title: Gentisic acid sodium salt, a phenolic compound, is superior to norepinephrine in reversing cardiovascular collapse, hepatic mitochondrial dysfunction and lactic acidemia in Pseudomonas aeruginosa septic shock in dogs.
abstract: BACKGROUND
  The development of lactic acidemia (LA) in septic shock (SS) is associated with an ominous prognosis. We previously showed that the mechanism of LA in SS may relate to impaired hepatic uptake of lactate, but the mechanism was not clear. Uptake of lactate by the liver occurs by a membrane-associated, pH-dependent, antiport system known as the monocarboxylate transporter. In the hepatocyte, lactate can then be metabolized by oxidative phosphorylation or converted to glucose in the cytosol. In the present study, we examined (1) whether hepatic mitochondrial dysfunction accounted for decreased uptake of lactate in a canine model of Pseudomonas aeruginosa SS, (2) whether norepinephrine (NE) treatment by increasing mean arterial pressure (MAP) could improve mitochondrial dysfunction and LA in this model, and (3) whether gentisic acid sodium salt (GSS), a novel phenolic compound, was superior to NE in these effects.
  
  
  METHODS
  In anesthetized/ventilated dogs, we infused the bacteria over ~10 h and measured hemodynamics in various treatment groups (see below). We then euthanized the animal and isolated the hepatic mitochondria. We measured hepatic mitochondrial oxygen consumption rates using the novel Seahorse XF24 analyzer under conditions that included: basal respiration, after the addition of adenosine- diphosphate to produce coupled respiration, and after the addition of a protonophore to produce maximal respiration.
  
  
  RESULTS
  We found that in the septic control group, mean arterial pressure decreased over the course of the study, and that mitochondrial dysfunction developed in which there was a reduction in maximal respiration. Whereas both NE and GSS treatments reversed the reduction in mean arterial pressure and increased maximal respiration to similar extents in respective groups, only in the GSS group was there a reduction in LA.
  
  
  CONCLUSIONS
  Hepatic mitochondrial dysfunction occurs in SS, but does not appear to be required for the development of LA in SS, since NE improved mitochondrial dysfunction without reversing LA. GSS, a phenolic compound restored mean arterial pressure, mitochondrial dysfunction, and LA in SS. This reduction in LA may be independent of its effect on improving hepatic mitochondrial function.
authors.affiliation: Departments of Medicine and Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada. minksn@cc.umanitoba.ca.|Health Sciences Centre, GF-221, 820 Sherbrook St, Winnipeg, MB, R3A-1R9, Canada. minksn@cc.umanitoba.ca.
authors.forename: Steven
authors.initials: S
authors.lastname: Mink
authors.affiliation: Division of Neurodegenerative Disorders at the St. Boniface Hospital Research Centre, Winnipeg, MB, Canada.
authors.forename: Subir K
authors.initials: SK
authors.lastname: Roy Chowdhury
authors.affiliation: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico.|Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Jose
authors.initials: J
authors.lastname: Gotes
authors.affiliation: Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Zhao-Qin
authors.initials: ZQ
authors.lastname: Cheng
authors.affiliation: Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Krika
authors.initials: K
authors.lastname: Kasian
authors.affiliation: Division of Neurodegenerative Disorders at the St. Boniface Hospital Research Centre, Winnipeg, MB, Canada.|Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Fernyhough
keywords: ATP; Antioxidants; Electron transport chain; Gentisic acid; Infection; Lactic acidosis; Mitochondria; Norepinephrine; Septic shock; Vasodilation; Vasopressors