cholecystokinin and Shock--Septic

Our previous studies demonstrated that pretreatment with cholecystokinin octapeptide (CCK-8) could alleviate endothelial cell injury and reverse abnormal vascular reactivity as well as reduce LPS-induced inflammation cascades, which suggested that CCK-8 plays a potential role in anti-endotoxic shock. The present study aimed to determine the therapeutic effects of CCK-8 on rat liver and kidney microcirculatory perfusion disorder under endotoxic shock (ES) conditions.. Sprague-Dawley rats were induced to lethal endotoxic shock by an injection of LPS. CCK-8 was administered 30 min after LPS injection. Either a specific CCK-1R antagonist or CCK-2R antagonist was injected before CCK-8 treatment. The mean arterial pressure (MAP), liver and kidney microcirculatory perfusion, and heart rate (HR) were recorded with a multi-channel data acquisition system. The serum concentrations of alanine aminotransferase (ALT) and creatinine (Cr) were measured, and the histopathological changes in the liver and kidney were also observed.. Administration of CCK-8 significantly delayed the LPS-induced decreases in not only the liver and kidney microcirculation perfusion but also the HR. The pathology changes induced by LPS in the liver and kidney tissues were significantly mitigated in the LPS + CCK-8 group. The levels of ALT and Cr in the serum of the LPS + CCK-8 group were obviously lower than those in the LPS group. In addition, the specific antagonist at the CCK-2 receptor (CCK-2R) abrogated the action of CCK-8 significantly.. These results indicated that CCK-8 has potential therapeutic effects on microcirculation failure in an ES rat model via the CCK-2 receptor.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cholecystokinin; Kidney; Kidney Diseases; Lipopolysaccharides; Liver; Male; Microcirculation; Oligopeptides; Rats; Rats, Sprague-Dawley; Shock, Septic; Sincalide

Cholecystokinin (CCK) was first described as a gastrointestinal hormone, but its receptors have been located in cardiac and vascular tissues, as well as in immune cells. Our aims were to investigate the role of CCK on lipopolysaccharide (LPS)-induced hypotension and its ability to modulate previously reported inflammatory mediators, therefore affecting cardiovascular function. To conduct these experiments, rats had their jugular vein cannulated for drug administration, and also, the femoral artery cannulated for mean arterial pressure (MAP) and heart rate records. Endotoxemia induced by LPS from Escherichia coli (1.5 mg/kg; i.v.) stimulated the release of CCK, a progressive drop in MAP, and increase in heart rate. Plasma tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), nitrate, vasopressin, and lactate levels were elevated in the endotoxemic rats. The pretreatment with proglumide (nonselective CCK antagonist; 30 mg/kg; i.p.) aggravated the hypotension and also increased plasma TNF-α and lactate levels. On the other hand, CCK (0.4 μg/kg; i.v.) administered before LPS significantly restored MAP, reduced aortic and hepatic inducible nitric oxide synthase (iNOS) production, and elevated plasma vasopressin and IL-10 concentrations; it did not affect TNF-α. Physiological CCK concentration reduced nitrite and iNOS synthesis by peritoneal macrophages, possibly through a self-regulatory IL-10-dependent mechanism. Together, these data suggest a new role for the peptide CCK in modulating MAP, possibly controlling the inflammatory response, stimulating the anti-inflammatory cytokine, IL-10, and reducing vascular and macrophage iNOS-derived nitric oxide production. Based on these findings, CCK could be used as an adjuvant therapeutic agent to improve cardiovascular function.

Topics: Animals; Aorta; Blood Pressure; Cholecystokinin; Drug Evaluation, Preclinical; Endotoxemia; Heart Rate; Hypotension; Inflammation Mediators; Interleukin-10; Lactic Acid; Lipopolysaccharides; Liver; Macrophages, Peritoneal; Male; Nitric Oxide Synthase Type II; Proglumide; Rats; Rats, Wistar; Shock, Septic; Tumor Necrosis Factor-alpha; Vasopressins

