Stimulation of canine pancreatic polypeptide, gastrin, and gastric acid secretion by ranatensin, litorin, bombesin nonapeptide and substance p

doi:10.1016/0167-0115(81)90051-3

Regulatory Peptides

Volume 1, Issue 4, January 1981, Pages 279-288

https://doi.org/10.1016/0167-0115(81)90051-3 Get rights and content

Abstract

Four dogs with chronic gastric fistulas were given intravenous bombesin nonapeptide (B9), ranatensin, and litorin by constant infusion for 90 min at 1.2 μg·kg⁻¹·h⁻¹ on separate days. A dose response study with substance P (1.5, 3.0, 60, 18 and 54 μg·kg⁻¹·h^t-1 was also carried out and all tests compared to a standard protein meal (10 μg·kg⁻¹. Plasma gastrin and PP were measured by radioimmunoassay and gastric acid by autobiuret titration. Substance P failed to stimulate gastric acid secretion or release either pancreatic polypeptide (PP) or gastrin. Basal gastrin levels were $8±2$ fmol/ml. The peak increment of gastrin released by bombesin was $95±16$ , ranatensin $22±6$ , litorin $18±4$ , and meal $39±5$ fmol/ml. Bombesin caused significantly greater release of gastrin than a meal, litorin or ranatensin $(P<0.01)$ Basal gastric secretion was $23±4$ μequiv./min. B9 produced a peak acid secretion of $356±124$ μequiv./min. There are no significant difference between the bombesin-like peptides ( $P<0.01$ ). Basal plasma PP was $38±12$ fmol/ml. B9 produced a peak PP increment of $600±50$ , litorin $137±36$ , ranatensin $98±11$ , and a meal $305±58$ fmol/ml. B9 released significantly more PP than either litorin or ranatensin ( $P<0.01$ ). The different amino acid sequences of the peptides are probably responsible for their potency. The substitution of a penultimate phenylalanine residue in litorin and ranabombesin, alytensin, and litorin suggesting that it might have other effects as yet undescribed.

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Cited by (21)

