Li H, Xu K Y, Zhou L, Kalai T, Zweier J L, Hideg K, Kuppusamy P
Division of Cardiology, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21224, USA.
J Pharmacol Exp Ther. 2000 Nov;295(2):563-71.
The efficacy and mechanism of protection of a new 2,2,5, 5-tetramethylpyrroline derivative of mexiletine, MEX-NH, against ischemia/reperfusion-induced cardiac dysfunction are reported. The MEX-NH and its nitroxide metabolite are membrane-permeable antioxidants. Studies were performed in an isolated rat heart model to measure the efficacy of MEX-NH in preventing postischemic injury. Serial measurements of contractile function and coronary flow were performed on hearts subjected to 30 min of global 37 degrees C ischemia followed by 45 min of reperfusion. Hearts were either untreated or treated with 25 microM MEX-NH or MEX for 1 min before ischemia. The hearts treated with MEX-NH showed marked recovery of left ventricular developed pressure (96.3 +/- 2.7% of preischemic value) compared with untreated (13.7 +/- 1.0%) or MEX-treated (19.9 +/- 2.7%) hearts. The cardiac sarcolemmal Na(+),K(+)-ATPase activity showed that the enzyme activity was fully restored in hearts treated with MEX-NH compared with 65 +/- 5.3% inhibition in the untreated hearts. Competitive inhibition of [(3)H]ouabain binding revealed that the MEX-NH binds at the K(+)-binding site of the enzyme. The present study establishes that the compound MEX-NH provides marked protection against ischemia/reperfusion-induced contractile dysfunction in isolated hearts. A combination of reversible inhibition of Na(+)/K(+)-ATPase activity during ischemia and site-targeted antioxidative effect upon reperfusion seems to contribute to this cardioprotection.
报道了美西律的一种新型2,2,5,5-四甲基吡咯啉衍生物MEX-NH对缺血/再灌注诱导的心脏功能障碍的保护作用及其机制。MEX-NH及其氮氧化物代谢产物是可透过细胞膜的抗氧化剂。在离体大鼠心脏模型中进行研究，以测量MEX-NH预防缺血后损伤的效果。对经历30分钟37℃全心缺血随后45分钟再灌注的心脏进行收缩功能和冠状动脉血流的连续测量。心脏在缺血前未处理或用25μM MEX-NH或美西律处理1分钟。与未处理（13.7±1.0%）或美西律处理（19.9±2.7%）的心脏相比，用MEX-NH处理的心脏左心室舒张末压显著恢复（缺血前值的96.3±2.7%）。心脏肌膜Na(+)，K(+)-ATP酶活性显示，与未处理心脏中65±5.3%的抑制率相比，用MEX-NH处理的心脏中该酶活性完全恢复。[(3)H]哇巴因结合的竞争性抑制表明MEX-NH在该酶的K(+)结合位点结合。本研究证实化合物MEX-NH对离体心脏缺血/再灌注诱导的收缩功能障碍具有显著保护作用。缺血期间对Na(+)/K(+)-ATP酶活性的可逆抑制与再灌注时的位点靶向抗氧化作用相结合似乎有助于这种心脏保护作用。
