Phillip L. Rayford

Secretin, Cholecystokinin and Newer Gastrointestinal Hormones

IN 1902, Bayliss and Starling1 demonstrated that the introduction of hydrochloric acid into a denervated loop of small intestine elicited the brisk secretion of pancreatic juice. The implications o...

Cholecystokinin Metabolism in Man and Dogs

We have developed a sensitive, specific and reproducible radioimmunoassay for cholecystokinin (CCK) with which basal levels of CCK of between 400-800 pg/ml have been measured in normal man, in patients with diabetes and with duodenal ulcer disease, and in normal dogs. After a meal, circulating levels of CCK rose to 1000-1200 pg/ml in human subjects. Release of CCK was more rapid in diabetic and duodenal ulcer patients than in normal subjects, but elevated postprandial levels persisted much longer in normal subjects. Patients with the Zollinger-Ellison syndrome had elevated values of cholecystokinin which rose after a meal. Lack of correlation between elevated basal levels of gastrin and CCK in patients with the Zollinger-Ellison syndrome suggest that the hypercholecystokininemia may be absolute. The disappearance half-time of exogenous CCK was about 21/2 minutes in normal subjects as well as in diabetic and duodenal ulcer patients. Studies in dogs demonstrated no uptake of basal levels of cholecystokinin by the kidney; on infusion of exogenous CCK-33, the kidney extracted 43% of the total CCK presented and 56% of the integrated CCK. We conclude that: 1) circulating basal and postprandial levels of CCK may be measured in a reproducible fashion; 2) postprandial release of CCK is more rapid in diabetic and duodenal ulcer patients than in normal man; 3) the disappearance half-time of exogenous CCK in man and dogs is about 21/2 minutes; 4) the kidney is a major site for uptake of CCK.

Release of Cholecystokinin in Conscious Dogs; Correlation With Simultaneous Measurements of Gallbladder Pressure and Pancreatic Protein Secretion

We have used an antibody that cross-reacts with cholecystokinin-33/39 to measure cholecystokinin release into plasma; this release was correlated with simultaneous measurements of gallbladder pressure and pancreatic protein secretion in response to intestinal administration of fat. Nine conscious dogs were prepared with chronic gastric, pancreatic, and gallbladder fistulas. Plasma cholecystokinin, gallbladder pressure, and pancreatic protein output were measured simultaneously before, and at intervals during, a 2-h intraduodenal infusion of sodium oleate. This infusion resulted in significant (p less than 0.05) elevations of plasma cholecystokinin (from 64 +/- 7 to 181 +/- 27 pg/ml), in gallbladder pressure (from 13 +/- 1 to 27 +/- 3 cmH2O), and in pancreatic protein output (from 65 +/- 7 to 148 +/- 21 mg/15 min); all measurements are from the basal state to 120 min after the onset of duodenal perfusion. Plasma concentrations of cholecystokinin were significantly correlated with gallbladder pressure (r = 0.91, p less than 0.05) and pancreatic protein output (r = 0.84, p less than 0.05). These data provide evidence that release of endogenous cholecystokinin, as measured by radioimmunoassay, can be correlated with the classic biologic actions ascribed to cholecystokinin.

Suppression of gastrin release and gastric secretion by gastric inhibitory polypeptide (GIP) and vasoactive intestinal polypeptide (VIP).

Five dogs prepared with Heidenhain pouches received infusions of saline, GIP and VIP before and after a standard meat meal. Blood samples were obtained under basal conditions and at subsequent intervals for measurement of gastrin, insulin, GIP and VIP by radioimmunoassay. GIP and VIP infusions had no effect on basal levels of gastrin. GIP and VIP (in common with secretin and glucagon) were found to suppress food-stimulated release of gastrin and gastrin-stimulated acid secretion from the Heidenhain pouch. Insulin levels were significantly elevated during GIP and VIP infusions. Food released GIP (and perhaps VIP).

Daily variations in the formation of gastric ulcers caused by cervical cord transection in the rat

Cervical spinal cord transection is used as a model of mammalian stress ulcerogenesis. Circadian variations in gastric ulceration have been demonstrated in other animal models. We investigated whether gastric ulceration changed after cervical cord transection throughout a 24-h period by subjecting different groups of rats to cord transection. Ulcers were quantitated using an index described by Szabo and colleagues. Ulcer formation showed significant variation as a function of time of lesioning, with least severe ulceration at 8 AM. We found that cord transection, like other models of gastric ulceration, is also influenced by the circadian system.

