title: Transient and partial mitochondrial inhibition for the treatment of postresuscitation injury: getting it just right.
abstract: OBJECTIVE
  Within minutes of reperfusing ischemic cardiomyocytes, oxidant stress dramatically increases and is associated with postresuscitation injury. Because mitochondria produce deleterious oxidants and useful metabolic substrates, utilization of electron transport chain inhibitors against reperfusion injury, though promising, must not overly compromise recovery of mitochondrial function. This study sought to further characterize the oxidant source at reperfusion and develop a strategy for therapeutic intervention by manipulation of dose, duration, and the degree of reversibility of mitochondrial inhibition.
  
  
  METHODS
  Comparative laboratory investigation.
  
  
  METHODS
  Laboratory of a research university.
  
  
  METHODS
  Embryonic chick cardiomyocytes.
  
  
  METHODS
  Synchronously contracting chick cardiomyocytes were exposed to 1 hr of simulated ischemia and 3 hrs of reperfusion and were monitored for cell viability (propidium iodide) and oxidant generation (dichlorofluorescein). Inhibitors were administered either all course or for the first 15 mins of reperfusion.
  
  
  RESULTS
  : Application of diethyldithiocarbamic acid, 2-anthracene-carboxylic acid (rhein tech), and alpha-nicotinamide adenine dinucleotide dehydrogenase (NADH) demonstrated attenuation of the oxidant burst. In addition, diethyldithiocarbamic acid (1 mM), rhein tech (0.1 microM), and alpha-NADH (20 microM) significantly attenuated cell death from a control of 49.7% +/- 6.7% to 15.7% +/- 4.7% (n = 5, p < .01), 26.1% +/- 4.1% (n = 5, p < .01), and 13.8% +/- 1.3% (n = 5, p < .001), respectively. All doses of stigmatellin attenuated reactive oxygen species, but only a 2-20 nM dose during the first 15 mins of reperfusion abrogated cell death from 53.8% +/- 3.5% to 10.8% +/- 2.9% (n = 5, p < .001). Increased doses and durations of stigmatellin abolished reactive oxygen species but augmented injury. Although rotenone (5 microM) attenuated reactive oxygen species, no dose or duration of exposure that ameliorated cell death was found.
  
  
  CONCLUSIONS
  Early events of reperfusion are marked by rapid mitochondrial oxidant generation and postresuscitation injury. Electron transport chain blockade provides an effective method of attenuating reactive oxygen species. However, inhibitor administration should be both transient and reversible to necessitate cardioprotection and successful metabolic recovery.
authors.affiliation: Emergency Resuscitation Center, Sections of Emergency Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Travis C
authors.initials: TC
authors.lastname: Anderson
authors.forename: Chang-Qing
authors.initials: CQ
authors.lastname: Li
authors.forename: Zuo-Hui
authors.initials: ZH
authors.lastname: Shao
authors.forename: Truc
authors.initials: T
authors.lastname: Hoang
authors.forename: Kim Chai
authors.initials: KC
authors.lastname: Chan
authors.forename: Kimm J
authors.initials: KJ
authors.lastname: Hamann
authors.forename: Lance B
authors.initials: LB
authors.lastname: Becker
authors.forename: Terry L
authors.initials: TL
authors.lastname: Vanden Hoek
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology; D016887:Cardiopulmonary Resuscitation / Q000009:adverse effects; D002642:Chick Embryo; D004050:Ditiocarb / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport; D008929:Mitochondria, Heart / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009243:NAD / Q000494:pharmacology; D011090:Polyenes / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology
chemical_list: D000873:Anthracenes; D002264:Carboxylic Acids; D011090:Polyenes; D017382:Reactive Oxygen Species; D012402:Rotenone; D009243:NAD; C107996:anthracene-1-carboxylic acid; C041573:stigmatellin; D004050:Ditiocarb