EXPLOITATION OF THE KATP CHANNEL OPENER DIAZOXIDE DURING CARDIAC SURGERY

描述(由申请人提供)：暴露于高钾停搏液、低渗应激或代谢抑制的形式的心肌细胞应激导致显著的心肌细胞肿胀，这与心肌细胞收缩能力的显著降低直接相关。因此，心肌细胞结构紊乱被认为是心肌顿抑的一种机制。这些结构和功能的紊乱可以通过添加三磷酸腺苷敏感性钾(KATP)通道开放剂二氮嗪来消除，二氮嗪已知可以模拟缺血预适应，并通过未知的机制在多种模型中提供心脏保护。本应用将通过以下特定目的来研究肌膜KATP通道在心肌容量紊乱中的作用以及在细胞和整个器官水平上应用二氮卓作为心脏保护剂的有效性，具体目的如下：特定目的#1确定肌膜KATP通道在应激期间心肌细胞体积稳态(以及由此产生的功能保护)中的作用，特定目的#2从心肌细胞水平确定KATP通道开放剂二氮嗪作为心肌保护剂的有效性，以及特定目的#3确定KATP通道开放剂二氮卓在整个器官水平作为持续心肌缺血期间心脏保护剂的有效性。提高对这种本质上具有保护作用的离子通道的了解程度以及通道开放剂药物的效果，将使未来能够直接进行药物靶向，从而减少每年数十万患者出现的心肌顿抑。

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.