Discrepancies between the Doses of Cholecystokinin or Caerulein-Stimulating Exocrine and Endocrine Responses in Perfused Isolated Rat Pancreas

Ōtsuki, Makoto; Sakamoto, Choitsu; Yuu, Hosai; Maeda, Mitsuo; Morita, Soichiro; A, Ohki; Kobayashi, Noboru; Terashi, Katsuhiro; Okano, Keiichi; Baba, Shigeaki

doi:10.1172/jci109325

Cited by 76 publications

(28 citation statements)

References 28 publications

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“…Recently, several potent CCK antagonists with a structure of 4-benzamido-N,N-di-alkyl-glutaramic acid have been synthesized [18,19,21,22], Among them, CR 1409 was found to be the most potent antagonist of CCK action on the pancreas, that is 3-4 times more potent than CR 1392 (K; 0.6 pM; present study), with the Kj for the pancreatic CCK receptor being 0.13-0.2 pM [19,21,22], In the present study, however, CR 1409 at a concentration of 1 mM caused amylase release of 107.4 ± 0.6% of the initial content in the acini, whereas the same concentration of CR 1392 (1 mM) caused an increase in amylase release up to 19.9 ± 2.3% of initial content. All the acini incubated with 1 mM CR 1409 for 30 min were unable to exclude trypan blue, whereas only few acini incu bated with 1 mM CR 1392 were stained blue.…”

Section: Discussionmentioning

confidence: 99%

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Effects of a New Proglumide Analogue CR 1392 on Pancreatic Exocrine Secretion in the Rat

Ōtsuki

Fujii²,

Nakamura³

et al. 1989

Digestion

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The effects of proglumide analogue. CR 1392, on pancreatic exocrine secretion were studied in the isolated pancreatic acini and the isolated perfused pancreata of rats. In the isolated acini, CR 1392 caused a parallel rightward shift of the dose-response curve for amylase secretion stimulated by cholecystokinin octapeptide (CCK-8). CR 1392 inhibited maximally stimulated amylase release by CCK-8 (100 pM) in a concentration-dependent manner, with a half maximal inhibition (ID₅₀) at 8.0 ± 0.6 μM. CR 1409, another proglumide analogue, also caused a concentration-dependent inhibition (ID₅₀: 3.2 ± 0.4 μM). Although CR 1409 was about 2.5-fold more potent than CR 1392 in inhibiting the stimulated amylase release, 1 mM CR 1409 caused 107.4 ± 0.9% increase in amylase release, suggesting acinar cell damage. CR 1392(1 mM) also caused 19.9 ± 2.3% increase in amylase release, but was less toxic than CR 1409. The antagonism produced by CR 1392 was selective for CCK and had no effect on amylase release stimulated by other receptor secretagogues or by agents bypassing receptors. CR 1392 added 20 min after the CCK-8 stimulation rapidly abolished pancreatic exocrine secretion in both isolated acini and isolated perfused pancreas. Although the inhibitory effect of CR 1392 was fully reversible in the isolated acini, the pancreata perfused with 100 μM CR 1392 for 20 min did not respond to the subsequent stimulation with CCK-8 for more than 20 min. These results indicate that CR 1392 is a potent, competitive, specific and long acting antagonist of CCK in rat pancreas.

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Section: Discussionmentioning

confidence: 99%

“…The isolated perfused rat pancreas was prepared as reported previously [21]. The perfusate used was a Krcbs-Ringer bicarbonate solution containing 4.6% dextran T-70, 0.25% bovine plasma albumin, and 8.3 mM glucose.…”

Section: Isolated Perfused Pancreasmentioning

confidence: 99%

Effects of a New Proglumide Analogue CR 1392 on Pancreatic Exocrine Secretion in the Rat

Ōtsuki

Fujii²,

Nakamura³

et al. 1989

Digestion

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“…In addition to these actions on gastrointestinal functions, studies both in vivo and in vitro in several species have indicated that CCK stimulates insulin release (4)(5)(6)(7)(8)(9). We lhave recently developed a sensitive and specific bioassay for measuring plasma CCK levels in humans (10, 1 1).…”

Section: Introductionmentioning

confidence: 99%

Physiological role for cholecystokinin in reducing postprandial hyperglycemia in humans.

