vasoactive-intestinal-peptide and parecoxib

Breakdown of the intestinal barrier is a driving force of sepsis and multiple organ failure. Radical scavengers or cytokine inhibitors may have a therapeutic impact on intestinal failure. Therapeutic effects on different sites of small intestine and colon have not been compared. Therefore, we investigated time-dependent intestinal permeability changes and their therapeutic inhibition in colon and small intestine with an ex vivo model.. Male Sprague-Dawley rats were either pretreated for 24 h with lipopolysaccharide (LPS) intraperitoneally alone or in combination with a radical scavenger (pyruvate or Tempol) or a cytokine inhibitor (parecoxib or vasoactive intestinal peptide). The gastrointestinal permeability was measured by time-dependent fluorescein isothiocyanate inulin diffusion using washed and everted tube-like gut segments. Blood and tissue samples were taken to investigate the development of inflammatory cytokine level (interleukin 6) in the context of cytokine inhibition and reactive oxygen species level via nicotinamide adenine dinucleotide phosphate oxidase activity in radical scavenger groups.. After LPS treatment, mucosal permeability was enhanced up to 170% in small intestine and colon. In the small intestine the most significant reduction in permeability was found for pyruvate and parecoxib. Treatment with vasoactive intestinal peptide and parecoxib resulted in the most pronounced reduction of permeability in the colon.. Our data suggest that cytokine inhibitors and radical scavengers have pronounced effects in LPS-induced disrupted intestinal barrier of the colon and small intestine. Our novel model comparing different anatomic sites and different points in time after the onset of sepsis may contribute to gain new insight into mechanisms and treatment options of sepsis-related gut mucosal breakdown.

Topics: Animals; Cyclic N-Oxides; Cyclooxygenase 2 Inhibitors; Drug Evaluation, Preclinical; Free Radical Scavengers; Interleukin-6; Intestinal Mucosa; Isoxazoles; Lipopolysaccharides; Male; Multiple Organ Failure; NADPH Oxidases; Neutrophils; Permeability; Pyruvic Acid; Rats, Sprague-Dawley; Sepsis; Spin Labels; Vasoactive Intestinal Peptide

To examine whether modulation of paracellular solute permeability affects the capability of the duodenum to adjust luminal osmolality.. Proximal duodenum was perfused with a hypotonic NaCl solution and effects on paracellular permeability to (51)Cr-EDTA, motility, anion secretion, net fluid flux and perfusate osmolality determined in anaesthetized rats in the absence and presence of the COX-2 inhibitor parecoxib. Vasoactive intestinal peptide (VIP) was used to reduce and lidocaine to augment the hypotonicity-induced increase in paracellular permeability.. Luminal hypotonicity slightly increased paracellular permeability in control animals. Parecoxib induced motility, increased electrolyte and fluid secretion, potentiated the hypotonicity-induced rise in paracellular permeability and enhanced the capability to adjust luminal osmolality. VIP, given to control animals stimulated electrolyte and fluid secretion and augmented the capability to adjust luminal osmolality. Administration of VIP to parecoxib-treated animals increased secretion further, markedly reduced the hypotonicity-induced increase in permeability but did not change the osmolality-adjusting capability. Luminal lidocaine potentiated the hypotonicity-induced increase in permeability, reduced the hypotonicity-induced net fluid absorption and the osmolality-adjusting capability was 50% greater than in controls. Lidocaine, given to parecoxib-treated animals potentiated the hypotonicity-induced increase in permeability, reduced the hypotonicity-induced net fluid absorption but did not change the osmolality-adjusting capability.. Vasoactive intestinal peptide reduces the osmolality-adjusting capacity of the duodenum by inhibiting paracellular solute permeability but improves this capacity by stimulating active electrolyte and fluid secretion. In contrast, lidocaine improves the osmolality-adjusting capability by augmenting paracellular solute transport but depresses it by reducing the hypotonicity-induced net fluid absorption.

Topics: Anesthetics, Local; Animals; Bicarbonates; Biological Transport; Blood Pressure; Cell Membrane Permeability; Cyclooxygenase Inhibitors; Duodenum; Gastrointestinal Agents; Gastrointestinal Motility; Infusions, Intravenous; Intestinal Absorption; Intestinal Mucosa; Isoxazoles; Lidocaine; Male; Osmolar Concentration; Perfusion; Rats; Rats, Inbred Lew; Vasoactive Intestinal Peptide