title: Caffeine restores myocardial cytochrome oxidase activity and improves cardiac function during sepsis.
abstract: OBJECTIVE
  Impaired mitochondrial function is a potential cause of sepsis-associated myocardial depression. Cytochrome oxidase (CcOX), the terminal oxidase of the electron transport chain, is inhibited in the septic heart. Caffeine increases CcOX activity by increasing cyclic adenosine monophosphate and protein kinase A activity. We hypothesized that caffeine will restore myocardial CcOX activity, increase cardiac function, and improve survival during sepsis.
  
  
  METHODS
  Prospective randomized controlled study.
  
  
  METHODS
  University hospital-based laboratory.
  
  
  METHODS
  One hundred twenty Sprague-Dawley male rats.
  
  
  METHODS
  Sprague-Dawley male rats underwent cecal ligation and puncture (CLP) or sham operation. At 24 and 48 hours, rats underwent intraperitoneal injection of either caffeine (7.5 mg/kg, the equivalent of 1-1.5 cups of coffee) or equal volume of saline.
  
  
  RESULTS
  One hour following the 48-hour injection, steady-state CcOX kinetic activity was measured in isolated mitochondria and normalized to citrate synthase activity. Cardiac function was assessed using an isolated rat heart preparation and survival was tracked to 96 hours. CLP significantly decreased myocardial CcOX activity, oxygen consumption, left ventricular pressure, and pressure developed during isovolumic contraction (+dP/dt) and relaxation (-dP/dt). Caffeine restored CcOX activity and increased left ventricular pressure and +/-dP/dt toward sham values following CLP. Survival significantly improved following CLP in caffeine-injected animals compared with saline injection.
  
  
  CONCLUSIONS
  Caffeine may be a novel therapy to treat sepsis-associated myocardial depression.
authors.affiliation: Department of Anesthesiology, Maria Fareri Children's Hospital of Westchester Medical Center, New York Medical College, Valhalla, NY, USA.
authors.forename: Richa
authors.initials: R
authors.lastname: Verma
authors.forename: Zhishan
authors.initials: Z
authors.lastname: Huang
authors.forename: Clifford S
authors.initials: CS
authors.lastname: Deutschman
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Levy
mesh_terms: D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D003576:Electron Transport Complex IV / Q000378:metabolism*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000201:enzymology* / Q000503:physiopathology*
chemical_list: D002110:Caffeine; D003576:Electron Transport Complex IV