title: Dopexamine can attenuate the inflammatory response and protect against organ injury in the absence of significant effects on hemodynamics or regional microvascular flow.
abstract: BACKGROUND
  The effects of dopexamine, a β2-agonist, on perioperative and sepsis-related hemodynamic, microvascular, immune, and organ dysfunction are controversial and poorly understood. We investigated these effects in a rodent model of laparotomy and endotoxemia.
  
  
  METHODS
  In two experiments, 80 male Wistar rats underwent laparotomy. In 64 rats, this was followed by administration of endotoxin; the remainder (16) underwent sham endotoxemia. Endotoxemic animals received either dopexamine at 0.5, 1, or 2 μg/kg/min or 0.9% saline vehicle (controls) as resuscitation fluid. The effects of dopexamine on global hemodynamics, mesenteric regional microvascular flow, renal and hepatic function and immune activation were evaluated.
  
  
  RESULTS
  Endotoxin administration was associated with a systemic inflammatory response (increased plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10, as well as cell-adhesion molecules CD11a and CD11b), and increased pulmonary myeloperoxidase (MPO) activity (indicating pulmonary leukocyte infiltration), whereas biochemical changes demonstrated lactic acidosis with significant renal and hepatic injury. Dopexamine administration was associated with less-severe lactic acidosis (pooled dopexamine versus controls, (lactate, 2.2 mM±0.2 mM versus 4.0 mM±0.5 mM; P<0.001) and reductions in the systemic inflammatory response (pooled dopexamine versus control, 4 hour (TNF-α): 324 pg/ml±93 pg/ml versus 97 pg/ml±14 pg/ml, p<0.01), pulmonary myeloperoxidase (MPO) activity, and hepatic and renal injury (pooled dopexamine versus control (ALT): 81 IU/L±4 IU/L versus 138 IU/L±25 IU/L; P<0.05; (creatinine): 49.4 μM±3.9 μM versus 76.2 μM±9.8 μM; P<0.005). However, in this study, clinically relevant doses of dopexamine were not associated with clinically significant changes in MAP, CI, or gut regional microvascular flow.
  
  
  CONCLUSIONS
  In this model, dopexamine can attenuate the systemic inflammatory response, reduce tissue leukocyte infiltration, and protect against organ injury at doses that do not alter global hemodynamics or regional microvascular flow. These findings suggest that immunomodulatory effects of catecholamines may be clinically significant when used in critically ill surgical patients and are independent of their hemodynamic actions.
authors.forename: Mansoor N
authors.initials: MN
authors.lastname: Bangash
authors.forename: Nimesh S A
authors.initials: NS
authors.lastname: Patel
authors.forename: Elisa
authors.initials: E
authors.lastname: Benetti
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Hinds
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
authors.forename: Rupert M
authors.initials: RM
authors.lastname: Pearse
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019446:Endotoxemia / Q000503:physiopathology / Q000517:prevention & control*; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D007249:Inflammation / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008833:Microcirculation / Q000187:drug effects* / Q000502:physiology; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D020011:Protective Agents; D014665:Vasodilator Agents; C046318:dopexamine; D004298:Dopamine