title: NHE1 inhibition improves tissue perfusion and resuscitation outcome after severe hemorrhage.
abstract: BACKGROUND
  This study tested the hypothesis that blockade of the pH-regulatory protein, Na+/H+ exchanger (NHE1) during prolonged hemorrhagic shock can protect against whole-body ischemia-reperfusion injury, resulting in improved neurological outcomes.
  
  
  METHODS
  We used a total of 24 male pigs in this study. We excluded two animals: one because of cardiac arrest after the initial hemorrhage, and the second because of a catheter malfunction for color microspheres. In Series 1, anesthetized pigs underwent an initial hemorrhage of 40 mL/kg for 30 min, and then were given either 3 mg/kg of NHE1 selective inhibitor BIIB513 (n = 6) or vehicle (n = 6). At 1 h after treatment, all animals received fluid resuscitation. We assessed survival and neurologic outcomes 72 h postresuscitation. In Series 2, we measured organ blood flow in a separate group of control (n = 5) and BIIB513-treated pigs (n = 5) undergoing the same experimental paradigm.
  
  
  RESULTS
  Five of six control animals failed to be weaned from mechanical ventilation. We killed another control animal the next day because of severe complications. In contrast, all six animals treated with BIIB513 were weaned off the ventilator, and all but one survived the 72-h experimental period with normal neurological outcome. Results showed that NHE1 inhibition with BIIB513 improved blood flow to the brain, heart, and kidney, and prevented the development of metabolic acidosis in the 1-h hypovolemic period. In addition, BIIB513 facilitated the hemodynamic response to fluid resuscitation, increased mixed venous blood oxygen saturation and oxygen delivery, and reduced proinflammatory cytokine release and multiorgan injury compared with vehicle controls.
  
  
  CONCLUSIONS
  In this study, NHE1 inhibition with BIIB513 improved vital organ blood flow, prevented the development of metabolic acidosis during prolonged hypovolemia, and facilitated the hemodynamic response to fluid resuscitation, resulting in increased survival and normal neurological outcomes.
authors.affiliation: Division of Neonatology, Department of Research, Mount Sinai Medical Center, Miami Beach, Florida 33140, USA. dongmeiwu@bellsouth.net
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wu
authors.forename: Kristina
authors.initials: K
authors.lastname: Russano
authors.forename: Irene
authors.initials: I
authors.lastname: Kouz
authors.forename: William M
authors.initials: WM
authors.lastname: Abraham
mesh_terms: D000138:Acidosis / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D001921:Brain / Q000098:blood supply; D001925:Brain Damage, Chronic / Q000209:etiology / Q000517:prevention & control; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003131:Combined Modality Therapy; D003326:Coronary Circulation / Q000187:drug effects; D004311:Double-Blind Method; D005440:Fluid Therapy; D008297:Male; D008698:Mesylates / Q000494:pharmacology / Q000627:therapeutic use*; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D012079:Renal Circulation / Q000187:drug effects; D012151:Resuscitation / Q000379:methods*; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology / Q000628:therapy; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013552:Swine; D016896:Treatment Outcome
chemical_list: D008698:Mesylates; D020011:Protective Agents; D017923:Sodium-Hydrogen Exchangers; C402725:BIIB 513