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Stimulation of the exocrine pancreas via a third CCK-receptor subtype?
Livestock Science 108 (2007) 61 – 64 www.elsevier.com/locate/livsci
Stimulation of the exocrine pancreas via a third CCK-receptor subtype?☆ S. Rengman ⁎, B.R. Weström, S.G. Pierzynowski Department of Cell and Organism Biology, Lund University, Helgonav. 3B, SE-223 62 Lund, Sweden
Abstract The physiological role of the cholecystokinin1 receptor (CCK1R) and the cholecystokinin/gastrin receptor (CCK2R) in the enzyme release from the exocrine pancreas in various mammal species has been debated. Experiments in pigs have indicated that physiological levels of cholecystokinin-33 (CCK-33) elicit pancreatic enzyme release via CCK2Rs located in the gastro-duodenal region. Since gastrin and CCK have similar affinity for the CCK2R, the aim was to examine if gastrin can elicit a similar enzyme response as CCK, after infusion via the gastric artery. Weaned pigs were anaesthetised and surgically prepared with appropriate catheters. Pentagastrin (n = 6) or CCK-33 (n = 6), 13 pmol/kg, was infused via the gastric artery into the gastro-duodenal region and 20 min. later 130 pmol/kg of the same hormone was infused via the jugular vein to the general circulation. Pancreatic juice was collected in intervals after each infusion and analysed for its protein and enzyme (trypsin) content. CCK-33 gave rise to significantly higher protein and trypsin output compared to pentagastrin for both doses and infusion routes. The results indicate that low doses of CCK-33 infused to the duodenal region do not stimulate the exocrine pancreas via the CCK2R since the result can't be reproduced with pentagastrin. Since previous studies have indicated that CCK1R is not involved the present results indicate that a third CCK-receptor subtype might be involved in the stimulation of the exocrine pancreas. © 2007 Elsevier B.V. All rights reserved. Keywords: Exocrine pancreas; Pentagastrin; Cholecystokinin; Cholecystokinin/gastrin receptor; Pig
1. Introduction Gastrin and cholecystokinin (CCK) are hormones with important roles in the regulation of digestion processes in the gastro-intestinal tract. Gastrin and CCK have been found in various forms with active sizes from 5–34 amino acids (AA) for gastrin and 5–83AA for ☆ This paper is part of the special issue entitled “Digestive Physiology in Pigs” guest edited by José Adalberto Fernández, Mette Skou Hedemann, Bent Borg Jensen, Henry Jørgensen, Knud Erik Bach Knudsen and Helle Nygaard Lærke. ⁎ Corresponding author. Tel.: +46 46 222 9732; fax: +46 46 222 4539. E-mail address: [email protected] (S. Rengman).
1871-1413/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.livsci.2007.01.038
CCK. Both hormones have the same composition of the first five AA in the C-terminal (Gregory and Tracy, 1964; Mutt and Jorpes, 1968) and this pentapeptide includes the bioactive tetrapeptide, necessary for the efficacy of both hormones. CCK has two known receptors, CCK1R (Wank et al., 1992) and CCK2R (Kopin et al., 1992), the latter also being identified as the gastrin receptor. The CCK/gastrin receptor (CCK2R) binds CCK and gastrin while the CCK1R only bind sulphated CCK (Shulkes and Baldwin, 1997). Which of the CCK receptors that is physiological relevant in the regulation of the exocrine pancreatic enzyme release have been debated since the expression of the receptor subtypes in the exocrine
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S. Rengman et al. / Livestock Science 108 (2007) 61–64
Fig. 1. After surgery and recovery two basal samples of pancreatic juice are collected in 2 × 10 min interval before the first hormone infusion is given. After the infusions, samples are collected in 2 × 5 min. and 1 × 10 min.
