tetragastrin and gastrin-17

Cholecystokinin (CCK) and gastrin stimulate growth of rodent pancreas in vivo. However, it remains unclear whether these growth effects are mediated specifically by CCK-A receptors, CCK-B receptors, or both. To clarify this issue, the present study examined the effect of highly selective and biologically active CCK agonists on pancreatic growth.. Rats were subcutaneously injected with either (1) CCK-8, a nonselective CCK agonist (2.50 micrograms/kg body wt); (2) A-71623, a selective CCK-A agonist, tert-butyl-oxycarbonyl-Trp-Lys (epsilon-N-2-methylphenylaminocarbonyl)-Asp-(N-methyl)-Phe-NH2 (1.84 micrograms/kg body wt); (3) SNF-8815; a selective CCK-B agonist, [(2R,3S)-beta-MePhe28, N-MeNle31]CCK26-33 (2.40 micrograms/kg body wt); or (4) saline (control) for 21 days. Rats were killed, and pancreatic weight, protein content, RNA content, DNA content, protein-DNA ratio, RNA-DNA ratio, pancreatic area per nucleus, and number of mitoses per 10,000 acinar cells were determined.. Nonselective CCK agonist significantly increased pancreatic weight, protein, RNA, and DNA contents, and number of mitoses per 10,000 acinar cells. Likewise, selective CCK-A agonist significantly increased pancreatic weight, protein, RNA, and DNA contents, protein-DNA ratio, RNA-DNA ratio, pancreatic area per nucleus, and number of mitoses per 10,000 acinar cells. In contrast, selective and biologically active CCK-B agonist had no effect.. These findings indicate that pancreatic growth is mediated specifically by CCK-A receptors in the rat in vivo.

Topics: Animals; Binding, Competitive; Cholecystokinin; DNA; Gastrins; Male; Mitosis; Pancreas; Peptide Fragments; Proteins; Rats; Rats, Inbred Lew; Receptor, Cholecystokinin A; Receptors, Cholecystokinin; RNA; Tetragastrin

This report describes the molecular cloning and pharmacological characterization of a transiently expressed chicken brain cholecystokinin receptor (CCK-CHR) in COS-7 cells. A polymerase chain reaction (PCR)-based cloning strategy was applied using: (1) an initial PCR with deoxyinosine-containing primers designed to target conserved regions in CCK receptors, followed by (2) rapid amplification of cDNA ends (RACE), and (3) full-length PCR of the CCK-CHR cDNA. The full-length cloned bicistronic CCK-CHR cDNA contained a short upstream open reading frame (uORF) coding for a putative six-amino-acid-long peptide of unknown function, followed by a long open reading frame (lORF) encoding the 436-amino-acid-long CCK-CHR receptor protein. At the amino acid level, the CCK-CHR shared approximately 50% homology with mammalian and Xenopus laevis CCK receptors. The pharmacological profile of CCK-CHR resembled that of CCK-B receptors using agonists (CCK-8, CCK-4, gastrin-17), whereas CCK-CHR showed higher affinity for the CCK-A receptor antagonist, devazepide, than for the CCK-B receptor antagonist, L-365,260. To the best of our knowledge, this is the first description and functional expression study of a cloned chicken CCK receptor cDNA.

Topics: Amino Acid Sequence; Animals; Benzodiazepinones; Brain; Chickens; Cloning, Molecular; COS Cells; Devazepide; DNA, Complementary; Gastrins; Inosine; Molecular Sequence Data; Phenylurea Compounds; Polymerase Chain Reaction; Radioligand Assay; Receptors, Cholecystokinin; RNA, Messenger; Sequence Homology, Amino Acid; Sincalide; Tetragastrin

1. The cardiovascular actions of cholecystokinin and related peptides were investigated in the pithed rat. The receptors and the mechanisms involved in these experiments were characterized. 2. Sulphated cholecystokinin octapeptide (sCCK-8, 0.1-100 nmol kg-1, i.v.) elicited a dose-dependent bradycardia and increase in mean arterial blood pressure. Neither gastrin-17 nor pentagastrin had any effect at concentrations up to 100 nmol kg-1. 3. Both the pressor response and bradycardia elicited by sCCK-8 were reduced by the selective CCKA receptor antagonists, devazepide (0.5-50 nmol kg-1) and lorglumide (1-7 mumol kg-1). The selective CCKB receptor antagonists, CI-988 (1 mumol kg-1) and L-365,260 (15 mumol kg-1) did not inhibit the effects of sCCK-8. 4. The pressor response induced with sCCK-8 was reduced by treatment with either phentolamine (3 mumol kg-1) or guanethidine (2 mumol kg-1) and was unaffected by treatment with propranolol, atropine or hexamethonium. The pressor response also persisted following bilateral adrenalectomy. 5. The bradycardia induced with sCCK-8 was unaffected by treatment with phentolamine, propranolol, guanethidine, atropine, hexamethonium or bilateral adrenalectomy. 6. The tetrapeptide of cholecystokinin (CCK-4) elicited a dose-dependent pressor response but did not induce bradycardia. The pressor response was unaffected by devazepide (50 nmol kg-1), L-365260 (15 mumol kg-1) or phentolamine (3 mumol kg-1). 7. In the pithed rat, sCCK-8 acted via CCKA receptors to increase arterial blood pressure indirectly, at least in part, through activation of alpha-adrenoceptors. The observed bradycardia was also mediated byCCKA receptors but possibly through a direct action on the heart.

Topics: Adrenalectomy; Adrenergic Agents; Animals; Benzodiazepinones; Blood Pressure; Bradycardia; Cholecystokinin; Decerebrate State; Devazepide; Dose-Response Relationship, Drug; Gastrins; Guanethidine; Heart Rate; Hormone Antagonists; Hormones; Hypertension; Indoles; Male; Meglumine; Pentagastrin; Phentolamine; Proglumide; Rats; Receptors, Cholecystokinin; Sincalide; Tetragastrin

The aim of this study was to determine the cholecystokinin (CCK) receptor subtype involved in the direct myogenic effect of CCK on pig ileum. Smooth muscle cells were dispersed from pig ileum circular muscle layer and incubated in the presence of various concentrations of CCK agonists and antagonists. Contraction was assessed by measuring the length of 50 cells and expressed as the percentage decrease in cell length from control. Maximal contraction varied between 19% +/- 3% (gastrin II, 10 nmol/L) and 26% +/- 3% [CCK octapeptide (CCK-8), 10 nmol/L]. EC50 for CCK tetrapeptide (CCK-4) was the same than for pentagastrin (30 pmol/L), which were more potent than CCK-8 (100 pmol/L) and unsulfated gastrin 17 (100 pmol/L), which in turn were more potent than unsulfated CCK heptapeptide (CCK-7; 300 pmol/L) and sulfated gastrin II (300 pmol/L). The maximal contraction induced by synthetic analogs of CCK was 22% +/- 1% for 1 nmol/L JMV 170 and 23% +/- 1% for 10 nmol/L JMV 180. EC50 was 10 pmol/L for JMV 170 and 800 pmol/L for JMV 180. Contraction induced by 10 nmol/L CCK was inhibited as follows: L 365,260 half maximal inhibition (IC50) = 1 nmol/L greater than L 364,718 (IC50 = 90 nmol/L) greater than proglumide (IC50 = 1 mumol/L). Contraction induced by 10 nmol/L unsulfated gastrin 17 was inhibited as follows: L 365,260 (IC50 = 1 pmol/L) greater than L 364,718 (IC50 = 60 nmol/L) greater than proglumide (IC50 = 4 mumol/L). Removal of Ca2+ from the extracellular medium did not alter the contraction induced by CCK-8 (10 nmol/L) but impaired the contraction induced by unsulfated gastrin 17 (10 nmol/L) -56% in Ca(2+)-free medium, -77% in Ca(2+)-free medium plus 2 mmol/L EGTA, and -70% in the presence of 1 mumol/L nifedipine. These results show that the CCK receptor of pig ileum smooth muscle cells is closely similar to the B receptor and is not dependent on an influx of extracellular Ca2+ to induce cell contraction. By contrast, gastrin could act through a specific receptor subtype, the "gastrin receptor," triggering a Ca2+ influx into the cell to induce cell contraction.

Topics: Animals; Calcium; Cholecystokinin; Dose-Response Relationship, Drug; Gastrins; Ileum; In Vitro Techniques; Male; Muscle Contraction; Pentagastrin; Peptide Fragments; Proglumide; Receptors, Cholecystokinin; Sincalide; Swine; Tetragastrin

Similar maximal rates of gastric acid secretion are achieved with histamine and gastrin stimulation in human, dog, or cat, but gastrin produces higher rates than histamine in the rat. Gastric acid secretion was measured in seven nonsedated, alert, chaired rhesus monkeys (Macaca mulatta). Dose-response studies were performed using intravenous histamine or tetragastrin. These studies showed histamine to be a much more efficacious and more potent stimulant of gastric acid secretion than tetragastrin in the monkey. Both histamine and tetragastrin had similar potency and efficacy in the dog, while tetragastrin, pentagastrin, and hog heptadecapeptide were similarly less active than histamine in the monkey. Background carbachol (4 micrograms/kg/hr) did not affect the histamine or tetragastrin dose-response curves. Histamine stimulation with background tetragastrin (64 micrograms/kg/hr) did not produce a dose-response curve statistically different from histamine alone. Tetragastrin stimulation with background histamine (60 micrograms/kg/hr) increased the tetragastrin dose-response curve, with a probable additive effect. We conclude that the rhesus monkey differs from cat, dog, and man in that gastrin and its analogs are not able to stimulate maximal acid secretion to the level achieved by histamine.

Topics: Animals; Carbachol; Dose-Response Relationship, Drug; Gastric Acid; Gastrins; Histamine; Macaca mulatta; Pentagastrin; Swine; Tetragastrin; Time Factors