Diazoxide maintains human myocyte volume homeostasis during stress.
Diazoxide maintains human myocyte volume homeostasis during stress.
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DOI：
10.1161/jaha.112.000778
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发表时间：
2012-04
影响因子：
5.4
通讯作者：
Lawton JS
中科院分区：
文献类型：
--
作者：
Maffit SK;Sellitto AD;Al-Dadah AS;Schuessler RB;Damiano RJ Jr;Lawton JS
暴露于低温高钾心脏骤停、低氧应激或代谢抑制会导致动物心肌细胞显著肿胀（6%至10%），随后收缩力降低（10%至20%）。两者都被三磷酸腺苷敏感的钾通道开启剂二氮氧化物（DZX）消除。肿胀和收缩力降低之间的关系提示结构改变可能是术后心肌昏迷的一种机制。本研究对应激状态下的人肌细胞体积进行了评估，以探讨在人肌细胞中是否存在类似的现象。从心脏手术中获得的组织中分离的人心房肌细胞灌注Tyrode生理溶液（20分钟，37°C）、测试溶液（20分钟）和Tyrode生理溶液（37°C， 20分钟）。测试溶液（每个n=6至12个肌细胞）包括Tyrode’s（37°C或9°C）、Tyrode’s+DZX（9°C）、高钾血症性心停液（9°C）±DZX、心停液+DZX+HMR 1098（肌层三磷酸腺苷敏感钾通道抑制剂，9°C）、心停液+DZX+5-羟基去酸盐（线粒体三磷酸腺苷敏感钾通道抑制剂，9°C）、轻度低氧溶液±DZX、代谢抑制±DZX、代谢抑制+DZX+5-羟基去酸盐。每5分钟记录一次心肌细胞体积。暴露于低温高钾心脏骤停、低氧应激或代谢抑制导致显著的人肌细胞肿胀（分别为8%、7%和6%；与对照组相比，P均<0.05）。在所有组中，DZX消除或减轻肿胀。通道抑制剂的加入没有显著改变结果。DZX通过一种未知的机制维持应激状态下人类肌细胞体积的稳态。在阐明其特定的作用机制后，DZX可能被证明是临床有用的。[J] .中华心脏杂志，2012;1:jah3-e000778 doi: 10.1161/JAHA.112.000778.]
Exposure to hypothermic hyperkalemic cardioplegia, hyposmotic stress, or metabolic inhibition results in significant animal myocyte swelling (6% to10%) and subsequent reduced contractility (10% to 20%). Both are eliminated by the adenosine triphosphate-sensitive potassium channel opener diazoxide (DZX). The relationship between swelling and reduced contractility suggests that the structural change may represent one mechanism of postoperative myocardial stunning. This study evaluated human myocyte volume during stress to investigate if similar phenomena exist in human myocytes. Human atrial myocytes isolated from tissue obtained during cardiac surgery were perfused with Tyrode's physiological solution (20 minutes, 37°C), test solution (20 minutes), and Tyrode's (37°C, 20 minutes). Test solutions (n=6 to 12 myocytes each) included Tyrode's (37°C or 9°C), Tyrode's+DZX (9°C), hyperkalemic cardioplegia (9°C)±DZX, cardioplegia+DZX+HMR 1098 (sarcolemmal adenosine triphosphate-sensitive potassium channel inhibitor, 9°C), cardioplegia+DZX+5-hydroxydeconoate (mitochondrial adenosine triphosphate-sensitive potassium channel inhibitor, 9°C), mild hyposmotic solution±DZX, metabolic inhibition±DZX, and metabolic inhibition+DZX+5-hydroxydeconoate. Myocyte volume was recorded every 5 minutes. Exposure to hypothermic hyperkalemic cardioplegia, hyposmotic stress, or metabolic inhibition resulted in significant human myocyte swelling (8%, 7%, and 6%, respectively; all P<0.05 vs control). In all groups, the swelling was eliminated or lessened by DZX. The addition of channel inhibitors did not significantly alter results. DZX maintains human myocyte volume homeostasis during stress via an unknown mechanism. DZX may prove to be clinically useful following the elucidation of its specific mechanism of action. (J Am Heart Assoc. 2012;1:jah3-e000778 doi: 10.1161/JAHA.112.000778.)