Morton I. Grossman

INHIBITION OF GASTRIC EMPTYING IS A PHYSIOLOGICAL ACTION OF CHOLECYSTOKININ

This study was designed to determine whether cholecystokinin (CCK) plays a physiological role in the inhibition of gastric emptying. Physiological conditions were simulated by giving CCK by continuous intravenous infusion rather than by bolus injection, by using doses known to be distinctly submaximal for pancreatic protein secretion, and for gallbladder contraction, and by releasing endogenous CCK. The rate of gastric emptying was determined in 4 dogs with gastric fistulas by measuring the volume of fluid remaining in the stomach 10 min after instillation of 300 ml of 0.15 M NaCl. Rate of emptying was studied during intravenous infusion of saline (control) and of different doses of 98% pure CCK, commerically available 20% pure CCK, synthetic COOH-terminal octapeptide of CCK (OP-CCK), pentagastrin, and heptadecapeptide gastrin. The effect of endogenously released CCK was studied by measuring the rate of emptying of solutions in which different concentrations of tryptophan replaced equiosmolar amounts of NaCl. The d50s of 20% pure CCK (3 U kg minus-1 hr minus-1) and of OP-CCK (125 ng kg minus-1 hr minus-1) for inhibition of gastric emptying were about the same as their D50s for cholecystokinetic and pancreozyminic actions. By contrast, although both pentagastrin and heptadecapeptide gastrin inhibited gastric emptying, the doses required for this action were much higher than the D50s required for stimulation of gastric acid secretion. The effectiveness of OP-CCK indicates that inhibition of gastric emptying is attributable to CCK itself and not to an impurity in the CCK preparation. We have confirmed this directly by showing that pure CCK is a potent inhibitor of gastric emptying. Tryptophan also inhibited gastric emptying. In other dogs pancreatic protein secretion and gallbladder contraction were shown to be stimulated during the time tryptophan was inhibiting gastric emptying. This evidence supports the view that inhibition of gastric emptying is one of the physiological actions of CCK, but in the case of gastrin it must be regarded as a pharmacological action.

Inhibition of Acid Secretion in Dog by Metiamide, A Histamine Antagonist Acting on H2 Receptors

In dogs with Heidenhain pouches and gastric fistulae of the main stomach, metiamide, a histamine antagonist of the H2-blocking variety, in a dose of 12 µmoles kg-1 intravenously, inhibited gastric acid secretion during stimulation by histamine, pentagastrin, 2-deoxyglucose, and food (liver extract). Atropine sulfate (0.14 µmole kg-1 intravenously) also inhibited the response to all of these stimulants except histamine. To account for these findings, we speculate that the receptors on the parietal cell for histamine, gastrin, and acetylcholine interact.

Unusual Effect of Secretin on Serum Gastrin, Serum Calcium, and Gastric acid Secretion in a Patient with Suspected Zollinger-Ellison Syndrome

Previous studies in normal man demonstrated that secretin inhibits pentagastrin-stimulated gastric acid secretion. This report describes a patient with suspected Zollinger-Ellison syndrome (i.e., elevated serum gastrin and hypersecretion of gastric acid) in whom secretin produced significant increases in serum calcium and gastrin, and in gastric acid secretion. The mechanism of this effect is unknown.

Increased sensitivity to stimulation of acid secretion by pentagastrin in duodenal ulcer.

The effect of graded doses of pentagastrin (2.7-6,000 ng/kg times h) on gastric acid secretion was measured in 20 duodenal ulcer (DU) and 20 non-DU subjects. Confirming many previous studies, the mean observed highest response and the mean calculated maximal response were significantly greater in DU than in non-DU subjects. The mean dose (plus or minus SE) in ng/kg times h for half maximal response, calculated from responses corrected for basal secretion and normalized for maximal secretion, was 92.1 plus or minus 1.7 in DU and 246.8 plus or minus 24.6 in non-DU subjects, a significant difference. By parallel line bioassay non-DU subjects required 2.8 times more pentagastrin (95% confidence limits 2.1-3.7) than DU highest response. Thus, this study shows that, compared with non-DU subjects, DU patients not only secrete more acid in response to stimulation by pentagastrin but also are more sensitive to stimulation by pentagastrin, that is, need smaller doses to achieve the same fraction of maximal response.