Sepsis in critical illness is associated with the progressive failure of multiple organs. This study aims to establish a correlation between the severity of sepsis and exocrine pancreatic dysfunction.. In a prospective cohort study pancreatic exocrine function was tested by means of a secretin-cholecystokinin test in 21 critically ill, mechanically ventilated patients with sepsis according to criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee (ACCP/SCCM): 11 patients with shock and 10 patients without shock. Data were compared with seven healthy controls.. The volume of duodenal fluid was not statistically different in the three groups. Sepsis patients without shock had significantly reduced content of amylase and chymotrypsin in duodenal juice compared with healthy controls (P < 0.01). Secretion of amylase, chymotrypsin, trypsin (P < 0.01 each) and bicarbonate in duodenal fluid (P < 0.05) was impaired in the septic shock patients when compared with the healthy controls. The content of trypsin was different between sepsis patients and septic shock patients (P < 0.05). Spearman correlation analysis was significant between the amylase secretion and the APACHE III and SOFA scores (P < 0.01). The SOFA score was also related to secretion of trypsin (P < 0.05). In patients on pressor therapy, use of norepinephrine was associated with a significant decrease in bicarbonate secretion (P < 0.05).. Sepsis is associated with secretory pancreatic dysfunction that is worse in septic shock than in sepsis without shock. Impaired exocrine function was significantly correlated to the APACHE III and SOFA scores.

Topics: Adult; Aged; Cholecystokinin; Cohort Studies; Female; Humans; Male; Middle Aged; Pancreas; Pancreatic Diseases; Prospective Studies; Secretin; Sepsis; Shock, Septic

To determine the exocrine pancreatic function in critically ill patients.. Prospective cohort study.. Medical intensive care unit.. A total of 18 critically ill patients (11 patients with septic shock according to the criteria of the American College of Chest Physicians/Society of Critical Care Medicine, 7 nonseptic patients). The results obtained in these subjects were compared with the data obtained in seven healthy volunteers.. Examination of exocrine pancreatic function was done by means of a cholecystokinin-secretin test. Intravenous stimulation of the exocrine pancreas with cholecystokinin and secretin (1 unit/kg body weight/hr each) and aspiration of duodenal fluid by a gastroscopically inserted oroduodenal tube was done during a period of 1 hr.. The content of amylase, chymotrypsin, and trypsin in aspirated duodenal fluid was significantly reduced in patients with septic shock compared with nonseptic patients as well as healthy subjects (p < .01). The volume of aspirated fluid was significantly reduced in patients with septic shock compared with healthy controls (p = .03), but not in nonseptic patients. The content of bicarbonate was not statistically different in the three groups. No significant correlation was to find between variables of exocrine pancreatic function and Acute Physiology and Chronic Health Evaluation III score, sepsis-related organ failure assessment score, systolic arterial pressure and mean arterial pressure in septic shock patients. Positive end-expiratory pressure was significantly correlated with the content of trypsin (r2 = 0.52; p = .02). Postmortem examinations of five septic patients who died during the intensive care stay did not reveal gross morphologic alterations of pancreatic tissue.. The study shows two pancreatic enzyme systems, namely, amylase as a carbohydrate splitting enzyme and the proteolytic enzymes trypsin and chymotrypsin, strongly affected in critically ill patients with septic shock.

Topics: Aged; Amylases; Cholecystokinin; Chymotrypsin; Cohort Studies; Critical Care; Exocrine Pancreatic Insufficiency; Female; Humans; Male; Middle Aged; Pancreas; Pancreatic Function Tests; Prospective Studies; Secretin; Shock, Septic; Trypsin

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

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

The gastrointestinal tract is the source of numerous peptide hormones. Since the gut will be altered severely during prolonged general circulatory low flow states, the reactions of the gut hormones are of great interest. In this study 18 anesthetized pigs were put into shock states to get first informations about the changes of the plasma levels of cholecystokinin (CCK). 12 pigs (group I and II) were exposed to a general circulatory shock state by a 2-hr intravenous infusion of a sublethal dose of Escherichia coli endotoxin. 6 of them (gr. II) first received a gastroenterectomy apart from a small duodenal remnant proximal and distal to the papilla of Vater. The remaining 6 pigs (gr. III) suffered a severe hemorrhagic-hypovolemic shock over a 150-min period by arterial bleeding. Plasma CCK increased significantly (p less than 0.05) in the aorta (gr. I, II), the portal vein (gr. I, II), the superior caval vein (gr. I), and the internal jugular vein (gr. I) at the end of the 2-hr endotoxin infusion. In group II, the rise of CCK levels in the superior caval vein was also marked, but insignificant. The CCK-concentrations in the internal jugular vein were measured only in group I. By contrast, no changes in plasma CCK were seen in hemorrhagic shock (gr. III). Within each group plasma samples taken from the various blood vessels at identical time points showed no significant differences. Since the plasma concentrations of CCK remained unchanged during hemorrhagic shock, the release of CCK by E. coli endotoxin is not due to the general circulatory low flow state.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cholecystokinin; Digestive System Physiological Phenomena; Endotoxins; Escherichia coli Infections; Female; Male; Shock, Hemorrhagic; Shock, Septic; Swine