title: Altered vasoconstrictor and dilator responses after a "two-hit" model of sequential hemorrhage and bacteremia.
abstract: BACKGROUND
  The "two-hit" theory of multiple organ dysfunction (MOD) proposes that an initial insult, such as hemorrhage (HEM), primes the host for an abnormal response to a second stress such as infection. The immunologic/inflammatory component of this theory has been well examined; however, the effects on vascular responsiveness are poorly understood. We hypothesized that HEM primes the vasculature for an altered response to a second pathophysiologic stress.
  
  
  METHODS
  Male Sprague-Dawley rats underwent a fixed-volume HEM with resuscitation (H/R) or sham procedure (Sham). At 48 h, animals were given iv E. coli or saline and followed for 1 h. Thoracic aortic rings were then placed in organ baths containing Krebs buffer aerated with 95% O2, 5% CO2. Cumulative dose-response curves to phenylephrine (PHE) and acetylcholine (ACH) were obtained. Maximum force of contraction (Fmax) was measured and pD2 values (receptor sensitivity) were derived.
  
  
  RESULTS
  H/R alone resulted in heightened constrictor tone and blunted dilator tone. E. coli reduced Fmax in response to PHE by 50% in Sham vs 76% in H/R. Receptor sensitivity (pD2) to PHE was reduced to a greater degree in H/R (3-fold vs 2-fold). These animals also had a more pronounced enhancement of ACH receptor sensitivity (7-fold vs 2-fold).
  
  
  CONCLUSIONS
  Hemorrhage primes the vasculature for an altered response to a subsequent stress. When infection is added as a "second hit," responsiveness to adrenergic agents is diminished and dilator tone is increased. These data may explain the cardiovascular derangements seen clinically in patients who develop MODS after major hemorrhage followed sequentially by infection.
authors.affiliation: University of Louisville, Louisville Veterans Administration Medical Center, Louisville, Kentucky, 40292, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Price
authors.forename: D A
authors.initials: DA
authors.lastname: Spain
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: D000109:Acetylcholine / Q000008:administration & dosage; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D016470:Bacteremia / Q000150:complications* / Q000503:physiopathology; D001794:Blood Pressure; D004926:Escherichia coli; D006470:Hemorrhage / Q000150:complications* / Q000503:physiopathology; D008297:Male; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects; D010656:Phenylephrine / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000008:administration & dosage; D014664:Vasodilation; D014665:Vasodilator Agents / Q000008:administration & dosage
chemical_list: D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D000109:Acetylcholine