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J W Black - One of the best experts on this subject based on the ideXlab platform.
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the use of receptor desensitization to analyse ccka and cckb gastrin receptors coupled to contraction in guinea pig stomach muscle
British Journal of Pharmacology, 1995Co-Authors: L A Bishop, V P Gerskowitch, R A D Hull, N P Shankley, J W BlackAbstract:1. The results of previous studies have been in conflict with respect to the involvement of specific cholecystokinin (CCKA) and CCKB/gastrin receptors in guinea-pig gastric muscle. Here, in an in vitro, guinea-pig gastric muscle assay, pentagastrin (PG) and tetragastrin (TG) behaved as high potency agonists and produced symmetrical concentration-effect curves. In contrast, cholecystokinin-octapeptide (CCK-8), while also behaving as a high potency agonist, produced flat asymmetrical curves. Unlike recent data reported using this tissue (Boyle et al., 1993), the CCKA receptor-selective antagonist, Devazepide (3, 10, 30 nM) produced a rightward shift of the upper region of the CCK-8 curve rendering it biphasic. The lower phase was abolished by the CCKB/gastrin receptor-selective antagonist, L-365260 (300 nM) indicating that the contractile effects of CCK-8 in this tissue are mediated by both receptor types. 2. L-365260 produced a concentration-dependent, parallel rightward displacement of PG concentration-effect curves. However, a flat Schild plot slope parameter (0.77 +/- 0.06) was obtained. Therefore, an empirical pA2 value of 8.64 +/- 0.21 was estimated from the smallest dose ratio. This value is consistent with published values characteristic of an interaction at CCKB/gastrin receptors. 3. TG (1 microM) was used to densensitize selectively the CCKB/gastrin receptors in the gastric muscle assay and thereby expose a population of receptors capable of responding to subsequent stimulation by CCK-8 but not by PG. The selectivity of TG for CCKB/gastrin- over CCKA receptors was demonstrated by its low efficacy compared to CCK-8 in the guinea-pig gallbladder assay, a tissue shown previously to contain a homogeneous population of CCKA receptors. In TG-desensitized gastric muscle, CCK-8 concentration-effect curves were symmetrical and could be displaced in a simple parallel fashion by Devazepide at nanomolar concentrations consistent with an interaction at CCKA receptors (pKB approximately 10). 4. These results indicate that the guinea-pig gastric muscle contains both CCKA- and CCKB/gastrin receptors and the effects of CCK-8 are mediated via both of these receptors. Notwithstanding the complexity of the behaviour of L-365260, it was possible to obtain a reasonable description of the system using a simple 2-receptor model in which the effects of individual receptor activation were assumed to be additive. The absence of a simple competitive interaction of PG with L-365260 may indicate, for example, non-homogeneity of CCKB/gastrin receptors or lack of concentration equilibrium between the bath and the receptor biophase.
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combined dose ratio analysis of cholecystokinin receptor antagonists Devazepide lorglumide and loxiglumide in the guinea pig gall bladder
British Journal of Pharmacology, 1992Co-Authors: L A Bishop, V P Gerskowitch, R A D Hull, N P Shankley, J W BlackAbstract:1. Interactions between cholecystokinin octapeptide (CCK-8) and CCKA-receptor antagonists derived from benzodiazepines (Devazepide) and glutamic acid (lorglumide and loxiglumide) have been examined in an improved bioassay using the guinea-pig, isolated, gall bladder preparation. 2. The presence of CCKB-receptors in the assay was provisionally-ruled out on the basis of the low potency of pentagastrin in the assay. By applying analyses of both agonism and antagonism, pentagastrin was shown to behave as a partial agonist at the CCKA-receptor. 3. Devazepide, lorglumide and loxiglumide behaved as simple competitive antagonists of CCKA-receptors and pKB values of 9.98, 7.59 and 7.07 were estimated, respectively. 4. Application of a combined dose-ratio analysis to the interactions between CCK-8 and combinations of Devazepide/lorglumide and Devazepide/loxiglumide indicated that these molecules behave as syntopic, competitive, antagonists at the CCKA-receptor. 5. We conclude that the guinea-pig gall bladder assay contains a homogeneous population of CCKA-receptors and offer an explanation for the differences between our results and those obtained recently by Maubach et al. (1991) which were taken as preliminary evidence for CCKA-receptor heterogeneity.
Jan Axelson - One of the best experts on this subject based on the ideXlab platform.