Liddle¹,

Rushakoff²,

Morita³

et al. 1988

J. Clin. Invest.

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It is known that the ingestion of glucose alone causes a greater increase in plasma glucose levels than ingestion of the same amount of glucose given with other nutrients. Since physiological plasma concentrations of cholecystokinin (CCK) prolong gastric emptying, it is proposed that after a meal, CCK may modify plasma glucose levels by delaying glucose delivery to the duodenum. To evaluate the effect of CCK on oral glucose tolerance, plasma CCK, insulin, and glucose levels and gastric emptying rates were measured in eight normal males before and after the ingestion of 60 g glucose with the simultaneous infusion of either saline or one of two doses of CCK-8 (12 or 24 pmol/kg per h). Gastric emptying rates were measured by gamma camera scintigraphy of technetium 99m sulfur colloid and plasma CCK levels were measured by a sensitive and specific bioassay.Basal CCK levels averaged 1.0±0.1 pM (mean±SEM, n = 8) and increased to 7.1±1.1 pM after a mixed liquid meal. After glucose ingestion, but without CCK infusion, CCK levels did not change from basal, and the gastric emptying t1/2 was 68±3 min. Plasma glucose levels increased from basal levels of 91±3.9 mg/dl to peak levels of 162±11 mg/dl and insulin levels increased from 10.7±1.8 ,gU/ml to peak levels of 58±11 i&U/ml. After glucose ingestion, with CCK infused at 24 pmol/ kg per h, plasma CCK levels increased to 8 pM and the gastric emptying t112 increased to 148±16 mmi. In concert with this delay in gastric emptying, peak glucose levels rose to only 129±17 mg% and peak insulin levels rose to only 24.2±4.2 M&U/ml. With CCK at 12 pmol/kg per h, similar but less dramatic changes were seen.To demonstrate that endogenous CCK could modify the plasma glucose and insulin responses to oral glucose, oral glucose was given with 50 g of lipid containing long-chain triglycerides. This lipid increased peak CCK levels to 3.7±0.9 pM. Concomitant with this rise in CCK was a delay in gastric emptying and a lowering of plasma glucose and insulin values.To confirm that CCK reduced hyperglycemia by its effect on gastric motility, 36 g glucose was perfused directly into the duodenum through a nasal-duodenal feeding tube in four subjects. With duodenal perfusion of glucose, there was no change in plasma CCK levels, but plasma glucose levels increased from basal levels of 93±5 to 148±6 mg/dl and insulin levels rose from 10.6±3.5 to 29.5±5.2 gU/Ml. When CCK was infused at 24 pmol/kg per h, neither the plasma glucose nor insulin responses to the duodenal administration of glucose were modified. Thus we conclude that CCK, in physiological concentrations, delays gastric emptying, slows the delivery of glucose to the duodenum, and reduces postprandial hyperglycemia. These data indicate, therefore, that CCK has a significant role in regulating glucose homeostasis in humans.

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“…Previous in vitro studies in rats using natural porcine CCK [2. 13] or cerulein [8,13,14], and in vivo experiments using natural porcine CCK [15] have shown that the insulinotropic effect of CCK is glu cose dependent. This is confirmed in the present study in that even the highest levels of CCK-8 had no effect on insulin release at a perfusate glucose concentration of 2.8 mM ( fig.…”

Section: Discussionmentioning

confidence: 99%

Glucose-Dependent Insulinotropic Action of Cholecystokinin Octapeptide in the Isolated Perfused Rat Pancreas

Müller¹,

Demol²,

Fladrich³

et al. 1983

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Whether cholecystokininoctapeptide (CCK-8) stimulates insulin secretion at submaximal or supramaximal levels for pancreatic exocrine secretion was investigated. CCK-8 was delivered to the isolated perfused rat pancreas by a linear gradient ranging from 0 to 1,100 or 0 to 220 pg/ml at two different glucose concentrations. At 2.8 mM glucose CCK-8 was not insulinotropic even at supramaximal stimulation for exocrine pancreatic secretion. At 15.8 mM glucose CCK-8 was insulinotropic starting already at concentrations which were submaximal for stimulation of exocrine pancreatic secretion. It was concluded that CCK-8 warrants consideration as a hormone involved in the enteroinsular axis.

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Discrepancies between the Doses of Cholecystokinin or Caerulein-Stimulating Exocrine and Endocrine Responses in Perfused Isolated Rat Pancreas

Cited by 76 publications

References 28 publications

Effects of a New Proglumide Analogue CR 1392 on Pancreatic Exocrine Secretion in the Rat

Effects of a New Proglumide Analogue CR 1392 on Pancreatic Exocrine Secretion in the Rat

Physiological role for cholecystokinin in reducing postprandial hyperglycemia in humans.

Glucose-Dependent Insulinotropic Action of Cholecystokinin Octapeptide in the Isolated Perfused Rat Pancreas

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