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Transient and partial mitochondrial inhibition for the treatment of postresuscitation injury: Getting it just right

Anderson, Travis C. BS; Li, Chang-Qing MD; Shao, Zuo-Hui MD; Hoang, Truc MD; Chan, Kim Chai MD; Hamann, Kimm J. PhD; Becker, Lance B. MD; Vanden Hoek, Terry L. MD

doi: 10.1097/01.CCM.0000246014.19486.A1
Scientific Reviews

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.

Design: Comparative laboratory investigation.

Setting: Laboratory of a research university.

Subjects: Embryonic chick cardiomyocytes.

Interventions: 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.

Measurements and Main Results: Application of diethyldithiocarbamic acid, 2-anthracene-carboxylic acid (rhein tech), and α-nicotinamide adenine dinucleotide dehydrogenase (NADH) demonstrated attenuation of the oxidant burst. In addition, diethyldithiocarbamic acid (1 mM), rhein tech (0.1 μM), and α-NADH (20 μM) 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 μM) 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.

From the Emergency Resuscitation Center, Sections of Emergency Medicine (TCA, CQL, ZHS, TH, KJH, LBB, TLVH) and Pulmonary/Critical Care (KJH), Department of Medicine, University of Chicago, Chicago, IL; and Emergency Department, Tan Tock Seng Hospital, Singapore (KCC).

Drs. Hamann, Becker, and Vanden Hoek contributed to this article as senior collaborating authors.

Supported, in part, by National Institutes of Health grants HL65558, HL68951, and HL79641.

© 2006 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins