Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, USA.
J Mol Cell Cardiol. 2011 Aug;51(2):215-25. doi: 10.1016/j.yjmcc.2011.04.016. Epub 2011 May 7.
This study compared the effects of ATP-regulated potassium channel (K(ATP)) openers, diazoxide and pinacidil, on diseased and normal human atria and ventricles. We optically mapped the endocardium of coronary-perfused right (n=11) or left (n=2) posterior atrial-ventricular free wall preparations from human hearts with congestive heart failure (CHF, n=8) and non-failing human hearts without (NF, n=3) or with (INF, n=2) infarction. We also analyzed the mRNA expression of the K(ATP) targets K(ir)6.1, K(ir)6.2, SUR1, and SUR2 in the left atria and ventricles of NF (n=8) and CHF (n=4) hearts. In both CHF and INF hearts, diazoxide significantly decreased action potential durations (APDs) in atria (by -21±3% and -27±13%, p<0.01) and ventricles (by -28±7% and -28±4%, p<0.01). Diazoxide did not change APD (0±5%) in NF atria. Pinacidil significantly decreased APDs in both atria (-46 to -80%, p<0.01) and ventricles (-65 to -93%, p<0.01) in all hearts studied. The effect of pinacidil on APD was significantly higher than that of diazoxide in both atria and ventricles of all groups (p<0.05). During pinacidil perfusion, burst pacing induced flutter/fibrillation in all atrial and ventricular preparations with dominant frequencies of 14.4±6.1 Hz and 17.5±5.1 Hz, respectively. Glibenclamide (10 μM) terminated these arrhythmias and restored APDs to control values. Relative mRNA expression levels of K(ATP) targets were correlated to functional observations. Remodeling in response to CHF and/or previous infarct potentiated diazoxide-induced APD shortening. The activation of atrial and ventricular K(ATP) channels enhances arrhythmogenicity, suggesting that such activation may contribute to reentrant arrhythmias in ischemic hearts.
本研究比较了三磷酸腺苷调节钾通道（K(ATP)）开放剂，二氮嗪和吡那地尔，对病变和正常人心房和心室的影响。我们用光映射了充血性心力衰竭（CHF，n=8）和非衰竭人心（NF，n=3）或梗死人心（INF，n=2）的冠状灌注右（n=11）或左（n=2）后房-室游离壁标本的心内膜。我们还分析了 NF（n=8）和 CHF（n=4）心脏左心房和左心室的 K(ATP)靶点 K(ir)6.1、K(ir)6.2、SUR1 和 SUR2 的 mRNA 表达。在 CHF 和 INF 心脏中，二氮嗪显著缩短心房（-21±3%和-27±13%，p<0.01）和心室（-28±7%和-28±4%，p<0.01）的动作电位持续时间（APD）。二氮嗪未改变 NF 心房的 APD（0±5%）。吡那地尔显著缩短了所有研究心脏的心房（-46 至-80%，p<0.01）和心室（-65 至-93%，p<0.01）的 APD。在所有组的心房和心室中，吡那地尔对 APD 的作用明显高于二氮嗪（p<0.05）。在吡那地尔灌注期间，爆发起搏在所有心房和心室标本中诱发扑动/颤动，其主导频率分别为 14.4±6.1 Hz 和 17.5±5.1 Hz。格列本脲（10 μM）终止这些心律失常并将 APD 恢复至对照值。K(ATP)靶点的相对 mRNA 表达水平与功能观察相关。对 CHF 和/或先前梗死的反应性重塑增强了二氮嗪引起的 APD 缩短。心房和心室 K(ATP)通道的激活增强了致心律失常性，表明这种激活可能导致缺血性心脏中的折返性心律失常。
