title: Decreased alpha-adrenergic response in the intestinal microcirculation after "two-hit" hemorrhage/resuscitation and bacteremia.
abstract: BACKGROUND
  The two-hit theory of multiple organ dysfunction syndrome proposes that an initial insult primes the host for an altered response to subsequent stimuli. We have previously documented enhanced dilator tone in the small intestine after a two-hit insult; however, the effects on vasoconstrictor function are unknown. We postulated that prior hemorrhage and resuscitation followed by bacteremia would alter microvascular responsiveness to alpha-adrenergic stimulation.
  
  
  METHODS
  Male Sprague-Dawley rats underwent fixed-volume hemorrhage with resuscitation (H/R) or sham procedure (Sham). At 24 or 72 h, in vivo videomicroscopy of the small intestine was performed (inflow A1 and premucosal A3 arterioles). Constrictor function was assessed by topical application of norepinephrine (NE; 10(-8)-10(-6) M) before and 1 h after intravenous Escherichia coli or saline.
  
  
  RESULTS
  Sham, 24 or 72 h H/R, and E. coli alone produced no significant changes in A1 or A3 response to NE. Sequential H/R + E. coli resulted in decreased constrictor response in both A1 (72 h H/R + E. coli-38% from baseline vs Sham - 54%, P < 0.05) and A3 arterioles (-8% vs -51%, P < 0.05) at high doses of NE (10(-6) M).
  
  
  CONCLUSIONS
  Prior H/R primes the intestinal microvasculature for an altered response during a subsequent stress and these effects persist for up to 72 h following H/R. Sequential insults in this two-hit model caused marked hyporesponsiveness to NE. These alterations in control of microvascular tone might contribute to the hemodynamic compromise of sepsis, impair mucosal blood flow, and contribute to the development of MODS.
authors.affiliation: Departments of Surgery and Physiology and Biophysics, University of Louisville, Louisville, Kentucky, 40292, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Spain
authors.forename: T
authors.initials: T
authors.lastname: Kawabe
authors.forename: P C
authors.initials: PC
authors.lastname: Keelan
authors.forename: M A
authors.initials: MA
authors.lastname: Wilson
authors.forename: P D
authors.initials: PD
authors.lastname: Harris
authors.forename: R N
authors.initials: RN
authors.lastname: Garrison
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D016470:Bacteremia / Q000503:physiopathology*; D004927:Escherichia coli Infections / Q000503:physiopathology; D006470:Hemorrhage / Q000628:therapy*; D007422:Intestines / Q000098:blood supply*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation
chemical_list: D000316:Adrenergic alpha-Agonists; D009638:Norepinephrine