title: Endogenous activation of mitochondrial KATP channels protects human failing myocardium from hydroxyl radical-induced stunning.
abstract: BACKGROUND
  During reperfusion of ischemic myocardium, a burst of hydroxyl radicals (OH) induces contractile dysfunction ("myocardial stunning"), and OH in the plasma of patients after myocardial infarction predict the development of heart failure. The effects of OH on myocardial function in patients with heart failure; however, have never been assessed. Furthermore, although ATP-dependent K+ channels (K(ATP) channels) are implicated in myocardial protection during ischemia/reperfusion ("ischemic preconditioning"), their role in heart failure has hardly been elucidated.
  
  
  OBJECTIVE
  To investigate the effects of OH on cardiac contractile function in human failing myocardium, and to clarify the role of K(ATP) channels during this response.
  
  
  RESULTS
  In isolated left ventricular trabeculae of nonfailing hearts, OH (produced by Fe3+-nitrilotriacetic acid and H2O2) induced substantial systolic and diastolic dysfunction, whereas in failing myocardium, stunning was virtually absent. Although in failing myocardium, protein expression of sarcolemmal K(ATP) channels (Kir6.2/SUR2) was approximately 2-fold upregulated, their blockade with HMR-1098 did not impair contractile function in the presence of OH. In contrast, when blocking mitochondrial K(ATP) channels during OH exposure (with 5-HD), failing myocardium developed contractile dysfunction to a degree that was comparable to H-induced stunning in nonfailing myocardium without K(ATP) channel blockade.
  
  
  CONCLUSIONS
  Human failing left ventricular myocardium is resistant to OH-induced stunning, and this resistance is related to endogenous activation of putative mitochondrial K(ATP) channels. Given that certain sulfonylurea drugs that also block mitochondrial K(ATP) channels (eg, glibenclamide) are frequently used for the treatment of diabetes, our results imply that in patients with heart failure and diabetes, these drugs may impair left ventricular function during ischemia/reperfusion.
authors.affiliation: Medizinische Klinik und Poliklinik, Innere Medizin III (Kardiologie/Angiologie), Universitätskliniken des Saarlandes, Homburg/Saar, Germany. maack@gmx.org
authors.forename: Christoph
authors.initials: C
authors.lastname: Maack
authors.forename: Ewtim R
authors.initials: ER
authors.lastname: Dabew
authors.forename: Mathias
authors.initials: M
authors.lastname: Hohl
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schäfers
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
mesh_terms: D016279:Atrial Function, Left / Q000187:drug effects; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology; D048909:Diabetes Complications / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005905:Glyburide / Q000009:adverse effects / Q000494:pharmacology; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D017682:Myocardial Stunning / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism / Q000473:pathology; D000099161:Kcnj11 Channel
chemical_list: D005905:Glyburide; D017665:Hydroxyl Radical; D007004:Hypoglycemic Agents; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel