Maack Christoph, Dabew Ewtim R, Hohl Mathias, Schäfers Hans-Joachim, Böhm Michael
Medizinische Klinik und Poliklinik, Innere Medizin III (Kardiologie/Angiologie), Universitätskliniken des Saarlandes, Homburg/Saar, Germany.
Circ Res. 2009 Oct 9;105(8):811-7. doi: 10.1161/CIRCRESAHA.109.206359. Epub 2009 Sep 3.
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.
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.
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.
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.
在缺血心肌再灌注期间，一阵羟基自由基（OH）会诱发收缩功能障碍（“心肌顿抑”），并且心肌梗死后患者血浆中的OH可预测心力衰竭的发生。然而，OH对心力衰竭患者心肌功能的影响从未得到评估。此外，尽管ATP依赖性钾通道（K(ATP)通道）与缺血/再灌注期间的心肌保护作用（“缺血预处理”）有关，但其在心力衰竭中的作用几乎尚未阐明。
研究OH对人类衰竭心肌心脏收缩功能的影响，并阐明K(ATP)通道在此反应中的作用。
在非衰竭心脏的离体左心室小梁中，OH（由Fe3+-次氮基三乙酸和H2O2产生）可诱发显著的收缩期和舒张期功能障碍，而在衰竭心肌中，几乎不存在顿抑现象。尽管在衰竭心肌中，肌膜K(ATP)通道（Kir6.2/SUR2）的蛋白表达上调了约2倍，但在存在OH的情况下，用HMR-1098阻断这些通道并未损害收缩功能。相反，在OH暴露期间阻断线粒体K(ATP)通道（用5-HD）时，衰竭心肌出现的收缩功能障碍程度与未阻断K(ATP)通道的非衰竭心肌中H诱导的顿抑相当。
人类衰竭的左心室心肌对OH诱导的顿抑具有抗性，且这种抗性与假定的线粒体K(ATP)通道的内源性激活有关。鉴于某些也阻断线粒体K(ATP)通道的磺脲类药物（如格列本脲）常用于治疗糖尿病，我们的结果表明，在心力衰竭合并糖尿病的患者中，这些药物可能在缺血/再灌注期间损害左心室功能。
