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Circulation Research
0009-7330 Vol.105, 08(2009)
Endogenous Activation of Mitochondrial KATP Channels Protects Human Failing Myocardium From Hydroxyl Radical-Induced Stunning
Maack, Christoph; Dabew, Ewtim R.; Hohl, Mathias; Schafers, Hans-Joachim; Bohm, Michael
 Abstract:Rationale: During reperfusion of ischemic myocardium, a burst of hydroxyl radicals (H) induces contractile dysfunction ("myocardial stunning"), and H in the plasma of patients after myocardial infarction predict the development of heart failure. The effects of H on myocardial function in patients with heart failure; however, have never been assessed. Furthermore, although ATP-dependent K+ channels (KATP 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 H on cardiac contractile function in human failing myocardium, and to clarify the role of KATP channels during this response. Methods and Results: In isolated left ventricular trabeculae of nonfailing hearts, H (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 KATP channels (Kir6.2/SUR2) was 2-fold upregulated, their blockade with HMR-1098 did not impair contractile function in the presence of H. In contrast, when blocking mitochondrial KATP channels during H exposure (with 5-HD), failing myocardium developed contractile dysfunction to a degree that was comparable to H-induced stunning in nonfailing myocardium without KATP channel blockade. Conclusions: Human failing left ventricular myocardium is resistant to H-induced stunning, and this resistance is related to endogenous activation of putative mitochondrial KATP channels. Given that certain sulfonylurea drugs that also block mitochondrial KATP 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.
 Keyword:stunning ? myocardial ? reperfusion ? ion channels ? contractility ? heart failure
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