pancreas seem to vary between different mammalian species (Morisset et al., 1996; Bourassa et al., 1999; Philippe et al., 1997; Lhoste et al., 1995; Owyang, 1996). Earlier experiments from our lab (Evilevitch et al., 2003, 2004), using a specific CCK1R- and CCK2R blockers and different administration routes for CCK33 have indicated that the pancreatic enzyme release is regulated via CCK2Rs located in the gastroduodenal region (Evilevitch et al., 2003) when CCK33 was given in a low dose (13 pmol/kg) mimicking postprandial levels in pigs (Cuber et al., 1989). The aim of the study was to examine if gastrin can elicit a similar enzyme response as CCK after gastro-duodenal administration since gastrin and CCK have a similar affinity and potency for the CCK2R (Dufresne et al., 2006).
Pentagastrin (Sigma-Aldrich) (n = 6) or CCK-33 (Ferring AB, Malmö, Sweden) (n = 6), 13 pmol/kg, was infused via the gastric artery to reach in first pass the gastro-duodenal region and later in the dose 130 pmol/ kg via the jugular vein to the general circulation. Pancreatic juice was collected in 2 × 5 and 1 × 10 min intervals after each infusion (Fig. 1).
2. Material and methods
2.4. Analyses
2.1. Animals
The protein content in the pancreatic juice was determined by the Lowry method (Lowry et al., 1951). The trypsin activity in the pancreatic juice was evaluated by using a modified micro method (Pierzynowski et al., 1990). The trypsin activity was measured in units (U) where 1 U is defined as the amount of enzyme needed to
Twelve crossbred [(Yorkshire × Swedish Landrace) × Hampshire] barrows, weighing 18.6 ± 8.2 kg (mean ± SD), were used in the experiment. The pigs were obtained from the Odarslöv research farm belonging to the Swedish University of Agricultural Sciences (Alnarp, Sweden) at an age of 7–11 weeks.
ketamin (Ketalar® Pfizer AB, Täby, Sweden) since halothane severely decrease the exocrine pancreatic activity (Rådberg et al., 1999). A continuous intra venous infusion of Secretin (Sigma-Aldrich Chemicals, St. Louis, MO, USA) 20 pmol/kg/h, was started at the same time to maintain a stable pancreatic secretion. 2.3. Experimental procedures
2.2. Surgical procedures The pigs were tracheal intubated and anaesthetised with halothane (Fluothan®, Astra Läkemedel, Södertälje, Sweden), 3% mixed with air and supplemented with oxygen. The external jugular veins were catheterised (Silastic®, Down Corning Corp., Midland, TX, USA) for infusions of hormones, anaesthetics and blood sampling. A Linea alba laparotomy was performed in order to catheterise the gastric artery for gastro-duodenal infusions (the epiploic artery was ligated to prevent the hormonal infusions from reaching the stomach) and the pancreatic duct for collection of pancreatic juice. After the surgery the anaesthetic agent was changed from halothane to
Fig. 2. Protein output (mg/kg/h), presented as means ± SEM, in the pancreatic juice after stimulation with pentagastrin (n = 6) or CCK-33 (n = 6), 13 pmol/kg infused via the gastric artery and 130 pmol/kg infused via the jugular vein. The increases after the CCK-33 stimulations are significantly higher, (⁎p < 0.05) and (⁎⁎p < 0.01), compared to the increases seen after the corresponding infusions of pentagastrin.
S. Rengman et al. / Livestock Science 108 (2007) 61–64
Fig. 3. Trypsin output (U/kg/h), presented as means ± SEM, in the pancreatic juice after stimulation with pentagastrin (n = 6) or CCK-33 (n = 6), 13 pmol/kg infused via the gastric artery and 130 pmol/kg infused via the jugular vein. The increases after the CCK-33 stimulations are significantly higher, (⁎p < 0.05) and (⁎⁎p < 0.01), compared to the increases seen after the corresponding infusions of pentagastrin.