Pancreatic Polypeptide Metabolism and Effect on Pancreatic Secretion in Dogs

In dogs with gastric and pancreatic fistulas, porcine pancreatic polypeptide (PP) was infused intravenously in doses of 50, 100, 200, 400, and 800 pmol kg-1 hr-1 in the basal state and in doses of 100, 200, and 400 pmol kg-1 hr-1 during stimulation with submaximal doses of secretin (125 ng kg-1 hr-1) plus caerulein (50 ng kg-1 hr-1). Plasma concentrations of PP were measured by radioimmunoassay, and pancreatic bicarbonate and protein outputs were monitored. The half-time for disappearance of PP was 5.5 +/- 1.0 min, the metabolic clearance rate was 25.6 +/- 1.0 ml kg-1, and the volume of distribution was 209 +/- 42 ml kg-1. Basal pancreatic flow and protein output were significantly inhibited by the lowest dose of PP tested, 50 pmol kg-1 hr-1. The lowest dose of PP significantly inhibiting stimulated pancreatic secretion was 100 pmol kg-1 hr-1 for bicarbonate output and 200 pmol kg-1 hr-1 for protein output. The mean +/- SE peak increment in PP concentration in response to a meal of meat, 210 +/- 39 pM, was greater than the mean peak increment with the 400 pmol kg-1 hr-1 dose of exogenous PP, 175 +/- 19 PM. We conclude that exogenous doses of PP that produce smaller increments in PP concentration than those seen after feeding inhibit pancreatic bicarbonate and protein secretion stimulated by secretin and caerulein. This suggests that the amount of PP released by a meal is sufficient to inhibit pancreatic secretion.

Gastric Acid Secretion is Abnormally Sensitive to Endogenous Gastrin Released after Peptone Test Meals in Duodenal Ulcer Patients

We studied 25 duodenal ulcer patients and 14 age- and sex-matched normal controls to determine whether gastric acid secretion in duodenal ulcer patients is abnormally sensitive to stimulation by gastrin endogenously released in response to meals. Acid response to saline and to 0.5, 1.0, 2.0, 4.0, and 8.0% peptone infused into the stomach was measured by 30 min intragastric titration. Total serum gastrin (G-total) and serum heptadecapeptide gastrin (G17), fasting and 30 min after each test meal, were measured by specific radioimmunoassays. In 19 ulcer patients and 11 normal subjects (controls), acid response to graded doses (11, 33, 100, and 300 pmol kg(-1) h(-1)) of G17-I were also measured. Mean acid output in response to each dose of peptone was significantly higher in duodenal ulcer patients than in the controls. Gastrin levels in ulcer patients and controls were not significantly different. Within individual patients and controls, both G-total and G17 were significantly correlated with meal-stimulated acid output regardless of whether the absolute, basal-corrected, or distention-corrected values for acid output were examined (median r ranged from 0.82 to 0.94, P < 0.001). From the individual regression lines, the gastrin concentrations corresponding to half of the highest observed meal-stimulated acid response (D(50m)) were calculated. Mean D(50m) for G-total and G17 were significantly lower in duodenal ulcer patients than in controls both in the overall group and in pairs of ulcer patients and controls matched on the basis of highest observed meal-stimulated acid responses, or on the basis of maximal acid output in response to synthetic human G17. The dose of exogenously administered G17 required for half maximal G17 acid response mean D(50g), was significantly less in patients than in control subjects. In both ulcer and control subjects, D(50g) correlated significantly with D(50m). This and the significant correlation between meal-stimulated G17 and acid response strongly suggest that the endogenously released gastrin was responsible for most, if not all, of the postpeptone acid output.We conclude that after peptone test meals, gastric acid secretion in duodenal ulcer patients was abnormally sensitive to stimulation by endogenously released gastrin.

