cholecystokinin and Ischemia

Cholecystokinin (CCK) and related peptides are supposed to be potent analgesic neuropeptides. Studies in rodents suggest a dose-dependent biphasic effect. The present study aimed to examine the pain modulating effect of different doses (0.5 microgram and 5 micrograms) of ceruletide (CRL), infused i.v. for 30 min. Pain thresholds were obtained for ischemic, mechanical, and thermal pain. In addition, pain tolerance was measured for mechanical pain. According to a placebo-controlled double-blind within-subject design 25 healthy men attended three experimental sessions each. Pain perception was measured as a baseline and twice after the infusion. The effect of both doses of CRL to enhance the pain threshold for thermal stimuli is in line with former studies. However, perception of heat stimuli above or below the threshold was not substantially affected by CRL treatment. Algesic properties of CRL are also indicated, because the tolerance for mechanical pain decreased after administration of the high dose of CRL. Perception of ischemic pain was not obviously influenced by any of the treatments. The role of CRL in human pain modulation seems to vary, depending on the type of experimental pain.

Topics: Adult; Affect; Analgesics, Non-Narcotic; Blood Pressure; Ceruletide; Cholecystokinin; Double-Blind Method; Hot Temperature; Humans; Hydrocortisone; Ischemia; Male; Pain; Pain Measurement; Pain Threshold; Pressure; Reaction Time

Cholecystokinin (CCK-8) has been shown to exhibit pharmacological preconditioning and cardioprotective effects. However, the molecular mechanisms involved in CCK-8-induced pharmacological preconditioning have not yet been clarified.. The current study explored the molecular mechanisms involved in CCK-8-mediated pharmacological preconditioning effects on ischemic rat hearts.. Pharmacological preconditioning was induced in male Wistar rats by administration of CCK-8 (20 μg/kg) 24 h before heart isolation. The PI3K inhibitor LY294002 (10 mg/kg and 20 mg/kg) and the HIF-1α inhibitor YC-1 (1 mg/kg and 2 mg/kg) were administered 30 min before the administration of CCK-8. The hearts were subjected to ischemia-reperfusion (IR) injury using a Langendorff apparatus. Myocardial injury was quantified by measuring the release of LDH-1, CK-MB and cTnT. The levels of HIF-1α and p-Akt expression and the ratio of p-GSK-3β/GSK-3β, were assessed in the heart homogenates.. Pharmacological preconditioning with CCK-8 reduced IR-induced increases in the release of LDH, CK-MB and cTnT. Moreover, it restored the expression of HIF-1α and p-Akt, and the p-GSK-3β/GSK-3β ratio. However, administration of LY294002 or YC-1 with CCK-8 significantly abolished the cardioprotective effects of pharmacological preconditioning. The PI3K and HIF-1α inhibitors also abolished the effects of CCK-8 preconditioning on HIF-1α, p-Akt and p-GSK-3β/GSK-3β.. Based on these findings, it may be concluded that the molecular mechanisms participating in CCK-8-induced pharmacological preconditioning involve HIF-1α, PI3K, Akt, and GSK-3β signaling pathways.

Topics: Animals; Cholecystokinin; Glycogen Synthase Kinase 3 beta; Ischemia; Male; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar