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gastrin peptide than the CCK-33 peptide. However, preliminary results do not support this since results obtained with the larger Gastrin-17 peptide were similar to those obtained with pentagastrin. The significantly larger secretion initiated by CCK-33 might instead be regulated via a third putative CCK3R located in the duodenal region. Both pentagastrin and CCK-33 initiated pancreatic response when infused in high doses, 130 pmol/kg, in the peripheral circulation via the jugular vein. In pigs numerous CCK2Rs are present on the acinar cells but they should be relatively insensitive to CCK (Morisset et al., 1996). The physiological relevance of these responses is however hard to evaluate since the peripheral dose was unphysiologically high. 5. Conclusion
hydrolyse 1 mmol/minute of the substrate Na-benzoylDL-arginine-p-nitroanilide (Sigma-Aldrich) at 25 °C. 2.5. Statistics Student's t-test for samples with unequal variance, one-tailed, was used for the statistical evaluation of differences in protein and trypsin output after CCK-33 and pentagastrin stimulation. 3. Results 3.1. Protein and trypsin The protein (Fig. 2) and trypsin (Fig. 3) output was significantly higher after the CCK-33 infusions, both via the gastric artery, 13 pmol/kg, (⁎p < 0.05) and via the jugular vein, 130 pmol/kg, (⁎⁎p < 0.01) compared to the increase after the corresponding pentagastrin infusion. 4. Discussion Since both pentagastrin and CCK-33 possess identical bioactive C-terminals and are ligands with similar affinity and potency to the CCK2R we expected them to have a similar physiological action, when administered in equal doses and via the same infusion routes. In this experiment we were unable to reproduce the pancreatic response with pentagastrin as obtained with CCK-33. The gastric arterial infusion of 13 pmol/kg of pentagastrin only gave a diminutive response compared to the response after CCK-33 infusion. An explanation for this might be a faster degradation and/or elimination of the smaller penta-
The present results indicate that the stimulation of the exocrine pancreas with physiological doses of CCK33 is independent from both CCK2R and CCK1R. Instead a third CCK-receptor subtype, CCK3R, might be involved. References Bourassa, J., Lainé, J., Kruse, M.L., Gagnon, M.C., Calvo, E., Morisset, J., 1999. Ontogeny and species differences in the pancreatic expression and localizaton of the CCKA receptors. Biochem. Biophys. Res. Commun. 260, 820–828. Cuber, J.C., Corring, T., Levenez, F., Bernard, C., Chayvialle, J.A., 1989. Effects of cholecystokinin octapeptide on the pancreatic exocrine secretion in the pig. Can. J. Physiol. Pharm. 11, 1391–1397. Dufresne, M., Seva, C., Fourmy, D., 2006. Cholecystokinin and gastrin receptors. Physiol. Rev. 86, 805–847. Evilevitch, L., Weström, B.R., Pierzynowski, S.G., 2003. CCK regulates pancreatic enzyme secretion via short duodenal-pancreatic reflexes in pigs. Scand. J. Gastroenterol. 2, 201–206. Evilevitch, L., Weström, B.R., Pierzynowski, S.G., 2004. The CCK2 receptor antagonist YF476 inhibits pancreatic enzyme secretion at a duodenal level in pigs. Scand. J. Gastroenterol. 39, 886–890. Gregory, R.A., Tracy, H.J., 1964. The constitution and properties of two gastrins extracted from hog antral mucosa. Gut 5, 103–114. Kopin, A.S., Lee, Y.M., McBride, E.W., Miller, L.J., Lu, M., Lin, H.Y., Kolakowski Jr., L.F., Beinborn, M., 1992. Expression cloning and characterization of the canine parietal cell gastrin receptor. Proc. Natl. Acad. Sci. U S A. 89, 3605–3609. Lhoste, E.F., Gueugneau, A.M., Garofano, A., Philippe, C., Levenez, F., Corring, T., 1995. Role of CCK in the regulation of secretion and adaptation in the pig pancreas. Pancreas 1, 86–94. Lowry, O.H., Rosebrough, N., Farr, A., Randall, R.J., 1951. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193, 265–275. Morisset, J., Levenez, F., Corring, T., Benrezzak, O., Pelletier, G., Calvo, E., 1996. Pig pancreatic acinar cells possess predominantly the CCK-B receptor subtype. Am. J. Physiol. 271, 397–402.