The role of bombesin and bombesin-related peptides in the short-term control of food intake
2013, Progress in Molecular Biology and Translational Science
Citation Excerpt :
Physiologically, the BB2 receptor mediates a number of gastrointestinal functions, including regulation of gastric acid secretion through gastrin or somatostatin release176,177 and regulation of gastrointestinal motility/gastric emptying, and gallbladder contraction.178,179 In addition, the BB2 receptor mediates stimulation of pancreatic exocrine secretion180,181 and the release of insulin182 and other hormones, including CCK, PYY, and glucagon.60,183–185 This receptor also participates in immunological responses such as attracting peritoneal macrophages, monocytes, and lymphocytes.98,99,102
Bombesin (Bn) is a 14-amino acid peptide isolated from the skin of the frog Bombina bombina. The mammalian homologs of this peptide include three forms of gastrin-releasing peptide (GRP): GRP-10, GRP-27, and GRP-29, and a 10-amino acid peptide referred to as neuromedin-B (NMB). These peptides evoke a number of responses, including hyperthermia, bradycardia, inhibition of gastric emptying and inhibition of food intake, by activating one of three G protein-coupled receptors: an NMB-R or BB₁, a GRP-R or BB₂ and an orphan Bn receptor subtype-3 (BRS-3) or BB₃. Bombesin, GRP, and NMB have a role in the short-term control of food intake. These peptides reduce meal size (MS) and they prolong the intermeal interval (IMI), the time between the first and second meals. Studies have shown that the vagus and the splanchnic nerves in the upper gastrointestinal tract, which communicate with the feeding areas of the hindbrain, are necessary for reduction of MS and prolongation of the IMI by Bn, GRP, and NMB. In addition, one-tenth of the intraperitoneal dose of Bn, GRP, and NMB given in either the left gastric artery, which supplies the stomach, or the cranial mesenteric artery, which supplies the intestine, or the femoral vein, also reduces MS and prolongs the IMI. Thus, a potential neurocrine or an endocrine mode of action for these peptides requires further investigation.
Tachykinins in the gut. Part II. Roles in neural excitation, secretion and inflammation
1997, Pharmacology and Therapeutics
The preprotachykinin-A gene-derived peptides substance (substance P; SP) and neurokinin (NK) A are expressed in intrinsic enteric neurons, which supply all layers of the gut, and extrinsic primary afferent nerve fibers, which innervate primarily the arterial vascular system. The actions of tachykinins on the digestive effector systems are mediated by three different types of tachykinin receptor, termed NK₁, NK₂ and NK₃ receptors. Within the enteric nervous system, SP and NKA are likely to mediate, or comediate, slow synaptic transmission and to modulate neuronal excitability via stimulation of NK₃ and NK₁ receptors. In the intestinal mucosa, tachykinins cause net secretion of fluid and electrolytes, and it appears as if SP and NKA play a messenger role in intramural secretory reflex pathways. Secretory processes in the salivary glands and pancreas are likewise influenced by tachykinins. The gastrointestinal arterial system may be dilated or constricted by tachykinins, whereas constriction and an increase in the vascular permeability are the only effects seen in the venous system. Various gastrointestinal disorders are associated with distinct changes in the tachykinin system, and there is increasing evidence that tachykinins participate in the hypersecretory, vascular and immunological disturbances associated with infection and inflammatory bowel disease. In a therapeutic perspective, it would seem conceivable that tachykinin antagonists could be exploited as antidiarrheal, anti-inflammatory and antinociceptive drugs.
Bombesin receptor subtype mediation of gastroenteropancreatic hormone secretion in rats
1994, Peptides
Bombesin is a potent releaser of many gut and pancreatic hormones including gastrin, glucose-dependent insulinotropic polypeptide (GIP), pancreatic polypeptide (PP), cholecystokinin (CCK), enteroglucagon, and insulin. Three mammalian bombesin-like peptides, gastrin-releasing peptide (GRP), neuromedin C (NMC or GRP-10), and neuromedin B (NMB), and two bombesin receptor subtypes, GRP preferring and NMB preferring, have been characterized. We used a highly potent, selective antagonist of the GRP-preferring receptor, [d-Phe⁶]bombesin(6–13)-methylester {[d-Phe⁶]Bn(6–13)OMe}, to determine the receptor subtype mediating bombesin-induced secretion of gastrin, GIP, PP, peptide YY (PYY), and insulin, as well as the importance of endogenous bombesin-like peptides in controlling basal secretion of these hormones. Unanesthetized rats received femoral vein infusion of saline, bombesin (10 nmol/kg/h), [d-Phe⁶]Bn(6–13)OMe (1000 nmol/kg/h), or bombesin plus [d-Phe⁶]Bn(6–13)OMe. Blood was withdrawn from jugular vein catheters before and 30 min after the start of infusions. Plasma gastrin, GIP, PP, PYY, and insulin were measured by specific radioimmunoassays. [d-Phe⁶]Bn(6–13)OMe alone reduced basal insulin levels by 28% ( $p < 0.05$ ) but did not alter basal levels of plasma PP, GIP, PYY, or gastrin ( $p > 0.05$ for each). Bombesin infusion significantly increased plasma levels of each hormone ( $p < 0.0001$ for each). [d-Phe⁶]Bn(6–13)OMe completely blocked bombesin-induced increases in PP, insulin, and gastrin, and almost completely blocked increases in GIP and PYY ( $p < 0.01$ for each). Our results suggest that (a) exogenous bombesin significantly stimulates PP, insulin, GIP, PYY, and gastrin secretion, (b) bombesin-induced secretion of these hormones is primarily mediated by the GRP-preferring receptor, and (c) an endogenous bombesin-like peptide acting at this receptor subtype plays an important physiological role in control of basal secretion of insulin but not PP, GIP, PYY, or gastrin.
