title: Sabiporide improves cardiovascular function, decreases the inflammatory response and reduces mortality in acute metabolic acidosis in pigs.
abstract: BACKGROUND
  Acute metabolic acidosis impairs cardiovascular function and increases the mortality of critically ill patients. However, the precise mechanism(s) underlying these effects remain unclear. We hypothesized that targeting pH-regulatory protein, Na(+)/H(+) exchanger (NHE1) could be a novel approach for the treatment of acute metabolic acidosis. The aim of the present study was to examine the impact of a novel NHE1 inhibitor, sabiporide, on cardiovascular function, blood oxygen transportation, and inflammatory response in an experimental model of metabolic acidosis produced by hemorrhage-induced hypovolemia followed by an infusion of lactic acid.
  
  
  RESULTS
  Anesthetized pigs were subjected to hypovolemia for 30 minutes. The animals then received a bolus infusion of sabiporide (3 mg/kg) or vehicle, followed by an infusion of lactic acid for 2 hours. The animals were continuously monitored for additional 3 hours. Hypovolemia followed by a lactic acid infusion resulted in a severe metabolic acidosis with blood pH falling to 6.8. In association with production of the acidemia, there was an excessive increase in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). Treatment with sabiporide significantly attenuated the increase in PAP by 38% and PVR by 67%, as well as significantly improved cardiac output by 51%. Sabiporide treatment also improved mixed venous blood oxygen saturation (55% in sabiporide group vs. 28% in control group), and improved systemic blood oxygen delivery by 36%. In addition, sabiporide treatment reduced plasma levels of TNF-α (by 33%), IL-6 (by 63%), troponin-I (by 54%), ALT (by 34%), AST (by 35%), and urea (by 40%).
  
  
  CONCLUSIONS
  These findings support the possible beneficial effects of sabiporide in the treatment of acute metabolic acidosis and could have implications for the treatment of metabolic acidosis in man.
authors: Department of Research, Division of Neonatology, Mount Sinai Medical Center, Miami Beach, Florida, United States of America. dongmeiwu@bellsouth.net
authors: Dongmei
authors: D
authors: Wu
authors: Jeffrey A
authors: JA
authors: Kraut
authors: William M
authors: WM
authors: Abraham
mesh_terms: D000138:Acidosis / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology / Q000662:veterinary; D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects* / Q000503:physiopathology; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D065627:Familial Primary Pulmonary Hypertension; D006146:Guanidines / Q000008:administration & dosage*; D006470:Hemorrhage / Q000139:chemically induced / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology / Q000662:veterinary; D020896:Hypovolemia / Q000139:chemically induced / Q000503:physiopathology; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology / Q000662:veterinary; D019344:Lactic Acid / Q000633:toxicity; D008297:Male; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000235:genetics; D013552:Swine; D014655:Vascular Resistance
chemical_list: D027682:Cation Transport Proteins; D006146:Guanidines; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D019344:Lactic Acid; C476560:sabiporide