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Acute taurodeoxycholate-induced pancreatitis in the rat is associated with hyperCCKemia
International Journal of Pancreatology, 2000Co-Authors: Bodil Ohlsson, Jens F Rehfeld, Jan Axelson, Unne Stenram, Ingemar IhseAbstract:Background. Cholecystokinin (CCK) has been suggested to be involved in the development and course of acute pancreatitis. In the present study we measured plasma CCK concentrations in acute experimental pancreatitis (AEP) in the rat, and evaluated the role of circulating CCK levels on the initial pancreatic damage in pancreatitis. Methods. Endogenous hyperCCKemia was induced by surgical biliodigestive shunt (BDS) and exogenous hyperCCKemia by infusion of CCK-8S. The CCK-A receptor antagonist Devazepide was used to antagonize the effect of CCK. Pancreatitis was induced by pancreatic duct infusion of sodium taurodeoxycholate 4 wk after the BDS operation or 1 wk after the start of the infusions. Nonpancreatitic sham- and BDS-operated rats, respectively, were used as control animals as were groups of otherwise untreated rats with pancreatitis. The animals were sacrificed 6 h after induction of pancreatitis. Concentrations of CCK were determined in plasma as were protein and amylase levels in the pancreas and peritoneal exudates. The extent of pancreatic necroses was assessed microscopically. Results. Pancreatitis caused an 11–20-fold increase of circulating CCK as measured after 6 h. In pancreatitic rats with induced hyperCCKemia, there was a further marked increase of plasma CCK. Pancreatic weight and edema, protein and amylase contents, and extent of necroses were the same regardless of the level of plasma CCK. Devazepide had no influence on the studied pancreatic parameters. Conclusion. We conclude that acute taurodeoxycholate-induced pancreatitis in the rat is associated with elevated plasma CCK concentrations. There seems, however, not to be any correlation between the degree of hyperCCKemia and the extent of initial pancreatic damage.
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The effect of intermittent injections of CCK-8S and the CCK-A receptor antagonist Devazepide on cell proliferation in exocrine rat pancreas
International Journal of Pancreatology, 1998Co-Authors: Bodil Ohlsson, Jens F Rehfeld, Karin Borg, Ingemar Ihse, Jan AxelsonAbstract:Conclusion Intermittent injections of sulfated cholecystokinin-8 (CCK-8S) or Devazepide caused longlasting effects on cell proliferation in exocrine pancreas in contrast to continuous infusion. The acinar cells responded to both treatments with changes in the labeling index (LI) during the whole study period. When studying the influence of stimulation and inhibition of the CCK-A receptor on cell proliferation in the exocrine pancreas, not only are the drugs and doses of importance but also the mode of administration . Background Continuous infusion of CCK-8S or the CCK-A receptor antagonist Devazepide induces transient changes in acinar cell proliferation in rat pancreas. The aim of the present experiments was to study whether intermittent administration of CCK-8S or Devazepide prevents receptor desensitization and thereby affects exocrine pancreatic cell proliferation persistently. Methods Male Sprague-Dawley rats were injected subcutaneously twice daily with CCK-8S (6 μg), Devazepide (240 μg) or bovine serum albumin (BSA). The rats were sacrificed after 18 and 36 h and 3 and 7 d. One hour before sacrifice, the rats were injected intraperitoneally with 1 mCi/kg of tritiated thymidine. The pancreatic weight and the contents of water, protein, and DNA were determined. The LI (number of labeled cells/100 cells) of exocrine pancreatic cells was determined microscopically after autoradiography. Results The concentration of plasma CCK was slightly increased by Devazepide, but the increase was more pronounced by CCK-8S. The pancreatic wet weight was transiently increased 18 h after the start of CCK-8S injections (+14%), whereas Devazepide caused a reduction after 7 d (−22%). The protein content was uninfluenced and the DNA content was decreased at 36 h with either treatment. CCK-8S increased the LI in acinar and centroacinar cells throughout the study period, but the ductal cell LI was increased only after 18 and 36 h. Injection of Devazepide was followed by decreased LI of acinar cells throughout the study period. Also, the centroacinar and ductal cell LI decreased initially but returned to control values after 7 d.
