endothelin-1 and Gastrointestinal-Hemorrhage

The renal effects of octreotide, used for bleeding esophageal varices in cirrhosis, are controversial.. Fourteen cirrhotic patients (Child-Pugh; A/B/C: 1/12/1) were enrolled. Plasma nitrite and endothelin (ET) levels, urinary nitrite output, free water clearance (FWC) and fractional excretion of filtered sodium (FENa) were measured and renal Doppler ultrasound was carried out. Octreotide was infused at a rate of 0.75 microg/kg/h for 3 h after a bolus of 0.75 microg/kg body weight. All the parameters were reevaluated during octreotide administration while the patients acted as their own controls.. Octreotide induced significant reductions in urinary nitrite, FENa and FWC. Plasma ET levels increased (baseline: 6.7 pg/ml, octreotide: 8.4 pg/ml), whereas the plasma nitrite level did not change significantly after octreotide infusion. Overall, no significant change in renal resistive index (RRI) could be demonstrated on Doppler after octreotide administration. However, patients with elevated baseline RRI values had significantly more deterioration in FWC and FENa compared with patients with normal RRI in response to octreotide.. A marked decrease in FENa, FWC and urinary nitrite output, together with a significant increase in plasma ET level in response to octreotide, may indicate renal dysfunction in cirrhotic patients. This deleterious renal effect of octreotide may be more enhanced in patients with elevated baseline RRI.

Topics: Adult; Aged; Endothelin-1; Female; Gastrointestinal Agents; Gastrointestinal Hemorrhage; Humans; Hypertension, Portal; Kidney; Liver Cirrhosis; Male; Middle Aged; Nitrites; Octreotide; Salvage Therapy; Sodium; Ultrasonography, Doppler; Varicose Veins

To estimate the prognostic value of the hypoxic test, intragastric pH-metry, and endothelial dysfunction in cardiosurgical patients at risk of gastrointestinal hemorrhage.. This prospective study approved by the ethical committee was performed based at the Department of Anesthesiology and Resuscitation, Research Institute of Cardiology, Tomsk, in 2012-2013. It included 30 patients who had previously undergone myocardial revascularization with artificial circulation. Gastroduodenal complications were predicted based on the results of the general hypoxic test, monitoring intragastric pH, and determination of endothelial function markers (endothelin-1, nitric oxide metabolites) intra- and postoperatively.. 17 (56.7%) patients with negative results of hypoxic test were referred to the group at low-risk of gastrointestinal complications and given no antisecretory therapy. Plasma ET-1 level in the patients with gastric hemorrhage was almost 10 times that in the absence of complications. Multiple organ insufficiency was associated with a rise in RT-1 levels by the end of the first postoperative day. High ET-1 levels suggested the predominance of vasoconstrictive effect that eventually resulted in a break of the vascular wall and hypoperfusion of gastric mucosa.. High ET-1 levels and disbalance of nitric oxide metabolites in blood are the main predictors of postoperative complications that characterize the functional state of vascular endothelium and may cause vascular rupture in case of the atherosclerotic process. The use of hypoxic test and gastric pH-metry in the preoperative period make it possible to distinguish patients that do not need preventive antisecretory therapy.

Topics: Cardiovascular Surgical Procedures; Endothelin-1; Endothelium, Vascular; Female; Gastrointestinal Hemorrhage; Heart Diseases; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Nitric Oxide; Predictive Value of Tests; Prospective Studies

Iron regulatory proteins (Irps) 1 and 2 posttranscriptionally control the expression of transcripts that contain iron-responsive element (IRE) sequences, including ferritin, ferroportin, transferrin receptor, and hypoxia-inducible factor 2α (HIF2α). We report here that mice with targeted deletion of Irp1 developed pulmonary hypertension and polycythemia that was exacerbated by a low-iron diet. Hematocrits increased to 65% in iron-starved mice, and many polycythemic mice died of abdominal hemorrhages. Irp1 deletion enhanced HIF2α protein expression in kidneys of Irp1(-/-) mice, which led to increased erythropoietin (EPO) expression, polycythemia, and concomitant tissue iron deficiency. Increased HIF2α expression in pulmonary endothelial cells induced high expression of endothelin-1, likely contributing to the pulmonary hypertension of Irp1(-/-) mice. Our results reveal why anemia is an early physiological consequence of iron deficiency, highlight the physiological significance of Irp1 in regulating erythropoiesis and iron distribution, and provide important insights into the molecular pathogenesis of pulmonary hypertension.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Diet; Endothelial Cells; Endothelin-1; Erythropoietin; Gastrointestinal Hemorrhage; Gene Deletion; Hematopoiesis, Extramedullary; Hypertension, Pulmonary; Iron; Iron Regulatory Protein 1; Iron Regulatory Protein 2; Longevity; Mice; Models, Biological; Nerve Degeneration; Organ Specificity; Polycythemia; Protein Biosynthesis; Transcriptional Activation

