Pyloric antral inhibition of gastrin release.

Inconsistencies and omissions in current explanations for the well known depressions of gastric acid secretion and blood gastrin levels following acidification by antral stimulants are discussed. Evidence is presented which favors a reciprocal sensitivity relationship between the fundic mucosa and the antral G cells, such that blood gastrin levels rise when the secreting fundic mucosa is compromised and acid secretion in response to exogenous gastrin is increased when G cells are depressed or reduced. The functional connections between the two phenomena are considered to be nervous.

Isolation and structural characterization of a molecular variant of dog pancreatic secretory trypsin inhibitor.

A rapid two-step method has been developed for the purification of pancreatic secretory trypsin inhibitor (PSTI) from pancreatic juice obtained from dogs, stimulated with secretin and the octapeptide of cholecystokinin. The PSTI was isolated in two biologically active molecular forms. Determination of amino acid compositions and NH2-terminal amino acid sequences demonstrated that the major form represented the intact 57-amino-acid residue peptide, and the minor form (comprising 5-10% of the total activity) represented des[Asn1 Asn2 Met3] PSTI. The metabolite arises from cleavage of a Met-Leu bond, and its formation may be a consequence of incomplete inhibition of chymotrypsinogen activation in the juice.

Cholecystokinin and cholinergic agents on periodic gallbladder contraction in dogs.

1. The effect of cholecystokinin octapeptide (CCK-OP), methacholine, 2-deoxy-D-glucose (2DG) and gastric distension on gallbladder contraction in relation to interdigestive activity was studied in four conscious dogs with chronic biliary fistulae. 2. The gallbladder contraction in response to CCK-OP was inhibited by atropine and by a ganglionic blocking agent, the characteristics suggesting competitive inhibition. 3. Spontaneous contraction of the gallbladder was still observed after the administration of CCK-OP, methacholine or 2DG. With ganglionic blockade, CCK(-)-OP or methacholine initiated gallbladder contraction, but the spontaneous peak was no longer observed. 4. CCK-OP (100 ng kg-1), methacholine or 2DG advanced the spontaneous contraction of the gallbladder, but did not alter the duration of the cycle. 5. Gastric distension initiated gallbladder contraction. This was abolished by ganglionic blockade. The contraction did not continue in spite of continuous gastric distension, and the spontaneous contraction reappeared 100 min following the pre-distension control.

Novel C-terminal gastrin antagonists. Synthesis and biological activity.

The C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH2, is a full agonist of gastrin, but des-Phe analogues, including Boc-Trp-Met-Asp-NH2, are antagonists. To ascertain the minimum structural requirement for an antagonist, we used conventional solution phase methodology to synthesize analogues with further modifications including removal of the alpha-amino group of Trp, conversion of the indole to a phenyl ring, and methylation of amide bonds. These analogues were tested for their effect on pentagastrin-stimulated acid release in dogs surgically prepared with a gastric fistula. When infused intravenously at a dose of 20 pmol kg-1 h-1, the peptides significantly inhibited acid secretion. The extent of inhibition ranged from 12% to 60%. Thus, tripeptide analogues based on the C-terminal sequence of gastrin act as potent and specific antagonists of gastrin-stimulated acid secretion.

Isoprenaline and the pancreas in dogs.

1. In conscious dogs basal pancreatic secretion per 100 min was significantly reduced by 0.75 microgram kg-1h-1 of isoprenaline. The expected spontaneous peaking was seen only after stopping the drug. 2. Following propranolol, the 100-min pancreatic secretion was less than control but greater than secretion after isoprenaline. The interpeak interval was increased, and the perigee levels (interpeak) were higher than in the controls. Peak protein secretion was unaltered but volume was reduced. 3. Guanethidine did not abolish periodicity but it prolonged the interpeak interval. Protein peaks and 100-min totals were lower than control and volume perigees higher. 4. It is concluded that beta-adrenoreceptor stimulation inhibits pancreatic secretion. Adrenergic antagonists exert similar inhibitory effects indicating a complex role for the sympathetic nervous system in the control of pancreatic secretion.

The role of sympathetic innervation and sympathomimetics in gastric secretion in vivo.

It can, I believe, be argued in summary that pentagastrin-stimulated acid and pepsin secretion from innervated or denervated fundic mucosa is inhibited by doses of epinephrine and isoproterenol that produce an unequivocal cardiac stimulation, but this cannot be said of either histamine-, bethanechol-, or methacholine-, or food-stimulated secretion. There is substantial old evidence that epinephrine and isoproterenol, in doses that depress the pentagastrin effect, actually augment that of histamine and cholinomimetics. Large doses, of course, inhibit unequivocally. Sympathectomy, chemical or surgical, seems to increase the responsiveness of the fundus to acid stimuli, but again there is little uniformity; both less acid following feeding, after sympathectomy, and more following propranolol have been reported. It would be rash to draw any conclusions from the action of either sympathetic stimulation or ablation. The evidence that beta-adrenergic blocking agents can prevent insulin-stimulated increases in gastrin is fairly good, but the evidence that these agents have any effect on food-stimulated gastrin levels (whether the food is a meal or sham) is not good. Almost every aspect of this subject remains confused and confusing. At the end of a paper such as this, most readers would expect conclusions, but any conclusions other than those given above would be invention or else bias. This subject, at present unfashionable for research, represents a black hole in our knowledge.(ABSTRACT TRUNCATED AT 250 WORDS)

The action of a beta-adrenoreceptor agonist on gastric acid secretion in dogs.

1. In conscious dogs with gastric fistulae and Heidenhain pouches, isoprenaline (0.75 microgram kg-1 h-1) brought about an increase in methacholine stimulated gastric acid and pepsin secretion from the innervated mucosa. 2. The increase in acid consisted for the most part of the replacement of the usual post-peak fade by a sustained plateau and of the replacement of the usual wait for the spontaneous peak by immediate stimulation of secretion.

A comparative study of gastric secretory stimulants in conscious dogs.

1. In conscious dogs with gastric fistulae, Heidenhain pouches and Thomas duodenal fistulae, pentagastrin was found to be a more potent peak acid and pepsin stimulant in both innervated stomach and vagally denervated pouch than methacholine chloride. 2. Slopes of curves relating response to the logs of molar doses of pentagastrin and methacholine, at peak secretion, did not differ significantly. The maximal pentagastrin stimulated secretion from the pouch was smaller than that for methacholine; from the fistula they did not differ. 3. Ganglionic blockade depressed methacholine stimulated peak acid secretion, but did not affect pentagastrin stimulated acid secretion. Dose-response curves for methacholine-induced acid and pepsin secretion at the perigee did not differ from those obtained with ganglionic blockade. 4. Ganglionic blockade depressed pepsin secretion from the fistula whether stimulated with pentagastrin or methacholine. Pouch pepsin secretion was small and no difference between curves was seen.

Action of amino acids on stomach, pancreas, and gallbladder in dogs.

An intravenous infusion of a 3% solution of amino acids was given to 8 dogs, all with Heidenhain pouches and gastric fistulae. Four of these had duodenal cannulae opposite the pancreatic and 4 opposite the biliary ampulla. The usual basal 100 min spontaneous peaking of pancreatic juice volume and protein secretion was seen but peaks were abolished by the amino acid infusion and troughs were slightly elevated, but the total 90 min volume protein and bicarbonate outputs were not different from control. Gastric acid and pepsin secretions were augmented reaching a peak during the first hour with a subsequent decline. The 90 min acid and pepsin output was significantly higher than control. The gallbladder contracted during the first hour and remained thus until the infusion was terminated. This happened even when the duodenum was kept alkaline, but was abolished by ganglionic blockade. During intravenous amino acid infusion the patterns of gallbladder activity and pancreatic secretion resembled those of the post cibal rather than fasting state.

The relationship between blood gastrin levels and gastric secretion in conscious dogs.

1. In conscious dogs with gastric fistulae and Heidenhain pouches, acid and pepsin secretion, immunoreactive plasma pancreatic polypeptide (PP) and gastrin were measured following intravenously administered pentagastrin, cholinomimetics, and intragastric administration of milk. 2. Pentagastrin did not raise endogenous plasma gastrin. There was a significant positive dose-response relationship between pentagastrin and acid and fistula pepsin secretions, but not between plasma gastrin of endogenous origin and gastric secretion. 3. Carbachol raised plasma gastrin immunoreactivity; but in no instance was there a significant relationship between gastric secretion and plasma gastrin immunoreactivity. Gastric acid secretion faded, but plasma gastrin concentrations did not. 4. PP plasma immunoreactivity was elevated by methacholine and carbachol. Its levels correlated significantly with gastric acid secretion. Pentagastrin did not raise PP and its levels did not, therefore, correlate with gastric acid secretion. 5. Intragastric milk raised plasma gastrin immunoreactivity, but the acid secretion per pg of plasma gastrin was much smaller than with the cholinomimetics. Ganglionic blocking agents depressed both plasma gastrin and acid and pepsin secretion. 6. The results suggest that cholinomimetics sensitize parietal cells to the stimulating action of gastrin.

The effect of cholecystokinin-related peptides on periodic pancreatic secretion in fasting dogs.

1. The effect of cholecystokinin octapeptide (CCK-8) and pentagastrin on periodic pancreatic secretion was studied in fasting conscious dogs. 2. Both CCK-8 and pentagastrin, in small doses, prolonged the interval of periodic pancreatic secretion. Periodicity was disrupted by large doses of CCK-8 and pentagastrin. 3. CCK-8, at the dose which did not disrupt the cycle, raised the peak and the valley-to-valley means, but not the valley mean, of protein secretion in one cycle. Except at large doses, pentagastrin failed to increase the peak and valley mean, but increased mean, valley-to-valley protein secretion. Large doses of both pentagastrin and CCK-8 increased protein secretion at the valley. 4. The peak of periodic pancreatic protein secretion was about half the observed maximum protein response to CCK-8. 5. Atropine reduced pancreatic fluid and protein responses to small doses of CCK-8 to the levels of valleys. At large doses, however, both responses were augmented by atropine. Hexamethonium reduced the responses to any dose of CCK-8 to valley levels or less. Volume and protein responses to pentagastrin following atropine or hexamethonium were of similar magnitude to those at valleys. 6. It is concluded that CCK-8 and pentagastrin stimulate pancreatic enzyme secretion directly by acting on acinar cells and indirectly by modifying cholinergic ganglionic activities which control periodic secretion in conscious dogs.