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the effect of intermittent injections of cck 8s and the cck a receptor antagonist Devazepide on cell proliferation in exocrine rat pancreas
International Journal of Pancreatology, 1998Co-Authors: Bodil Ohlsson, Jens F Rehfeld, Karin Borg, Ingemar Ihse, Jan AxelsonAbstract:Conclusion Intermittent injections of sulfated cholecystokinin-8 (CCK-8S) or Devazepide caused longlasting effects on cell proliferation in exocrine pancreas in contrast to continuous infusion. The acinar cells responded to both treatments with changes in the labeling index (LI) during the whole study period. When studying the influence of stimulation and inhibition of the CCK-A receptor on cell proliferation in the exocrine pancreas, not only are the drugs and doses of importance but also the mode of administration.
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an evaluation of the influence of Devazepide and cck 8s on the intact and resected rat liver
European Surgical Research, 1998Co-Authors: Bodil Ohlsson, Jens F Rehfeld, Jan AxelsonAbstract:BACKGROUND: Recently, it has been shown that infusion of the CCK-A receptor antagonist Devazepide induced proliferation of hepatocytes and bile duct epithelium in the rat liver. The aim of this study was to further evaluate the influence of Devazepide and sulfated cholecystokinin-8 (CCK-8S) on the intact rat liver and rat liver after resection. METHODS: In the first experiment, either saline or Devazepide was injected subcutaneously twice daily to rats for 18 and 36 h and 3 and 7 days. In the second experiment, a 70% liver resection was followed by infusion of either DMSO, Devazepide, saline or CCK-8S for 2 or 7 days. Prior to sacrifice, all rats received 1 mCi/kg of tritiated thymidine intraperitoneally. The liver was excised and the contents of protein, DNA and water and incorporation of tritiated thymidine were measured. RESULTS: Intermittent injections of Devazepide increased the liver protein content after 36 h, followed by a decrease after 7 days. The weight, DNA content or cell proliferation was not affected. Two days after liver resection hyperCCKemia was evoked, which was less prominent after 7 days. Devazepide lowered the plasma concentration of CCK, while the infusion of CCK-8S resulted in extremely high concentrations at both time points. The DNA synthesis measured by thymidine incorporation was increased by Devazepide on day 2, whereas the weight or protein and DNA contents of the liver were not influenced. CCK-8S infusion decreased the body and liver weight throughout the study, and the protein and DNA contents after 7 days. CONCLUSIONS: Intermittent Devazepide treatment did not affect the intact liver. Devazepide increased the DNA synthesis 2 days after liver resection but was without other influences on the liver regeneration. CCK-8S induced decreased body weight with ensuing negative effects on the liver regeneration. Neither Devazepide nor CCK seem to be of any therapeutic use after liver resection or liver failure. (Less)
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The changes in the rat parotid glands following total parenteral nutrition and pancreatico-biliary diversion are not mediated by cholecystokinin
International Journal of Pancreatology, 1996Co-Authors: Jan Axelson, Bodil Ohlsson, Bo Guang Fan, Jens Rehfeld, Mats Ekelund, Ingemar IhseAbstract:Conclusions The results of the present study suggest that the pancreas and parotid glands both respond with hypoplasia during absence of food in the digestive tract and with hyperplasia following pancreactico-biliary diversion (PBD). Factors other than cholecystokinin (CCK) are, however, involved in the effects on the parotid glands, since infusion of CCK-8S and Devazepide was without influence. Background and Aim Total parenteral nutrition (TPN) causes reduced pancreatic weight, whereas PBD evokes hyperCCKemia and enlargement of the rat pancreas. The pancreas and parotid glands have in part similar morphology and function. Therefore, we studied the possible presence of alterations also in the parotid glands during TPN, after PBD and during infusion of sulfated cholecystokinin (CCK-8S) and the CCK-A receptor antagonist Devazepide, respectively. Materials and Results Rats either received TPN for 7 d, or were kept under otherwise identical conditions with free access to food and water. TPN markedly reduced both pancreatic and parotid wet weight and thereby also the protein and amylase contents, and pancreatic DNA content was decreased. There was a significant correlation between the pancreas and parotid glands when comparing these parameters. The concentration of plasma CCK was unaffected by TPN. PBD caused a sevenfold increase in plasma CCK and a threefold increase in the pancreatic weight compared to control rats 28 d after the operation. The protein and DNA contents in the pancreas were found to be increased. The parotid glands increased twofold in weight, but their protein and amylase contents were not affected. There was a significant correlation between the pancreas and parotid glands when comparing weight, and protein and amylase concentrations. Infusion of CCK-8S during 28 d caused a marked increase in pancreatic wet wt and protein and DNA contents. The CCK-A receptor antagonist Devazepide induced a reduction in protein and DNA contents in the pancreas. The parotid glands were not affected by either treatment. No effect on the labeling index of serous and ductal cells of the parotid gland was seen at 36 h, 3, 7, and 28 d of infusion with CCK-8S or Devazepide.
