Comparison of effect of peptide length and sulphation on acid secretory potency of gastrin in the cat in vivo and in vitro.

Hirst, Barry H.; Holland, Joy; Marr, Alexa; Parsons, M. E.; Sanders, David J.

doi:10.1113/jphysiol.1984.sp015510

Cited by 17 publications

(5 citation statements)

References 36 publications

(43 reference statements)

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“…This was evident from incubation of gastrin-52 in plasma, which resulted in a decreased NH 2 terminal immunoreactivity, whereas the COOH immunoreactivity was retained after 24 h. Also, sulfation of gastrin enhances resistance to metabolism, but this may only apply to small peptides. In humans, the MCRs of sulfated and nonsulfated gastrin-17 were found to be approximately the same (1), whereas MCR of sulfated hexagastrin in cat was nearly sixfold higher than the nonsulfated form (15). In the present study, sulfated gastrin-6 had a 30% lower MCR than the nonsulfated form.…”

Section: Discussionsupporting

confidence: 41%

The metabolism of gastrin-52 and gastrin-6 in pigs

Hansen

Goetze

Stadil

et al. 2000

American Journal of Physiology-Gastrointestinal and Liver Physi

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The kinetics and metabolism in various organs of three bioactive products of progastrin, the small sulfated and nonsulfated gastrin-6 and the large nonsulfated gastrin-52, were examined during intravenous administration in anesthetized pigs. The kidney, hindlimb, liver, head, and gut eliminated the hexapeptides efficiently, with a fractional extraction ranging from 0.50 to 0.28 (P<0.001-0.05). No metabolism was recorded in the lungs, and sulfation was without influence on the extraction of gastrin-6. Gastrin-52 was eliminated only in the kidney and the head, with a fractional extraction between 0.23 and 0.11 (P<0.01-0.05). The half-life of sulfated and nonsulfated gastrin-6 was 1.5+/-0.4 and 1.4+/-0.3 min, the metabolic clearance rate (MCR) was 80.8+/-7.6 and 116.0+/-13.5 ml x kg(-1) x min(-1) (P<0.05), and the apparent volume of distribution (V(dss)) was 199.3+/-70.1 and 231.4+/-37.3 ml/kg, respectively. The decay of gastrin-52 in plasma was biexponential. The half-lives of this biexponential after a bolus injection were 3.9+/-0.5 (T(1/2alpha)) and 25.7+/-1.4 (T(1/2beta)) min, and the MCR and V(dss) were 4.2+/-0.4 ml. kg(-1) x min(-1) and 116.2+/-16.2 ml/kg(1). We conclude that there is a differential elimination of progastrin products in splanchnic and nonsplanchnic tissue, which depends on the chain length of the peptides. Sulfation of gastrin-6 had no influence on the organ-specific extraction but reduced the MCR. Our results are in keeping with previous studies of nonsulfated gastrin-17, which is extracted in the kidney, head, limb, and gut but not in the liver.

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Section: Discussionsupporting

confidence: 41%

The metabolism of gastrin-52 and gastrin-6 in pigs

Hansen

Goetze

Stadil

et al. 2000

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In contrast, the CTFP of progastrin, Tyr 70 -progastrin-(71-80), was rapidly cleared from the circulation, with a disappearance half-life of 0.9 min. These findings are consistent with the proposal that the disappearance half-life of a class of peptide is related to the number of amino acids it contains (12,15,37). Accordingly, glycine-extended gastrin-17 had disappearance half-lives (primary, 2.2 Ϯ 0.6 min; secondary, 13 Ϯ 1 min) intermediate between the two progastrin peptides.…”

Section: Discussionsupporting

confidence: 79%

Metabolism of recombinant progastrin in sheep

Paterson

Baldwin

Shulkes

2002

American Journal of Physiology-Endocrinology and Metabolism

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Precursor forms of peptide hormones may be biologically active with effects distinct from the mature end product. Nonamidated progastrin-derived peptides stimulate growth of colonic epithelium and are elevated in the circulation of patients with colorectal carcinomas, whereas the amidated end product is the major regulator of gastric acidity. Using region-specific radioimmunoassays, we here compared the in vitro and in vivo metabolism of recombinant human progastrin-(6–80) and two other nonamidated gastrins, gastrin-17-Gly and Tyr70-progastrin-(71–80). Although progastrin-(6–80) was very stable in vitro, both progastrin-(6–80) and gastrin-17-Gly were degraded in vivo. The in vivo data were best fitted by a double-exponential decay curve, and the half-lives for progastrin-(6–80) ( t ½α = 5.1 ± 1.1, t ½β = 42 ± 11 min) were significantly ( P < 0.05) longer than for gastrin-17-Gly ( t ½α = 2.2 ± 0.6, t ½β = 13 ± 1 min). Tyr70-progastrin-(71–80) was degraded more rapidly. Comparison with amidated gastrins suggests that peptide length, rather than sequence, is the critical determinant of clearance. Progastrin has the clearance characteristics to be considered a circulating hormone.

