title: Cardiovascular and inflammatory response to cholecystokinin during endotoxemic shock.
abstract: 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.
authors.affiliation: Departamento de Fisiologia, Faculdade de Medicina de Ribeirão Preto, São Paulo, Brazil.
authors.forename: Rafael Simone
authors.initials: RS
authors.lastname: Saia
authors.forename: Giuliana
authors.initials: G
authors.lastname: Bertozi
authors.forename: Fabíola Leslie
authors.initials: FL
authors.lastname: Mestriner
authors.forename: José
authors.initials: J
authors.lastname: Antunes-Rodrigues
authors.forename: Fernando
authors.initials: F
authors.lastname: Queiróz Cunha
authors.forename: Evelin Capellari
authors.initials: EC
authors.lastname: Cárnio
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects; D002766:Cholecystokinin / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019446:Endotoxemia / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000097:blood*; D016753:Interleukin-10 / Q000097:blood; D019344:Lactic Acid / Q000097:blood; D008070:Lipopolysaccharides; D008099:Liver / Q000201:enzymology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D011377:Proglumide / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014667:Vasopressins / Q000097:blood
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D014667:Vasopressins; D016753:Interleukin-10; D019344:Lactic Acid; D002766:Cholecystokinin; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011377:Proglumide