A novel bombesin receptor antagonist (2258U89), potently inhibits bombesin evoked release of gastrointestinal hormones from rats and dogs, in vitro and in vivo
1992, Regulatory Peptides
Several bombesin-receptor antagonists are available that inhibit secretory and growth effects of bombesin, in vitro. In the present study, we examined the effects of a new class of bombesin receptor antagonists (modified GRP(15–27) peptides, with d-Pro²⁶ and d-Ala²⁴ moieties), on bombesin mediated effects, in vivo and in vitro. Of the 10 different compounds tested, BW-10 or 2258U89 ([de-NH₂)Phe¹⁹,d-Ala²⁴,d-Pro²⁶Ψ(CH₂NH)Phe²⁷]-GRP(19–27)) was most potent towards inhibiting bombesin binding to rat pancreatic acinar cancer cells with an ID₅₀ of 0.5 nM. BW-10 (1 and 10 nM) significantly inhibited the gastrin response to 1 nM bombesin, from isolated rat stomach, in vitro, in a dose-dependent fashion. BW-10 (10–100 nmol/kg) was equally effective at significantly inhibiting bombesin evoked gastrin release in anesthetized rats, in vivo. [d-Phe⁶]Bombesin(6–13)-propylamide (BIM), a member of another class of antagonists, reported previously to be the most potent antagonist, in vitro, on the other hand, enhanced bombesin provoked gastrin release in rats. The antagonistic effects of BIM, in vivo, may thus be more selective. Intravenous infusion of BW-10 (10 nmol/kg/h) partially depressed gastrin and pancreatic polypeptide and completely abolished insulin released in response to bombesin, in conscious dogs. These results suggest that BW-10 functions as one of the most potent bombesin receptor antagonists, in vitro and in vivo, which could potentially be used as a therapeutic compound in treatment of some human diseases.
Characterization of bombesin receptors on canine antral gastrin cells
1990, Peptides
Dispersed canine antral mucosal cells were prepared by sequential steps of collagenase digestion and EDTA treatment. Cell preparations enriched in gastrin cells were made by centrifugal elutriation followed by step density gradient centrifugation. Specific, saturable, and reversible binding of ¹²⁵I-[Tyr⁴]-bombesin was found in all preparations. This saturable binding was time, temperature, and cell number dependent. In both velocity (elutriator) and density cell separation experiments, saturable binding of bombesin correlated with the distribution of cells containing gastrin- but not somatostatin-like immunoreactivity. Maximal specific binding to gastrin (G) cell-enriched fractions was reached in 45 min at 37°C and constituted 90% of total binding. Addition of 100 nM nonradioactive bombesin to cells incubated with 50 pM ¹²⁵I-[Tyr⁴]-bombesin for 45 min resulted in time-dependent dissociation of specifically bound tracer to about 40% of the maximal equilibrium binding. Analysis of saturable equilibrium binding yielded a best fit to a one-site model of high affinity binding sites with an apparent K_d of 85±14 pM and a B_max of 231,000±71,000 receptors/gastrin cell. Nonradioactive [Tyr⁴]-bombesin and related analogs inhibited the specific binding of the tracer in a dose-related manner. The rank order of potency, determined at the IC₅₀, of [Tyr⁴]-bombesin and related analogs for inhibition of specific binding was bombesin > [Tyr⁴]-bombesin = hGRP-27 > GRP-10 > ranatensin > neuromedin B. Cholecystokinin, somatostatin, substance K, and kassinin each tested at a concentration of 1 μM did not inhibit bombesin binding. These results suggest that canine antral gastrin cells express a saturable binding site for bombesin with the functional properties of a bombesin receptor. We propose that this receptor mediates the stimulatory action of bombesin/GRP on gastrin secretion by gastrin cells.
Influence of cholecystokinin, vasoactive intestinal peptide and secretin on plasma concentration of avian pancreatic polypeptide in laying hens
1986, Comparative Biochemistry and Physiology -- Part A: Physiology
- 1.
  1. The influence of saline infusion (i.v.) followed by infusion of either cholecystokinin, vasoactive intestinal peptide, or secretin on plasma concentration of avian pancreatic polypeptide (aPP) was studied in sixteen 18–26-week old Single Comb White Leghorn hens.
- 2.
  2. Three concentrations were used for each hormone. Blood was drawn after both saline and hormone infusions and assayed for aPP content.
- 3.
  3. No significant influence of any of the three hormones on plasma aPP level was found in either fed or fasted hens.

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Stimulation of canine pancreatic polypeptide, gastrin, and gastric acid secretion by ranatensin, litorin, bombesin nonapeptide and substance p

Abstract

Lancet

Pure Appl. Chem.

Lancet

Gastroenterology

Gastrin release by bombesin in the dog

Br. J. Pharmacol.

Active polypeptide of nonmammalian origin

Pharmacol. Rev.

Biogenic amines and active peptides of the amphibian skin

Annu. Rev. Pharmacol.