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“…The response to concentrations of pentagastrin greater than 10-7M evoked lower acid responses (Figures 1 and 2). The biphasic nature of the dose-response curves to pentagastrin and gastrin has been observed in other preparations in vitro, including the mouse, rat, cat and dog (Bunce et al, 1978;Kuo & Shanbour, 1978;Davison & Najafi-Farashah, 1982;Spencer, 1982;Hirst et al, 1984;Lotti et al, 1986) and rabbit isolated gastric parietal cells (Magous & Bali, 1983). In addition, supramaximal concentrations of other stimulants (bethanechol, histamine and theophylline) resulted in reductions of acid secretion in the rat stomach in vitro (Spencer, 1982).…”

Section: Acid Secretory Response To Pentagastrinmentioning

confidence: 86%

“…The mucosal surface was perfused at 1 ml min-1 with warmed unbuffered mucosal solution. Acid secretion was recorded continuously by monitoring the pH of the mucosal perfusate, and converting this to H+ activity by an antilog function generator as described by Hirst et al (1984). Serosal Na+ and K+ concentrations were determined by flame photometry (Instrument Laboratory, IL543), and serosal pH, P02 and Pco2 using a blood-gas analyser (Radiometer, ABL 3).…”

Section: Introductionmentioning

confidence: 99%

Fade and tachyphylaxis of gastric acid secretory response to pentagastrin in rat isolated gastric mucosa

Hirst

Holland

Parsons³

et al. 1988

British J Pharmacology

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Gastric acid secretory responses to pentagastrin were characterized in the rat isolated gastric mucosa. In particular, the mechanisms underlying fade, declining response upon continued stimulation, and tachyphylaxis, progressively reduced responses upon repeated stimulation, were investigated. Pentagastrin, 10−9‐10−7m, resulted in concentration‐related increases in acid secretion, with a mean maximum of 2.65 μmolcm−2h−1 in response to pentagastrin, 10−7m. Higher concentrations of pentagastrin produced sub‐maximal secretory rates; we define this as auto‐inhibition. The responses to all concentrations of pentagastrin demonstrated fade. The rate of fade was correlated with the maximum acid secretory rate, declining at about 36% of the peak over the first 16min. The Po2, Pco2, [HCO3−], pH, [glucose], [lactate], [Na+] and [K+] did not decline during the fade of the acid secretory response to pentagastrin, 10−7 m. Addition of a second aliquot of pentagastrin was not able to reverse fade, but these tissues were responsive to histamine. Replacement of the serosal solution, before addition of a second aliquot of pentagastrin, increased the acid response from 3% to 24% of the first response. Serosal solution from donor tissues, allowed to respond to pentagastrin and then the acid secretion to fade, was able to stimulate secretion in fresh recipient tissues, although at lower rates. Acid secretory responses to a second dose of pentagastrin were not significantly different, whether the tissues were previously unstimulated, or stimulated with pentagastrin washed out after attaining its peak secretory response (after 10–20 min). The second response was significantly reduced if the first response was allowed to fade with the pentagastrin in contact for 100min; i.e. fade significantly influenced the extent of tachyphylaxis. Proglumide, 10−2m, a gastrin receptor antagonist, and omeprazole, 10−5 m, an inhibitor of the gastric (H+ + K+)‐ATPase, both inhibited pentagastrin‐stimulated acid secretion to similar extents. The second response to pentagastrin after pentagastrin alone, or pentagastrin plus omeprazole were both reduced compared to responses after no stimulation or omeprazole alone, respectively. After pentagastrin plus proglumide, the second response to pentagastrin was not lower than after proglumide alone. Proglumide, but not omeprazole, therefore, prevented pentagastrin tachyphylaxis. It is concluded that gastrin fade and tachyphylaxis are related phenomena. Part of the fade may be due to release of an inhibitor(s). The major proportion of tachyphylaxis is a result of specific interaction of gastrin with its receptors.

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Comparison of effect of peptide length and sulphation on acid secretory potency of gastrin in the cat in vivo and in vitro.

Cited by 17 publications

References 36 publications

The metabolism of gastrin-52 and gastrin-6 in pigs

The metabolism of gastrin-52 and gastrin-6 in pigs

Metabolism of recombinant progastrin in sheep

Fade and tachyphylaxis of gastric acid secretory response to pentagastrin in rat isolated gastric mucosa

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