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S. Rengman et al. / Livestock Science 108 (2007) 61–64
Mutt, V., Jorpes, J.E., 1968. Structure of porcine cholecystokinin– pancreozymin. Eur. J. Biochem. 6, 156–162. Owyang, C., 1996. Physiological mechanisms of cholecystokinin action on pancreatic secretion. Am. J. Physiol. 271, 1–7. Philippe, C., Lhoste, E.F., Dufresne, M., Moroder, L., Corring, T., Fourmy, D., 1997. Pharmacological and biochemical evidence for the simultaneous expression of CCKB/gastrin and CCKA receptors in the pig pancreas. Br. J. Pharmacol. 120, 447–454. Pierzynowski, S.G., Weström, B.R., Svendsen, J., Karlsson, B.W., 1990. Development of exocrine pancreas function in chronically cannulated pigs during 1–13 weeks of postnatal life. J. Pediatr. Gastroenterol. Nutr. 10, 206–212.
Rådberg, K., Botermans, J., Weström, B.R., Pierzynowski, S.G., 1999. Depressive effects of anaesthesia or sedation on exocrine pancreatic function in pigs. Lab. Anim. Sci. 49, 662–664. Shulkes, A., Baldwin, G.S., 1997. Biology of gut cholecystokinin and gastrin receptors. Clin. Exp. Pharmacol. Physiol. 24, 209–216. Wank, S.A., Harkins, R., Jensen, R.T., Shapira, H., de Weerth, A., Slattery, T., 1992. Purification, molecular cloning and functional expression of the cholecystokinin receptor from rat pancreas. Proc. Natl. Acad. Sci. USA. 89, 3125–3129.
Stimulation of the exocrine pancreas via a third CCK-receptor subtype?☆ S. Rengman ⁎, B.R. Weström, S.G. Pierzynowski Department of Cell and Organism Biology, Lund University, Helgonav. 3B, SE-223 62 Lund, Sweden
Abstract The physiological role of the cholecystokinin1 receptor (CCK1R) and the cholecystokinin/gastrin receptor (CCK2R) in the enzyme release from the exocrine pancreas in various mammal species has been debated. Experiments in pigs have indicated that physiological levels of cholecystokinin-33 (CCK-33) elicit pancreatic enzyme release via CCK2Rs located in the gastro-duodenal region. Since gastrin and CCK have similar affinity for the CCK2R, the aim was to examine if gastrin can elicit a similar enzyme response as CCK, after infusion via the gastric artery. Weaned pigs were anaesthetised and surgically prepared with appropriate catheters. Pentagastrin (n = 6) or CCK-33 (n = 6), 13 pmol/kg, was infused via the gastric artery into the gastro-duodenal region and 20 min. later 130 pmol/kg of the same hormone was infused via the jugular vein to the general circulation. Pancreatic juice was collected in intervals after each infusion and analysed for its protein and enzyme (trypsin) content. CCK-33 gave rise to significantly higher protein and trypsin output compared to pentagastrin for both doses and infusion routes. The results indicate that low doses of CCK-33 infused to the duodenal region do not stimulate the exocrine pancreas via the CCK2R since the result can't be reproduced with pentagastrin. Since previous studies have indicated that CCK1R is not involved the present results indicate that a third CCK-receptor subtype might be involved in the stimulation of the exocrine pancreas. © 2007 Elsevier B.V. All rights reserved. Keywords: Exocrine pancreas; Pentagastrin; Cholecystokinin; Cholecystokinin/gastrin receptor; Pig
1. Introduction Gastrin and cholecystokinin (CCK) are hormones with important roles in the regulation of digestion processes in the gastro-intestinal tract. Gastrin and CCK have been found in various forms with active sizes from 5–34 amino acids (AA) for gastrin and 5–83AA for ☆ This paper is part of the special issue entitled “Digestive Physiology in Pigs” guest edited by José Adalberto Fernández, Mette Skou Hedemann, Bent Borg Jensen, Henry Jørgensen, Knud Erik Bach Knudsen and Helle Nygaard Lærke. ⁎ Corresponding author. Tel.: +46 46 222 9732; fax: +46 46 222 4539. E-mail address: [email protected] (S. Rengman).
