meal. Biologically inactive basal levels of gastrin apparently originate from extra-antral sources. The post-vagotomy increase in basal (static) gastrin suggests vagal control of the metabolism of static, extra-antral gastrin.

Suppression of gastric secretion and serum gastrin by gastrin antibody

Fourteen dogs received varying doses of antigastrin antibody; after a single dose of 0.07 ml/kg, circulating gastrin levels could not be measured for as long as forty-seven days. Gastric secretion in response to food was not diminished by antigastrin antibody doses as high as 0.07 ml/kg daily for ten days. Larger doses, 0.2 and 0.4 ml/kg, were required to produce a temporary reduction in gastric-stimulated gastric acid secretion. Mucosal levels of gastrin in the antrum, fundus, and duodenum were greatly increased ten days after injection of antigastrin antibody. The therapeutic use of antigastrin antibody to control gastric secretion seems at the present time not feasible because of the scarcity of the antigastrin antibody and because large doses aare required to obtain only a temporary effect.