Cholecystokinin (CCK), as a gastrointestinal hormone, has an important protective role against sepsis or LPS-induced endotoxic shock. We aim to address the role of CCK in hepatic ischemia followed by reperfusion (I/R) injury.. A murine model of 60min partial hepatic ischemia followed by 6h of reperfusion was used in this study. CCK and CCKAR Levels in blood and liver were detected at 3h, 6h, 12h and 24h after reperfusion. Then the mice were treated with CCK or proglumide, a nonspecific CCK-receptor (CCK-R) antagonist. Mice were randomly divided into four groups as follows: (1) sham group, in which mice underwent sham operation and received saline; (2) I/R group, in which mice were subjected to hepatic I/R and received saline; (3) CCK group, in which mice were subjected to hepatic I/R and treated with CCK (400μg/kg); (4) proglumide group (Pro), in which mice underwent hepatic I/R and treated with proglumide (3mg/kg); CCK and proglumide were administrated via tail vein at the moment of reperfusion. Serum AST (sAST) and serum ALT (sALT) were determined with a biochemical assay and histological analysis were performed with hematoxylin-eosin (H&E). Cytokines (IL-1β, IL-6, IL-10, TNF-α) expressions in blood were determined with enzyme-linked immunosorbent assay (ELISA). The MPO (myeloperoxidase) assay were used to measure neutrophils' infiltration into the liver. The apoptotic index (TUNEL-positive cell number/total liver cell number×100%) was calculated to assess hepatocelluar apoptosis. Finally, activation of NF-κB and phosphor-p38 expression in liver homogenates were analyzed with Western Blot (WB).. Our findings showed that 1) CCK and CCK-AR were upregulated in our experimental model over time; 2) Treatment with CCK decreased sAST/sALT levels, inflammatory hepatic injury, neutrophil influx and hepatocelluar apoptosis, while proglumide aggravated hepatic injury.. These findings support our hypothesis and suggest that CCK played a positive role in the ongoing inflammatory process leading to liver I/R injury.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Cholecystokinin; Cytokines; Ischemia; Liver; Male; Mice, Inbred C57BL; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Peroxidase; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Reperfusion Injury

It has long been known that the toxic effects of endotoxins under experimental conditions can be induced only when they are administered parenterally. However, in naturally occurring enteroendotoxemic diseases (e. g. septic and intestinal ischemic shocks) the endotoxins--which are produced by gram negative members of intestinal flora-, absorb from the intestinal tract to the blood circulation and can elicit pathological processes. It is an important distinction between natural and experimental endotoxin shock. If the common bile duct of rats were chronically cannulated a significant amount of perorally administered endotoxin was absorbed into the blood. This endotoxin shock can be prevented by bile acids. The physiological surfactants, the bile acids, are important facts in the defense of macroorganisms against endotoxins (physico-chemical defense). The production and passage of bile acids depend from the function of liver and the cholecystokinine (CCK) synthesis of small intestine wall. If the bile (bile acid) content of the intestinal canal decreases the endotoxin can translocate to the body and elicits toxic symptoms. So most important parts of defense against endotoxins in natural conditions are the CCK and bile acids. The consequence of damage of liver (place of bile acid synthesis) or small intestine (place of CCK synthesis) is the absorption of endotoxins.

Topics: Absorption; Administration, Oral; Animals; Bacterial Toxins; Bacterial Translocation; Bile; Bile Acids and Salts; Cholecystokinin; Common Bile Duct; Endotoxemia; Endotoxins; Gram-Negative Bacterial Infections; Infusions, Parenteral; Intestinal Absorption; Intestine, Small; Intestines; Ischemia; Liver; Rats; Shock, Septic

Injury to the central or peripheral nervous system is often associated with persistent pain. After ischemic injury to the spinal cord, rats develop severe mechanical allodynia-like symptoms, expressed as a pain-like response to innocuous stimuli. In its short-lasting phase the allodynia can be relieved with the gamma-aminobutyric acid (GABA)-B receptor agonist baclofen, which also reverses the hyperexcitability of dorsal horn interneurons to mechanical stimuli. Furthermore, there is a reduction in GABA immunoreactivity in the dorsal horn of allodynic rats. Clinical neuropathic pain of peripheral and central origin often cannot be relieved by opiates at doses that do not cause side effects. The loss of sensitivity to opiates may be associated with the up-regulation of endogenous antiopioid substances, such as the neuropeptide cholecystokinin (CCK). CCK and its receptor (CCK-R) protein is normally not detectable in rat dorsal root ganglion cells. After peripheral nerve section, both CCK and CCK-R are up-regulated in the dorsal root ganglia. Furthermore, CI 988, an antagonist of the CCK-B receptor, chronically coadministered with morphine, reduces autotomy, a behavior that may be a sign of neuropathic pain following peripheral nerve section. Thus, opiate insensitivity may be due to the release of CCK from injured primary afferents. Similarly, in the chronic phase of the spinal ischemic model of central pain, the allodynia-like symptom is not relieved by systemic morphine, but is significantly reversed by the CCK-B antagonist. Consequently, up-regulation of CCK and CCK-R in the CNS may also underlie opiate drug insensitivity following CNS injury. Thus, dysfunction of central inhibition involving GABA and endogenous opioids may be a factor underlying the development of sensory abnormalities and/or pain following injury to neural tissue.