1871-1413/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.livsci.2007.01.038
CCK. Both hormones have the same composition of the first five AA in the C-terminal (Gregory and Tracy, 1964; Mutt and Jorpes, 1968) and this pentapeptide includes the bioactive tetrapeptide, necessary for the efficacy of both hormones. CCK has two known receptors, CCK1R (Wank et al., 1992) and CCK2R (Kopin et al., 1992), the latter also being identified as the gastrin receptor. The CCK/gastrin receptor (CCK2R) binds CCK and gastrin while the CCK1R only bind sulphated CCK (Shulkes and Baldwin, 1997). Which of the CCK receptors that is physiological relevant in the regulation of the exocrine pancreatic enzyme release have been debated since the expression of the receptor subtypes in the exocrine
62
S. Rengman et al. / Livestock Science 108 (2007) 61–64
Fig. 1. After surgery and recovery two basal samples of pancreatic juice are collected in 2 × 10 min interval before the first hormone infusion is given. After the infusions, samples are collected in 2 × 5 min. and 1 × 10 min.
pancreas seem to vary between different mammalian species (Morisset et al., 1996; Bourassa et al., 1999; Philippe et al., 1997; Lhoste et al., 1995; Owyang, 1996). Earlier experiments from our lab (Evilevitch et al., 2003, 2004), using a specific CCK1R- and CCK2R blockers and different administration routes for CCK33 have indicated that the pancreatic enzyme release is regulated via CCK2Rs located in the gastroduodenal region (Evilevitch et al., 2003) when CCK33 was given in a low dose (13 pmol/kg) mimicking postprandial levels in pigs (Cuber et al., 1989). The aim of the study was to examine if gastrin can elicit a similar enzyme response as CCK after gastro-duodenal administration since gastrin and CCK have a similar affinity and potency for the CCK2R (Dufresne et al., 2006).
Pentagastrin (Sigma-Aldrich) (n = 6) or CCK-33 (Ferring AB, Malmö, Sweden) (n = 6), 13 pmol/kg, was infused via the gastric artery to reach in first pass the gastro-duodenal region and later in the dose 130 pmol/ kg via the jugular vein to the general circulation. Pancreatic juice was collected in 2 × 5 and 1 × 10 min intervals after each infusion (Fig. 1).
2. Material and methods
2.4. Analyses
2.1. Animals
The protein content in the pancreatic juice was determined by the Lowry method (Lowry et al., 1951). The trypsin activity in the pancreatic juice was evaluated by using a modified micro method (Pierzynowski et al., 1990). The trypsin activity was measured in units (U) where 1 U is defined as the amount of enzyme needed to
Twelve crossbred [(Yorkshire × Swedish Landrace) × Hampshire] barrows, weighing 18.6 ± 8.2 kg (mean ± SD), were used in the experiment. The pigs were obtained from the Odarslöv research farm belonging to the Swedish University of Agricultural Sciences (Alnarp, Sweden) at an age of 7–11 weeks.