Edward M Sellers - One of the best experts on this subject based on the ideXlab platform.
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the ccka receptor antagonist Devazepide does not modify opioid self administration or drug discrimination comparison with the dopamine antagonist haloperidol
Brain Research, 1994Co-Authors: Guy A Higgins, Narges Joharchi, Yephat Wang, William A Corrigall, Edward M SellersAbstract:Abstract We previously reported that the selective cholecystokininA (CCKA) receptor antagonist, Devazepide, blocked the acquisition of a morphine conditioned place preference (ref 28). An interpretation of this finding is that Devazepide may either affect an opioid discriminative stimulus and/or modify the rewarding properties of opioids. The present study was designed to investigate these issues by determining the effect of equivalent doses of Devazepide in a morphine drug discrimination paradigm and a model of heroin self-administration. In each case, Devazepide (0.001–1 mg/kg) was ineffective, i.e there was no antagonism of a morphine discriminative cue, and in a separate group of rats trained to self-administer heroin (0.03 mg/kg/infusion, FR5 schedule, 1h per day), Devazepide did not alter the pattern of heroin responding. Because of evidence implicating an interaction between accumbens CCK and dopamine (DA) systems and evidence suggesting an apparent differential involvement of DA in opioid place conditioning, self-administration and drug discrimination behaviour, the effect of the DA antagonist haloperidol was examined in the latter two paradigms. In each test, haloperidol produced an effect inconsistent with a direct DAergic involvement. In a final study the CCKB antagonist L365-260 was also found not to affect an opioid discriminative cue. The present results therefore cast doubt on the potential utility of selective CCKA antagonists as treatments for opioid abuse, and further suggest that CCKB antagonists may not potentiate the subjective effects of opioids, an important finding considering that such drugs have been proposed as adjuncts to opioid therapy for the treatment of pain relief.
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blockade of morphine place conditioning by the ccka receptor antagonist Devazepide
European Journal of Pharmacology, 1991Co-Authors: Guy A Higgins, Peter V Nguyen, Edward M SellersAbstract:Bearing in mind the probable involvement of the mesolimbic dopamine system in morphine place conditioning and the interaction of CCK with certain elements of this pathway, we decided to investigate the effects of these CCK A and CCK B receptor antagonists on the acquisition of morphine place preference
L A Bishop - One of the best experts on this subject based on the ideXlab platform.
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the use of receptor desensitization to analyse ccka and cckb gastrin receptors coupled to contraction in guinea pig stomach muscle
British Journal of Pharmacology, 1995Co-Authors: L A Bishop, V P Gerskowitch, R A D Hull, N P Shankley, J W BlackAbstract:1. The results of previous studies have been in conflict with respect to the involvement of specific cholecystokinin (CCKA) and CCKB/gastrin receptors in guinea-pig gastric muscle. Here, in an in vitro, guinea-pig gastric muscle assay, pentagastrin (PG) and tetragastrin (TG) behaved as high potency agonists and produced symmetrical concentration-effect curves. In contrast, cholecystokinin-octapeptide (CCK-8), while also behaving as a high potency agonist, produced flat asymmetrical curves. Unlike recent data reported using this tissue (Boyle et al., 1993), the CCKA receptor-selective antagonist, Devazepide (3, 10, 30 nM) produced a rightward shift of the upper region of the CCK-8 curve rendering it biphasic. The lower phase was abolished by the CCKB/gastrin receptor-selective antagonist, L-365260 (300 nM) indicating that the contractile effects of CCK-8 in this tissue are mediated by both receptor types. 2. L-365260 produced a concentration-dependent, parallel rightward displacement of PG concentration-effect curves. However, a flat Schild plot slope parameter (0.77 +/- 0.06) was obtained. Therefore, an empirical pA2 value of 8.64 +/- 0.21 was estimated from the smallest dose ratio. This value is consistent with published values characteristic of an interaction at CCKB/gastrin receptors. 3. TG (1 microM) was used to densensitize selectively the CCKB/gastrin receptors in the gastric muscle assay and thereby expose a population of receptors capable of responding to subsequent stimulation by CCK-8 but not by PG. The selectivity of TG for CCKB/gastrin- over CCKA receptors was demonstrated by its low efficacy compared to CCK-8 in the guinea-pig gallbladder assay, a tissue shown previously to contain a homogeneous population of CCKA receptors. In TG-desensitized gastric muscle, CCK-8 concentration-effect curves were symmetrical and could be displaced in a simple parallel fashion by Devazepide at nanomolar concentrations consistent with an interaction at CCKA receptors (pKB approximately 10). 4. These results indicate that the guinea-pig gastric muscle contains both CCKA- and CCKB/gastrin receptors and the effects of CCK-8 are mediated via both of these receptors. Notwithstanding the complexity of the behaviour of L-365260, it was possible to obtain a reasonable description of the system using a simple 2-receptor model in which the effects of individual receptor activation were assumed to be additive. The absence of a simple competitive interaction of PG with L-365260 may indicate, for example, non-homogeneity of CCKB/gastrin receptors or lack of concentration equilibrium between the bath and the receptor biophase.