Topics: Animals; Baclofen; Central Nervous System; Cholecystokinin; GABA Agonists; Hormone Antagonists; Indoles; Ischemia; Meglumine; Narcotics; Neural Inhibition; Pain; Pain Measurement; Peripheral Nervous System; Rats; Receptors, GABA; Spinal Cord; Spinal Cord Injuries

In studies on the pathogenesis of ischemic cell injury and of other pancreatic diseases the knowledge of the actual pancreatic energy state is an important factor. Therefore, it would be advantageous to have a simple and inexpensive method to determine this parameter and its alterations in the pancreas. At uniform hormonal stimulation, the extent of exocrine pancreatic secretion showed a clear dependence on energy supply in this organ. The degree of pancreatic juice edema formed after bolus injection of cholecystokinin and secretin at ductal occlusion was found to be the most sensitive and reproducible measure of the functional capacity of the pancreatic energy metabolism. While this parameter can be applied to experimental studies, only, the juice volume secreted could be determined under clinical conditions, too. Both parameters of pancreatic secretion were clearly decreased after preceding short-term ischemia and recovered after an adequate interval of reperfusion.

Topics: Animals; Cholecystokinin; Dose-Response Relationship, Drug; Edema; Energy Metabolism; Female; Ischemia; Pancreas; Pancreatic Diseases; Pancreatic Juice; Rats; Secretin

Plasma levels of catecholamines and neuropeptides (met-enkephalin, ME; neurotensin, NT; neuropeptide Y, NPY; peptide YY, PYY; vasoactive intestinal polypeptide, VIP; cholecystokinin, CCK; bombesin, BMB) were examined in the femoral artery (FA), adrenal vein (AD), and portal vein (PV), in eight cats under halothane anesthesia at baseline (S1), at the end of a 2-hr ligation period of the major splanchnic arteries (celiac trunk, superior and inferior mesenteric arteries) (S2), immediately (S3) and 30 min (S4) after splanchnic reperfusion, and after the administration of naloxone (1 mg/kg, i.v.) (S5). During S2, there was a significant increase in portal vein VIP levels, while the other variables (hemodynamics, hormone levels) remained unchanged. During early shock (S3), significant (10- to 30-fold) increases in adrenal secretion of all catecholamines, ME, NT, NPY, and PYY occurred, while VIP and PYY were significantly released into the PV, and two- to tenfold increases in femoral artery catecholamine and ME levels were observed. Later shock (S4) led to a further fivefold increase, compared to S3, in adrenal release of norepinephrine (NE), dopamine (DA), and ME. Following naloxone administration (S5), the adrenal medullary release of NE, epinephrine (EPI), DA, NT, and NPY was significantly (twofold) increased; however, the animals' hemodynamic situation did not improve.

Topics: Adrenal Glands; Animals; Bombesin; Catecholamines; Cats; Cholecystokinin; Enkephalin, Methionine; Hemodynamics; Intestinal Mucosa; Ischemia; Ligation; Mesenteric Arteries; Naloxone; Neuropeptide Y; Neuropeptides; Neurotensin; Peptide YY; Peptides; Shock, Septic; Vasoactive Intestinal Peptide

Topics: Amylases; Animals; Bicarbonates; Blood Glucose; Chlorides; Cholecystokinin; Dogs; Insulin; Insulin Secretion; Ischemia; Ligation; Lymph; Pancreas; Potassium; Regional Blood Flow; Sodium; Stimulation, Chemical; Swine

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Cats; Cholecystokinin; Glucose; Glycogen; Ischemia; Lactates; Pancreas; Pancreatic Juice; Phosphocreatine; RNA; Secretin

Topics: Amylases; Animals; Carboxypeptidases; Cats; Cholecystokinin; Chymotrypsin; Ischemia; Lipase; Pancreas; Pancreatic Juice; Secretin; Trypsin