ketamin (Ketalar® Pfizer AB, Täby, Sweden) since halothane severely decrease the exocrine pancreatic activity (Rådberg et al., 1999). A continuous intra venous infusion of Secretin (Sigma-Aldrich Chemicals, St. Louis, MO, USA) 20 pmol/kg/h, was started at the same time to maintain a stable pancreatic secretion. 2.3. Experimental procedures
2.2. Surgical procedures The pigs were tracheal intubated and anaesthetised with halothane (Fluothan®, Astra Läkemedel, Södertälje, Sweden), 3% mixed with air and supplemented with oxygen. The external jugular veins were catheterised (Silastic®, Down Corning Corp., Midland, TX, USA) for infusions of hormones, anaesthetics and blood sampling. A Linea alba laparotomy was performed in order to catheterise the gastric artery for gastro-duodenal infusions (the epiploic artery was ligated to prevent the hormonal infusions from reaching the stomach) and the pancreatic duct for collection of pancreatic juice. After the surgery the anaesthetic agent was changed from halothane to
Fig. 2. Protein output (mg/kg/h), presented as means ± SEM, in the pancreatic juice after stimulation with pentagastrin (n = 6) or CCK-33 (n = 6), 13 pmol/kg infused via the gastric artery and 130 pmol/kg infused via the jugular vein. The increases after the CCK-33 stimulations are significantly higher, (⁎p < 0.05) and (⁎⁎p < 0.01), compared to the increases seen after the corresponding infusions of pentagastrin.
S. Rengman et al. / Livestock Science 108 (2007) 61–64
Fig. 3. Trypsin output (U/kg/h), presented as means ± SEM, in the pancreatic juice after stimulation with pentagastrin (n = 6) or CCK-33 (n = 6), 13 pmol/kg infused via the gastric artery and 130 pmol/kg infused via the jugular vein. The increases after the CCK-33 stimulations are significantly higher, (⁎p < 0.05) and (⁎⁎p < 0.01), compared to the increases seen after the corresponding infusions of pentagastrin.
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gastrin peptide than the CCK-33 peptide. However, preliminary results do not support this since results obtained with the larger Gastrin-17 peptide were similar to those obtained with pentagastrin. The significantly larger secretion initiated by CCK-33 might instead be regulated via a third putative CCK3R located in the duodenal region. Both pentagastrin and CCK-33 initiated pancreatic response when infused in high doses, 130 pmol/kg, in the peripheral circulation via the jugular vein. In pigs numerous CCK2Rs are present on the acinar cells but they should be relatively insensitive to CCK (Morisset et al., 1996). The physiological relevance of these responses is however hard to evaluate since the peripheral dose was unphysiologically high. 5. Conclusion
hydrolyse 1 mmol/minute of the substrate Na-benzoylDL-arginine-p-nitroanilide (Sigma-Aldrich) at 25 °C. 2.5. Statistics Student's t-test for samples with unequal variance, one-tailed, was used for the statistical evaluation of differences in protein and trypsin output after CCK-33 and pentagastrin stimulation. 3. Results 3.1. Protein and trypsin The protein (Fig. 2) and trypsin (Fig. 3) output was significantly higher after the CCK-33 infusions, both via the gastric artery, 13 pmol/kg, (⁎p < 0.05) and via the jugular vein, 130 pmol/kg, (⁎⁎p < 0.01) compared to the increase after the corresponding pentagastrin infusion. 4. Discussion Since both pentagastrin and CCK-33 possess identical bioactive C-terminals and are ligands with similar affinity and potency to the CCK2R we expected them to have a similar physiological action, when administered in equal doses and via the same infusion routes. In this experiment we were unable to reproduce the pancreatic response with pentagastrin as obtained with CCK-33. The gastric arterial infusion of 13 pmol/kg of pentagastrin only gave a diminutive response compared to the response after CCK-33 infusion. An explanation for this might be a faster degradation and/or elimination of the smaller penta-
