title: Time-dependent effect of clonidine on microvascular permeability during endotoxemia.
abstract: BACKGROUND
  Endothelial leakage with accompanying tissue edema and increased leukocyte adhesion are characteristics of the vascular inflammatory response. Tissue edema formation is a key mechanism in sepsis pathophysiology contributing to impaired tissue oxygenation and the development of shock. Sepsis mortality is directly associated with the severity of these microcirculatory alterations. Dysfunction of the sympathetic nervous system can have deleterious effects in generalized inflammation. This study evaluated the effect of the adrenergic alpha 2 agonist clonidine on microvascular permeability and leukocyte adhesion during endotoxemia.
  
  
  METHODS
  Macromolecular leakage, leukocyte adhesion, and venular wall shear rate were examined in mesenteric postcapillary venules of rats by using intravital microscopy (IVM). Lipopolysaccharide (LPS) (4mg/kg/h) or equivalent volumes of saline were continuously infused following baseline IVM at 0min. IVM was repeated after 60 and 120min in endotoxemic and nonendotoxemic animals. Clonidine (10μg/kg) was applied as an i.v. bolus. Animals received either (i) saline alone, (ii) clonidine alone, (iii) clonidine 45min prior to LPS, (iv) clonidine 10min prior to LPS, (v) clonidine 30min after LPS, or (vi) LPS alone. Due to nonparametric data distribution, Wilcoxon test and Dunn's multiple comparisons test were used for data analysis. Data were considered statistically significant at p<0.05.
  
  
  RESULTS
  LPS significantly increased microvascular permeability and leukocyte adhesion and decreased venular wall shear rate. Clonidine significantly reduced microvascular permeability when applied 45min before or 30min after LPS administration. Leukocyte adhesion and venular wall shear rate were not affected by clonidine during endotoxemia.
  
  
  CONCLUSIONS
  Clonidine reduces microvascular permeability in endotoxemic animals in a time-dependent manner. Adrenergic alpha 2 agonists might prove beneficial in stabilizing capillary leakage during inflammation.
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany. Electronic address: karsten.schmidt@med.uni-heidelberg.de.
authors.forename: Karsten
authors.initials: K
authors.lastname: Schmidt
authors.affiliation: Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Ludwigshafen, University of Heidelberg, Germany.
authors.forename: Jochen Frederick
authors.initials: JF
authors.lastname: Hernekamp
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Philipsenburg
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Aleksandar R
authors.initials: AR
authors.lastname: Zivkovic
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Brenner
authors.affiliation: Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hofer
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002448:Cell Adhesion; D003000:Clonidine / Q000008:administration & dosage*; D042783:Endothelial Cells / Q000166:cytology; D019446:Endotoxemia / Q000188:drug therapy*; D007249:Inflammation; D000069416:Intravital Microscopy; D007962:Leukocytes / Q000166:cytology; D008070:Lipopolysaccharides / Q000737:chemistry; D008297:Male; D008833:Microcirculation; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D033081:Shear Strength; D013314:Stress, Mechanical; D013564:Sympathetic Nervous System / Q000473:pathology; D013565:Sympatholytics / Q000008:administration & dosage; D013997:Time Factors
chemical_list: D008070:Lipopolysaccharides; D013565:Sympatholytics; D003000:Clonidine
keywords: Clonidine; Endothelial dysfunction; Endotoxemia; Intravital microscopy; Microvascular permeability