EXPLOITATION OF THE KATP CHANNEL OPENER DIAZOXIDE DURING CARDIAC SURGERY

描述（由申请方提供）：暴露于高钾心脏停搏液、低渗应激或代谢抑制形式的肌细胞应激导致显著的肌细胞肿胀，这与肌细胞收缩性显著降低直接相关。因此，心肌细胞结构紊乱被假设为心肌顿抑的机制之一。这些结构和功能紊乱可通过添加三磷酸腺苷敏感性钾（KATP）通道开放剂二氮嗪消除，已知二氮嗪可模拟缺血预处理并通过未知机制在多种模型中提供心脏保护。本申请将研究肌膜KATP通道在容量紊乱中的作用，以及二氮嗪作为心脏保护剂在缺血或再灌注期间对细胞和整个器官水平给药时的疗效，具体目的如下：具体目的#1确定肌膜KATP通道在肌细胞体积稳态中的作用具体目的#2为了在肌细胞水平确定在持续应激期间KATP通道开放剂二氮嗪作为心脏保护剂的有效性，和具体目标#3确定KATP通道开放剂二氮嗪在进行性心肌缺血期间在整个器官水平上作为心脏保护剂的有用性。提高对这种内在保护性离子通道的理解水平和通道开放剂药物的作用将允许未来直接的药理学靶向，这可能会减少每年数十万患者中出现的心肌顿抑。

DESCRIPTION (provided by applicant): Myocyte stress in the form of exposure to hyperkalemic cardioplegic solutions, hyposmotic stress, or metabolic inhibition results in significant myocyte swelling that is directly linked to a significant reduction in myocyte contractility. Myocyte structural derangement is therefore hypothesized to be one mechanism of myocardial stunning. These structural and functional derangements may be eliminated by the addition of an adenosine triphosphate -sensitive potassium (KATP) channel opener diazoxide which is known to mimic ischemic preconditioning and provide cardioprotection in multiple models by an unknown mechanism. This application will investigate the role of the sarcolemmal KATP channel in volume derangement and the efficacy of diazoxide as a cardioprotective agent when administered during ischemia or reperfusion on the cellular and whole organ levels by the following specific aims: Specific Aim #1 To determine the role of the sarcolemmal KATP channel in myocyte volume homeostasis (and resultant functional preservation) during stress, Specific Aim #2 To determine the effectiveness of KATP channel opener diazoxide as a cardioprotective agent during ongoing stress at the myocyte level, and Specific Aim #3 To establish the usefulness of KATP channel opener diazoxide as a cardioprotective agent during ongoing myocardial ischemia at the whole organ level. Increasing the level of understanding of this intrinsically protective ion channel and the effects of channel opener drugs will allow for direct pharmacologic targeting in the future that could lessen the myocardial stunning seen in hundreds of thousands of patients each year.