NHE3 is a target of inhibition by proinflammatory cytokines and pathogenic bacteria, an event contributing to diarrhea in infectious and idiopathic colitis. In mice, NHE3 deficiency leads to mild diarrhea, increased intestinal expression of interferon (IFN)-gamma, and distal colitis, suggesting its role in epithelial barrier homeostasis. Our aim was to investigate the role of NHE3 in maintaining mucosal integrity.. Control or dextran sulfate sodium (DSS)-treated, 6- to 8-week-old wild-type (WT) and NHE3(-/-) mice were used for the experiments. Small intestines were dissected for further analysis.. NHE3(-/-) mice have elevated numbers of CD8alpha(+) T and natural killer cells in the intraepithelial lymphocytes and lamina propria lymphocytes compartments, representing the source of IFN-gamma. NHE3(-/-) mice display alterations in epithelial gene and protein expression patterns that predispose them to a high susceptibility to DSS, with accelerated mortality resulting from intestinal bleeding, hypovolemic shock, and sepsis, even at a very low DSS concentration. Microarray analysis and intestinal hemorrhage indicate that NHE3 deficiency predisposes mice to DSS-induced small intestinal injury, a segment never reported as affected by DSS, and demonstrate major differences in the colonic response to DSS challenge in WT and NHE3(-/-) mice. In NHE3(-/-) mice, broad-spectrum oral antibiotics or anti-asialo GM1 antibodies reduce the expression of IFN-gamma and iNOS to basal levels and delay but do not prevent severe mortality in response to DSS treatment.. These results suggest that NHE3 participates in mucosal responses to epithelial damage, acting as a modifier gene determining the extent of the gut inflammatory responses in the face of intestinal injury.

Topics: Animals; Blood Cell Count; Colon; Dextran Sulfate; Down-Regulation; Endothelin-1; G(M1) Ganglioside; Gastrointestinal Hemorrhage; Homeostasis; Interferon-gamma; Intestinal Mucosa; Intestine, Small; Mice; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase Type II; Signal Transduction; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers

Shiga toxin, produced by Escherichia coli O157:H7, is important for the pathogenicity of the epidemic form of hemolytic uremic syndrome (HUS). This toxin has recently been found to stimulate endothelin-1 synthesis in cultured endothelial cells in vitro.. We investigated endothelin and cytokine levels in sera during a large outbreak of E. coli O157:H7 infection in Osaka, Japan, in 1996. Eleven patients with HUS and 9 patients with hemorrhagic colitis at the onset of E. coli O157:H7 infection were studied.. Serum IL-6 (p < 0.01), IL-8 (p < 0.05), IL-10 (p < 0.001) and endothelin (p < 0.001) levels were significantly increased in patients with HUS compared to those with colitis only. The serum thrombomodulin level, a molecular marker of endothelial damage, also showed a significant positive correlation with serum IL-6 (p < 0.01), IL-8 (p < 0.01), IL-10 (p < 0.01) and endothelin (p < 0.001) levels. In a HUS patient, the increase in serum IL-10 and endothelin levels reached a plateau prior to the peak of serum creatinine levels.. Increased serum endothelin synthesis by Shiga toxin in vivo was proven in HUS secondary to E. coli O157:H7 infection. Increased serum endothelin and IL-10 levels were speculated to be associated with the development of HUS through vascular endothelial damage caused by E. coli O157:H7 infection.

Topics: Case-Control Studies; Colitis; Creatinine; Disease Outbreaks; Endothelin-1; Escherichia coli Infections; Escherichia coli O157; Female; Gastrointestinal Hemorrhage; Hemolytic-Uremic Syndrome; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Japan; Male; Thrombomodulin; Time Factors