Proof of a Pyloro-Oxyntic Reflex for Stimulation of Acid Secretion

In 7 dogs with innervated antral pouch, gastric fistula, and Heidenhain pouch, acid secretion and serum gastrin (radioimmunoassay) were measured in response to distention of the antral pouch with 0.1 m NaHCO 3 or 0.1 m HCl at 0-, 10-, 20-, 30-, and 40-cm pressure. Distention with 0.1 ivt NaHCO 3 caused graded increases in serum gastrin and in acid output from both the gastric fistula and Heidenhain pouch. Acidification of the antral pouch abolished gastrin release and acid secretion from the Heidenhain pouch in response to distention, but did not abolish acid secretion from the gastric fistula. These results indicated that antral distention causes acid secretion by at least two mechanisms, only one of which is gastrin-dependent. Proof that the gastrin-independent mechanism is a pyloro-oxyntic reflex was obtained by showing that vagal denervation of the antral pouch completely abolished the response of the gastric fistula to distention of the antral pouch with acid. In addition to abolishing the pyloro-oxyntic reflex, antral vagal denervation also had these effects: (a) decreased the increment in serum gastrin caused by alkaline antral distention, and (b) increased the amount of acid secreted in response to any given increment in serum gastrin.

Role of Food in Gastrointestinal Ulceration Produced by Indomethacin in the Rat

This study was undertaken to determine the role of food in indomethacin-induced gastrointestinal lesions. Following a 24- or 48- fast, rats were given various amounts of rat Chow pellets or various types of diets (high-bulk non-nutritive diet, equicaloric liquid diet, or liquid diet containing cellulose) for 1 h. One half hour after the feeding, 30 mg/kg of indomethacin was administered subcutaneously, and 6 h later the animals were killed and gastrointestinal lesions measured. In the fasted rat, indomethacin produced lesions predominantly in the gastric corpus. In the rat that was fed Chow pellets, indomethacin produced lesions in both the gastric antrum and small intestine. By increasing food intake, the corpus lesions decreased while antral and intestinal lesions increased. In the rat that was fed cellulose or sawdust pellets, indomethacin produced lesions in all three areas. In contrast, indomethacin did not produce any lesions in the liquid diet group. However, when cellulose was added to the liquid diet, indomethacin produced lesions in both the antrum and small intestine, the lesions increasing in proportion to increasing concentrations of cellulose. It is concluded that in indomethacin-induced gastrointestinal lesions: (a) the nutritional component of food prevents the formation of corpus lesions, and (b) the solid component of food, whether nutritive or not, plays an essential role in the formation of antral and intestinal lesions.

Effect of gastric inhibitory polypeptide on pentagastrin-stimulated acid secretion in man

Eight male subjects were given pentagastrin by intravenous infusion in doses of 25, 74, 222, 667, and 2000 ng/kg/hr, each dose for 30 min. On another day the same subjects were given the same doses of pentagastrin while gastric inhibitory polypeptide (GIP) was being infused intravenously in a dose of 2 μg/kg/hr. At the 222 ng/kg/hr dose of pentagastrin, acid output was significantly lower with GIP; at all other doses of pentagastrin, acid output did not differ significantly in tests with and without GIP. Pepsin output in the tests with and without GIP did not differ significantly at any dose of pentagastrin. Plasma concentration of GIP, measured by radioimmunoassay, showed a mean±SE plateau level of 7.4±1.4 ng/ml during GIP infusion and 0.4±0.1 ng/ml peak level after a standard meal. We conclude that the increase in blood concentration of GIP produced by feeding is probably inadequate to cause significant inhibition of gastric acid or pepsin secretion in man.

Effect of Secretin on Acid and Pepsin Secretion in Cat and Dog

Secretin in doses which produced a maximal inhibition of gastric secretion in the dog and maximal stimulation of pancreatic secretion in the cat had no effect on gastrin-stimulated gastric secretion in the cat. Irrigation of the duodenum with acid produced a much smaller inhibition of gastrin-stimulated gastric secretion in the cat than in the dog, thus suggesting that endogenous secretin is not so important for the control of acid secretion in the cat as in the dog. We conclude that the disparity between the action of secretin on gastric secretion in the cat and dog represents a true species difference. Identical doses (on a body weight basis) of secretin, however, produced strong stimulation of pepsin secretion in both the cat and dog. Stimulation was produced by continuous intravenous infusions of secretin in doses submaximal for pancreatic secretion. In addition the effect of natural secretin was reproduced exactly by the synthetic hormone, indicating that the stimulation of pepsin secretion is a property of the secretin molecule. Endogenous secretin, released by either exogenous acid in the duodenum or by closing the gastric fistula, reproduced the effect of the exogenous secretin or pepsin secretion. We conclude, therefore, that the stimulation of pepsin secretion is a physiological action of secretin.