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New insights into neurohormonal regulation of pancreatic secretion
Chung Owyang, Craig D. Logsdon Gastroenterology Volume 127, Issue 3, Pages (September 2004) DOI: /j.gastro Copyright © 2004 American Gastroenterological Association Terms and Conditions
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Figure 1 Reverse-transcriptase polymerase chain reaction (RT-PCR) amplifies both CCK-A and CCK-B receptor mRNA from total RNA prepared from human whole pancreas and isolated acini. RT-PCR was performed using 70 ng DNase-purified RNA; the results are representative of 3 independent experiments. Sequencing verified that the bands amplified represented the expected genes. Note that standard RT-PCR indicates the presence of very low levels of message for the CCK-A receptors and much higher levels of CCK-B receptor, m3 muscarinic acetylcholine receptor, and gastrin-binding protein (GBP) mRNA. INS, insulin mRNA. Reprinted with permission from Ji et al.14 Gastroenterology , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions
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Figure 2 Human pancreatic acini secrete amylase in response to carbachol but not CCK-8 or gastrin. Isolated human pancreatic acini, either uninfected or infected for 4 hours with an adenovirus that expresses the human CCK-B receptor (AdCCKB), were incubated with increasing concentrations of CCK-8, gastrin, or carbachol at 37°C for 30 minutes. The concentration of amylase released into the medium was measured using a colorimetric reagent and was expressed as a percentage of initial acinar amylase content. Data are the means of 3 separate experiments. Reprinted with permission from Ji et al.14 Gastroenterology , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions
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Figure 3 Intracellular Ca2+ levels increase in human pancreatic acini in response to carbachol but not to CCK-8. An estimate of intracellular Ca2+ was obtained by measuring emitted fluorescence from fura-2-loaded acini using an Attofluor digital imaging system. CCK-8 (100 nmol/L) or carbachol (1 mmol/L) was introduced at the times indicated. (A) Freshly prepared acini were treated with CCK-8 and then carbachol. Acini infected for 4 hours with an adenovirus encoded with either human CCK-B receptor (B) or rat CCK-A receptor (C) were treated with CCK-8 (100 nmol/L). Data shown are typical and are representative of 4 separate experiments. Reprinted with permission from Ji et al.14 Gastroenterology , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions
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Figure 4 In humans, CCK-8 infusion evokes a dose-dependent increase in net output of both trypsin (A) and lipase (B). Atropine administration nearly abolishes CCK-8—stimulated enzyme release at CCK-8 doses of 5 and 10 ng·kg−1·h−1 but is relatively less potent at higher doses, i.e., 20 and 40 ng·kg−1·h−1 (f < 0.01, analysis of variance for repeated measures; results are means ± SE, n = 6). Reprinted with permission from Soudah et al.33 Gastroenterology , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions
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Figure 5 (A) Sites and mechanisms of action of CCK to stimulate pancreatic secretion in rats. Physiologic levels of CCK in plasma act via stimulation of the vagal afferent pathways. In contrast, supraphysiologic plasma CCK levels act on intrapancreatic neurons and to a larger extent on pancreatic acini. (B) Adaptive changes that occur after chronic vagotomy involve recruitment of intraduodenal cholinergic neurons that activate a gastrin-releasing peptide neural pathway to stimulate secretion. ACh, acetylcholine. Reprinted with permission from Li and Owyang.41 Gastroenterology , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions
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Figure 6 In rats, perivagal application of capsaicin and vagal afferent rootlet section each completely abolish the pancreatic response to physiological doses of CCK-8 (i.e., ≤40 pmol·kg−1·h−1), but neither affects the pancreatic response to supraphysiologic doses of CCK. Values are mean ± SE, n = 6 in each group. *P < Reprinted with permission from Li and Owyang.36 Gastroenterology , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions
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Figure 7 Effect of CCK-JMV-180 on the response of neurons from rat nodose ganglia to the diversion of bile-pancreatic juice (BPJ). Eight neurons that responded to a 60-minute BPJ diversion were tested. Administration of CCK-JMV-180 abolished the response to BPJ diversion in 3 of 8 neurons but had no effect on the response in the other 5 neurons. These observations suggest that endogenous CCK acts on both high- and low-affinity CCK-A receptors. *P < Reprinted with permission from Li et al.72 Gastroenterology , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions
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Figure 8 Effects of CCK-JMV-180 on CCK-8–induced pancreatic secretion in anesthetized rats. (A) Intravenous infusion of CCK-8 at 20 and 40 pmol·kg−1·h−1 increases protein secretion by 50% and 78% over basal, respectively. CCK-JMV-180 alone, 22 and 44 μg·kg−1·h−1, stimulates pancreatic protein secretion by 48% and 82% over basal, respectively. (B) CCK-JMV-180 does not inhibit but significantly enhances the pancreatic response to CCK-8. Values are means ± SE, n = 6 rats in each group. *P < 0.05 compared with infusion of CCK-8 alone. Reprinted with permission from Li et al.76 Gastroenterology , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions
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Figure 9 Pancreatic protein secretion induced by administration of casein and CCK-JMV-180. Duodenal infusion of 18% casein in conscious rats produces a 2.5-fold increase in protein secretion. Perivagal application of capsaicin abolishes the pancreatic response to casein. CCK-JMV-180 infusion (44 μg·kg−1·h−1) fails to inhibit the pancreatic response to intraduodenal casein infusion, which suggests that endogenous CCK acts on high- but not low-affinity CCK-A receptors to stimulate pancreatic secretion. *P < Reprinted with permission from Li et al.76 Gastroenterology , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions
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Figure 10 Action potentials of a rat nodose ganglia neuron that innervates the duodenal mucosa, after intraduodenal infusion of hypertonic NaCl. (A) Control: nodose neurons that innervate the duodenal mucosa have a very low basal level of activity. Duodenal infusion of normal saline does not affect vagal afferent discharge. (B) Duodenal infusion of hypertonic NaCl (500 mOsm/L, 2 mL/min) produces a marked increase in vagal afferent discharge, which peaks at 26 impulses within 20 seconds and returns to basal 20 seconds after the lumen is rinsed with isotonic saline. (C) Administration of the 5-HT3 receptor antagonist granisetron abolishes the nodose neuronal response evoked by hypertonic NaCl. Each action potential is portrayed as a standard pulse (upper line) and an original tracing (lower line). Reprinted with permission from Zhu et al.84 Gastroenterology , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions
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Figure 11 Response of a rat nodose ganglia neuron to intraduodenal infusion of maltose. (A) The neuron responds to maltose after a latency of 10 seconds. Activity lasts for the duration of the stimulus and ceases when the lumen is rinsed with isotonic saline. (B) Administration of the CCK-8 antagonist CR-1409 has no effect on the nodose neuronal response to maltose. (C) Administration of the 5-HT3 receptor antagonist granisetron abolishes the nodose neuronal response evoked by maltose. Each action potential is portrayed as a standard pulse (upper line) and an original tracing (lower line). Reprinted with permission from Zhu et al.84 Gastroenterology , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions
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Figure 12 Interaction between CCK and non-CCK—dependent pancreatic stimuli in rats. A subthreshold dose of CCK (15 pmol kg−1 h−1) potentiates the pancreatic responses to intraduodenal administration of maltose (300 mmol/L) (A) and hypertonic NaCl (500 mOsm/L) (B). Values are means ± SEM, n = 6 in each group. *P < Reprinted with permission from Li and Owyang.62 Gastroenterology , DOI: ( /j.gastro ) Copyright © 2004 American Gastroenterological Association Terms and Conditions
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