Physiologic Release of Secretin Measured in Peripheral and Portal Venous Blood of Dogs

The effect of food on circulating levels of secretin, measured by radioimmunoassay, was studied in 7 dogs. Significant postprandial increases in secretin were found in portal and peripheral plasma of dogs fasted for 18 h. Basal levels of secretin were significantly lower in dogs fasted for 72 h when compared with dogs after an 18-hour fast. After the prolonged fast, food caused a significant release of secretin, measured peripherally. We conclude that secretin is released by a physiologic stimulus (food) and that circulating levels of secretin are depressed after prolonged starvation.

Removal of Circulating Gastrin and Cholecystokinin into the Lumen of the Small Intestine

This study was undertaken to investigate the mechanism by which the small intestine removes circulating gastrin and cholecystokinin (CCK). A 100-cm (acute study, 10 dogs) or a 50-cm (chronic study, 5 dogs) segment of midjejunum was excluded in all 15 dogs. The excluded loop was perfused with 0.1 M phosphate buffer (pH 7.4), which was constantly recirculated by a peristaltic pump. It the acute control study (5 dogs), gastrin concentrations in the intestinal perfusate were increased gradually to a level of 320 +/- 49 pg/ml at 90 min (i.e., 7.6 +/- 0.9 times higher than serum gastrin levels). In the antrectomy group (5 dogs), perfusate gastrin concentrations were greatly decreased after antrectomy, in consonance with the decrease in serum gastrin concentrations. In the chronic study (5 dogs), perfusate gastrin concentrations were significantly increased after food stimulation, in consonance with the increase in serum gastrin concentrations. CCK was also released into the bowel lumen in considerable amounts basally and after endogenous release. Although one cannot exclude the possibility that a considerable amount of gastrin or CCK in the lumen may originate from the bowel segment, this study shows that the small bowel removes gastrin and CCK from the circulation by their secretion into the bowel lumen. Loss of this mechanism might partially explain the rise in gastrin levels that is observed in some patients after extensive small bowel resections.

Direct effect of bombesin on isolated gastric mucosa

Abstract The stimulatory effect of bombesin on gastric acid secretion has been assumed to be mediated by the release of gastrin. We report here that bombesin also has a direct effect on isolated bullfrog fundic mucosa mounted in Ussing chambers. It stimulates acid secretion and produces a transient increase in electric conductance and in short circuit current.

Restricted feeding schedules alter the circadian rhythms of serum insulin and gastric inhibitory polypeptide

Insulin and gastric inhibitory polypeptide (GIP) have a circadian rhythm of secretion that is altered by various feeding schedules. We acclimated rats over 3 weeks to one of 6 different feeding schedules. They were then killed at intervals over one feeding cycle. Blood was collected, and their stomachs were weighed. Hormones in the serum were measured by radioimmunoassay. When highest and lowest measured concentrations were compared in ad libitum fed rats, insulin more than doubled (445 +/- 50 to 993 +/- 180 pg/ml) and GIP more than tripled (682 +/- 108 to 1964 +/- 145 pg/ml) during a 24-h period. With restricted schedules, concentrations correlated with the feeding schedule, not the light-dark cycle. Hormone levels rose higher during feeding and fell lower with fasting than in ad lib fed rats. For example, GIP in one study fluctuated from 468 +/- 22 to 6433 +/- 432 pg/ml. In another example, insulin ranged from 30 +/- 5 to 2259 +/- 406 pg/ml during a 24-h period. However, insulin did not always correlate well with stomach weight. Circadian rhythms occurred for insulin with all feeding schedules and for GIP with all schedules except fasted rats. This finding implies an endogenous insulin rhythm, whereas food intake controls GIP secretion. Thus, disruption of normal circadian cycles of feeding may yield misleading information about gut hormone secretion.

Release of antral and duodenal gastrin in response to an intestinal meal.

AbstractIn dogs prepared with isolated, innervated antral pouches, intraduodenal perfusion with liver extract at pH 7, with the atrum buffered at pH 7, resulted in a significant release of gastrin selectively from the antrum and from the duodenum. Acidification of the meal to pH 1 abolished both antral and duodenal gastrin release, whereas acidification of the antrum abolished only the antral gastrin response. After antrectomy, liver extract at pH 7 caused a diminished but significant release of duodenal gastrin. These studies provide evidence that an intestinal meal may release (in addition to a specific intestinal phase hormone) gastrin from the intestine, and from antrum, by means of a pH-sensitive mechanism which may involve a humoral agent (enterobombesin?) from the small bowel.