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combined dose ratio analysis of cholecystokinin receptor antagonists Devazepide lorglumide and loxiglumide in the guinea pig gall bladder
British Journal of Pharmacology, 1992Co-Authors: L A Bishop, V P Gerskowitch, R A D Hull, N P Shankley, J W BlackAbstract:1. Interactions between cholecystokinin octapeptide (CCK-8) and CCKA-receptor antagonists derived from benzodiazepines (Devazepide) and glutamic acid (lorglumide and loxiglumide) have been examined in an improved bioassay using the guinea-pig, isolated, gall bladder preparation. 2. The presence of CCKB-receptors in the assay was provisionally-ruled out on the basis of the low potency of pentagastrin in the assay. By applying analyses of both agonism and antagonism, pentagastrin was shown to behave as a partial agonist at the CCKA-receptor. 3. Devazepide, lorglumide and loxiglumide behaved as simple competitive antagonists of CCKA-receptors and pKB values of 9.98, 7.59 and 7.07 were estimated, respectively. 4. Application of a combined dose-ratio analysis to the interactions between CCK-8 and combinations of Devazepide/lorglumide and Devazepide/loxiglumide indicated that these molecules behave as syntopic, competitive, antagonists at the CCKA-receptor. 5. We conclude that the guinea-pig gall bladder assay contains a homogeneous population of CCKA-receptors and offer an explanation for the differences between our results and those obtained recently by Maubach et al. (1991) which were taken as preliminary evidence for CCKA-receptor heterogeneity.
Lucila Leico Kagohara Elias - One of the best experts on this subject based on the ideXlab platform.
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cholecystokinin and hypothalamic corticotrophin releasing factor participate in endotoxin induced hypophagia
Experimental Physiology, 2011Co-Authors: Rodrigo Rorato, Wagner Luis Reis, Jose Antunesrodrigues, Lucila Leico Kagohara EliasAbstract:Cholecystokinin (CCK) provides a meal-related signal that activates brainstem neurons, which have reciprocal interconnections with the hypothalamic paraventricular nucleus. Neurons that express corticotrophin-releasing factor (CRF) in the hypothalamus possess anorexigenic effects and are activated during endotoxaemia. This study investigated the effects of CCK1 receptor blockade on lipopolysaccharide (LPS)-induced hypophagia and hypothalamic CRF neuronal activation. Male Wistar rats were pretreated with a specific CCK1 receptor antagonist (Devazepide; 1 mg kg−1; i.p.) or vehicle; 30 min later they received LPS (100 μg kg−1; i.p.) or saline injection. Food intake, corticosterone responses and Fos–CRF and Fos–α-melanocyte-stimulating hormone (α-MSH) immunoreactivity in the hypothalamus and Fos–tyrosine hydroxylase immunoreactivity in the nucleus of the solitary tract (NTS) were evaluated. In comparison with saline treatment, LPS administration decreased food intake and increased plasma corticosterone levels, as well as the number of Fos–CRF and Fos– tyrosine hydroxylase double-labelled neurons in vehicle-pretreated rats; no change in Fos–α-MSH immunoreactivity was observed after LPS injection. In saline-treated animals, Devazepide pretreatment increased food intake, but it did not modify other parameters compared with vehicle-pretreated rats. Devazepide pretreatment partly reversed LPS-induced hypophagia and Fos–CRF and brainstem neuronal activation. Devazepide did not modify the corticosterone and Fos–α-MSH responses in rats treated with LPS. In conclusion, the present data suggest that LPS-induced hypophagia is mediated at least in part by CCK effects, via CCK1 receptor, on NTS and hypothalamic CRF neurons.