EXPLOITATION OF THE KATP CHANNEL OPENER DIAZOXIDE DURING CARDIAC SURGERY

描述（由申请人提供）：暴露于高钾性心脏麻痹溶液、低渗应激或代谢抑制的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昏迷的一种机制。这些结构和功能紊乱可以通过添加三磷酸腺苷敏感钾（KATP）通道开启剂二氮氧化合物来消除，已知二氮氧化合物可以模拟缺血预处理，并通过未知机制在多种模型中提供心脏保护。本应用程序将研究肌上皮KATP通道在体积紊乱中的作用，以及在缺血或再灌注期间在细胞和整个器官水平上给予二氮氧化物作为心脏保护剂的功效，其具体目的如下：目的1：确定应激状态下肌上皮KATP通道在心肌细胞体积稳态（以及由此产生的功能保存）中的作用；目的2：确定持续应激状态下心肌细胞水平上KATP通道开启剂二氮氧化物作为心脏保护剂的有效性；目的3：在全器官水平上确定持续心肌缺血时KATP通道开启剂二氮氧化物作为心脏保护剂的有效性。提高对这种内在保护性离子通道的理解水平和通道开启药物的作用将使未来的直接药物靶向成为可能，从而减少每年成千上万患者的心肌休克。

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.