title: Modulation of myocardial mitochondrial mechanisms during severe polymicrobial sepsis in the rat.
abstract: BACKGROUND
  We tested the hypothesis that 5-Hydroxydecanoic acid (5HD), a putative mitoK(ATP) channel blocker, will reverse sepsis-induced cardiodynamic and adult rat ventricular myocyte (ARVM) contractile dysfunction, restore mitochondrial membrane permeability alterations and improve survival.
  
  
  RESULTS
  Male Sprague-Dawley rats (350-400 g) were made septic using 400 mg/kg cecal inoculum, ip. Sham animals received 5% dextrose water, ip. The Voltage Dependent Anion Channels (VDAC1), Bax and cytochrome C levels were determined in isolated single ARVMs obtained from sham and septic rat heart. Mitochondria and cytosolic fractions were isolated from ARVMs treated with norepinephrine (NE, 10 µmoles) in the presence/absence of 5HD (100 µmoles). A continuous infusion of 5HD using an Alzet pump reversed sepsis-induced mortality when administered at the time of induction of sepsis (-40%) and at 6 hr post-sepsis (-20%). Electrocardiography revealed that 5HD reversed sepsis-induced decrease in the average ejection fraction, Simpsons+m Mode (53.5±2.5 in sepsis and 69.2±1.2 at 24 hr in sepsis+5HD vs. 79.9±1.5 basal group) and cardiac output (63.3±1.2 mL/min sepsis and 79.3±3.9 mL/min at 24 hr in sepsis+5HD vs. 85.8±1.5 mL/min basal group). The treatment of ARVMs with 5HD also reversed sepsis-induced depressed contractility in both the vehicle and NE-treated groups. Sepsis produced a significant downregulation of VDAC1, and upregulation of Bax levels, along with mitochondrial membrane potential collapse in ARVMs. Pretreatment of septic ARVMs with 5HD blocked a NE-induced decrease in the VDAC1 and release of cytochrome C.
  
  
  CONCLUSIONS
  The data suggest that Bax activation is an upstream event that may precede the opening of the mitoK(ATP) channels in sepsis. We concluded that mitoK(ATP) channel inhibition via decreased mitochondrial membrane potential and reduced release of cytochrome C provided protection against sepsis-induced ARVM and myocardial contractile dysfunction.
authors.affiliation: Department of Biomedical Sciences, Texas A&M Health Science Center Baylor College of Dentistry, Dallas, Texas, United States of America.
authors.forename: Mani
authors.initials: M
authors.lastname: Chopra
authors.forename: Honey B
authors.initials: HB
authors.lastname: Golden
authors.forename: Srinivas
authors.initials: S
authors.lastname: Mullapudi
authors.forename: William
authors.initials: W
authors.lastname: Dowhan
authors.forename: David E
authors.initials: DE
authors.lastname: Dostal
authors.forename: Avadhesh C
authors.initials: AC
authors.lastname: Sharma
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D003652:Decanoic Acids / Q000378:metabolism / Q000494:pharmacology*; D006439:Hemodynamics; D006880:Hydroxy Acids / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000382:microbiology / Q000401:mortality / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D014409:Tumor Necrosis Factor-alpha; C494764:Vdac1 protein, rat; D051028:bcl-2-Associated X Protein; C117780:mitochondrial K(ATP) channel; C052853:5-hydroxydecanoic acid; D045304:Cytochromes c; D050995:Voltage-Dependent Anion Channel 1