big-gastrin and Achlorhydria

Carboxypeptidase E deficiency as seen in the fat/fat mice is associated with reduced antral somatostatin content but tripling of the progastrin product. Thus, fat/fat mice are able to maintain normal tissue concentrations of bioactive alpha-amidated gastrin in spite of grossly attenuated progastrin processing. After induction of achlorhydria, however, neither the amount of alpha-amidated gastrin nor the total progastrin product increased in the fat/fat mice. This is contrary to what is seen in wild-type mice. Furthermore, the synthesis of antral somatostatin and fundic chromogranin A is also abnormal. Hence the results suggest a breakdown in the feedback loop that regulates gastric acid secretion.

Topics: Achlorhydria; Animals; Base Sequence; Carboxypeptidase H; Carboxypeptidases; Chromogranin A; Chromogranins; DNA Primers; Feedback; Female; Gastric Acid; Gastrins; Male; Mice; Mice, Mutant Strains; Omeprazole; Protein Precursors; Proton Pump Inhibitors; Pyloric Antrum; Somatostatin

Immunoreactivities of urinary N-terminal big gastrin and serum C-terminal gastrin were determined in intact and antrectomized rats by radioimmunoassay using two antisera specific for N- and C-termini of big gastrin, respectively. Gel filtration of urine extract from intact rat showed a single giant peak of N-terminal big gastrin immunoreactivity eluted in a later position than 1-17 gastrin-34, indicating that N-terminal peptides smaller than 1-17 gastrin-34 are excreted in urine. Serum C-terminal gastrin concentration in antrectomized rats was about one sixth that in intact rats. Urinary excretion of N-terminal big gastrin in antrectomized rats was about one sixth that in intact rats. 2 week treatment with E3810, a proton pump inhibitor, (40 mg/kg/day, s.c.) induced urinary excretion of N-terminal big gastrin in parallel with a marked increase in serum C-terminal gastrin concentration in intact rats. Antrectomy completely prevented both the increase in urinary excretion of N-terminal big gastrin and the elevation of serum C-terminal gastrin induced by administration of E3810. There was an excellent correlation between serum concentration of C-terminal gastrin and urinary excretion of N-terminal big gastrin. These results suggest that urinary N-terminal big gastrin, which mostly originates from the gastric antrum, is a useful indicator of gastrin secretion in the rat.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Achlorhydria; Animals; Benzimidazoles; Female; Gastrectomy; Gastrins; Omeprazole; Peptide Fragments; Protein Precursors; Proton Pump Inhibitors; Pyloric Antrum; Rabeprazole; Rats; Rats, Sprague-Dawley

We previously demonstrated that extremely high amounts of N-terminal big gastrin (G-34) fragments are excreted in human urine and three of them are N-terminal octa-, nona-, and decapeptide of G-34. Our subsequent examination revealed that there exists a considerable amount of another N-terminal G-34 fragment in urine, less hydrophobic than the three peptides. We purified this fragment from urine of an achlorhydric patient and determined the structure: less than Glu-Leu-Gly-Pro-Gln-Gly. The purification was carried out by Sep-Pak C18 cartridges, Sephadex G-25, and reverse phase HPLC. The structure was determined by a combination of amino acid analysis, amino acid sequence analysis, and mass spectral analysis. N-terminal hexapeptide of G-34 is the second richest component of urinary N-terminal G-34 fragments next to N-terminal octapeptide of G-34 in normal subjects.

Topics: Achlorhydria; Amino Acid Sequence; Chromatography, Gel; Chromatography, High Pressure Liquid; Gastrins; Humans; Mass Spectrometry; Molecular Sequence Data; Protein Precursors; Solubility

We previously demonstrated that there existed extremely abundant NH2-terminal big gastrin immunoreactivity (NT G-34-IR) in human urine. This report describes the purification and sequence of NT G-34-IR from the urine of an achlorhydric patient. The purification was carried out by a combination of Sep-Pak C18 cartridges, Sephadex G-25, and HPLC steps using a radioimmunoassay specific for NH2-terminus of G-34 and ultraviolet absorption at 214 nm as monitors. Three peptides were isolated. The amino acid analysis, mass spectrometry, and sequence analysis confirmed the structures of urinary NT G-34 fragments being less than Glu-Leu-Gly-Pro-Gln-Gly-Pro-Pro, less than Glu-Leu-Gly-Pro-Gln-Gly- Pro-Pro-His, and less than Glu- Leu-Gly-Pro-Gln-Gly-Pro-Pro-His-Leu. NH2-terminal octapeptide of G-34 was the main component of urinary NT G-34-IR.

Topics: Achlorhydria; Amino Acid Sequence; Amino Acids; Chromatography, Gel; Chromatography, High Pressure Liquid; Gastrins; Humans; Mass Spectrometry; Molecular Sequence Data; Peptide Fragments; Protein Precursors; Radioimmunoassay

In 68 patients with chronic renal failure (CRF), 15 patients with duodenal ulcer and 15 normal subjects, basal plasma gastrin levels and basal and stimulated gastric acid secretion were measured. Two antisera were used: antiserum R2702 with specificity for human G34 and its N-terminal fragments [G34] and antiserum 2604 with specificity for the four main components of gastrin (total gastrin). Basal gastrin concentrations of both total gastrin and G34-like immunoreactivity (G34LI) were significantly higher in the CRF patients than in the other two groups, irrespective of dialysis. Total gastrin levels were not correlated with serum creatinine levels. Total gastrin levels were significantly decreased during hemodialysis, but G34LI levels showed no significant change. A small amount of total gastrin was detected in the dialysate by antiserum 2604. As to the postprandial gastrin release, in the first 30 min, the pattern of response in the patients with CRF was similar to that of the normal subjects, but the peak value was attained later, and the response was more rather prolonged. Gastric analysis showed a low basal acid out put and impaired acid secretion in response to secretagogue. It is concluded that (1) one of the predominant circulating forms of gastrin in CRF is G34LI, and (2) the hypergastrinemia in the CRF patients is probably due to reduced removal of gastrin by kidneys, increased gastrin production by impairment of the negative acid feedback mechanism induced by parietal cell dysfunction or reduced parietal cell sensitivity to gastrin by atrophic gastritis.

Topics: Achlorhydria; Adult; Endoscopy; Female; Food; Gastric Acid; Gastrins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Protein Precursors; Renal Dialysis