title: Insulin prevents oxidant-induced endothelial cell barrier dysfunction via nitric oxide-dependent pathway.
abstract: BACKGROUND
  The rigorous maintenance of normoglycemia by the administration of insulin is beneficial to critically ill patients. Because insulin induces endothelial nitric oxide (NO) release, and the constitutive release of NO maintains normal microvascular permeability, the authors postulated that insulin would prevent peroxide (H(2)O(2))-induced endothelial barrier dysfunction, an effect dependent on endothelial NO synthase (eNOS) activity.
  
  
  METHODS
  Murine lung microvascular endothelial cells (LMEC) grown to confluence on 8 micro pore polyethylene filters were exposed to media (control), H(2)O(2) (20 to 500 micromol/L), insulin (1 to 1,000 nmol/L) or insulin (100 nmol/L) + H(2)O(2) (10(-4)mol/L). Endothelial monolayer permeability was quantitated by measuring the transendothelial electrical resistance at 15-minute intervals for 120 minutes. Other cells were exposed to H(2)O(2) and insulin after pretreatment with a NO scavenger (PTIO), an eNOS inhibitor (L-NIO), or a phosphoinositol-3-kinase inhibitor (LY-294002).
  
  
  RESULTS
  H(2)O(2) caused a concentration- and time-dependent reduction in electrical resistance consistent with an increase in monolayer permeability. This effect was prevented by insulin. Inhibiting NO release (L-NIO, LY-294002) or scavenging NO (PTIO) abolished this protective effect.
  
  
  CONCLUSIONS
  These data suggest that insulin may modulate endothelial barrier function during oxidant stress by inducing the release of NO.
authors.affiliation: Department of Surgery, LSU Health Sciences Center in Shreveport, 1501 Kings Highway, Shreveport, LA 71130, USA.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Rath
authors.forename: Theodore
authors.initials: T
authors.lastname: Kalogeris
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mai
authors.forename: Gazi
authors.initials: G
authors.lastname: Zibari
authors.forename: J Steven
authors.initials: JS
authors.lastname: Alexander
authors.forename: David
authors.initials: D
authors.lastname: Lefer
authors.forename: Richard H
authors.initials: RH
authors.lastname: Turnage
mesh_terms: D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003470:Culture Media; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000008:administration & dosage / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D008833:Microcirculation / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009952:Ornithine / Q000031:analogs & derivatives / Q000494:pharmacology; D009994:Osmolar Concentration; D016877:Oxidants / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D013997:Time Factors
chemical_list: D002867:Chromones; D003470:Culture Media; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007093:Imidazoles; D007328:Insulin; D009025:Morpholines; D016877:Oxidants; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D009569:Nitric Oxide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C065027:N(G)-iminoethylornithine; D006861:Hydrogen Peroxide; D009952:Ornithine; D019001:Nitric Oxide Synthase; D005947:Glucose