The present results indicate that the stimulation of the exocrine pancreas with physiological doses of CCK33 is independent from both CCK2R and CCK1R. Instead a third CCK-receptor subtype, CCK3R, might be involved. References Bourassa, J., Lainé, J., Kruse, M.L., Gagnon, M.C., Calvo, E., Morisset, J., 1999. Ontogeny and species differences in the pancreatic expression and localizaton of the CCKA receptors. Biochem. Biophys. Res. Commun. 260, 820–828. Cuber, J.C., Corring, T., Levenez, F., Bernard, C., Chayvialle, J.A., 1989. Effects of cholecystokinin octapeptide on the pancreatic exocrine secretion in the pig. Can. J. Physiol. Pharm. 11, 1391–1397. Dufresne, M., Seva, C., Fourmy, D., 2006. Cholecystokinin and gastrin receptors. Physiol. Rev. 86, 805–847. Evilevitch, L., Weström, B.R., Pierzynowski, S.G., 2003. CCK regulates pancreatic enzyme secretion via short duodenal-pancreatic reflexes in pigs. Scand. J. Gastroenterol. 2, 201–206. Evilevitch, L., Weström, B.R., Pierzynowski, S.G., 2004. The CCK2 receptor antagonist YF476 inhibits pancreatic enzyme secretion at a duodenal level in pigs. Scand. J. Gastroenterol. 39, 886–890. Gregory, R.A., Tracy, H.J., 1964. The constitution and properties of two gastrins extracted from hog antral mucosa. Gut 5, 103–114. Kopin, A.S., Lee, Y.M., McBride, E.W., Miller, L.J., Lu, M., Lin, H.Y., Kolakowski Jr., L.F., Beinborn, M., 1992. Expression cloning and characterization of the canine parietal cell gastrin receptor. Proc. Natl. Acad. Sci. U S A. 89, 3605–3609. Lhoste, E.F., Gueugneau, A.M., Garofano, A., Philippe, C., Levenez, F., Corring, T., 1995. Role of CCK in the regulation of secretion and adaptation in the pig pancreas. Pancreas 1, 86–94. Lowry, O.H., Rosebrough, N., Farr, A., Randall, R.J., 1951. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193, 265–275. Morisset, J., Levenez, F., Corring, T., Benrezzak, O., Pelletier, G., Calvo, E., 1996. Pig pancreatic acinar cells possess predominantly the CCK-B receptor subtype. Am. J. Physiol. 271, 397–402.
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Mutt, V., Jorpes, J.E., 1968. Structure of porcine cholecystokinin– pancreozymin. Eur. J. Biochem. 6, 156–162. Owyang, C., 1996. Physiological mechanisms of cholecystokinin action on pancreatic secretion. Am. J. Physiol. 271, 1–7. Philippe, C., Lhoste, E.F., Dufresne, M., Moroder, L., Corring, T., Fourmy, D., 1997. Pharmacological and biochemical evidence for the simultaneous expression of CCKB/gastrin and CCKA receptors in the pig pancreas. Br. J. Pharmacol. 120, 447–454. Pierzynowski, S.G., Weström, B.R., Svendsen, J., Karlsson, B.W., 1990. Development of exocrine pancreas function in chronically cannulated pigs during 1–13 weeks of postnatal life. J. Pediatr. Gastroenterol. Nutr. 10, 206–212.
Rådberg, K., Botermans, J., Weström, B.R., Pierzynowski, S.G., 1999. Depressive effects of anaesthesia or sedation on exocrine pancreatic function in pigs. Lab. Anim. Sci. 49, 662–664. Shulkes, A., Baldwin, G.S., 1997. Biology of gut cholecystokinin and gastrin receptors. Clin. Exp. Pharmacol. Physiol. 24, 209–216. Wank, S.A., Harkins, R., Jensen, R.T., Shapira, H., de Weerth, A., Slattery, T., 1992. Purification, molecular cloning and functional expression of the cholecystokinin receptor from rat pancreas. Proc. Natl. Acad. Sci. USA. 89, 3125–3129.