DRUGS UPON MYOCARDIAL HYPOXIA

描述：这份面向格罗斯博士和他的研究团队的申请是 关注心肌梗死发病机制的确定 预适应。更具体地说，调查人员将确定 KATP在介导预适应中的作用及其与其他因素的相互作用 信号通路。他们的第一个目标是确定预适应 (PC)由缺血、缺氧、KATP开放剂或腺苷份额产生 常见的血流动力学或电生理(EP)机制。他们会 确定非选择性阻滞剂(格列本脲)对缺血的影响 选择性阻滞剂(5-HD)或血管选择性阻滞剂 预适应。他们还将确定推定的 胰腺选择性KATP阻滞剂对预适应的影响。他们会 确定动作电位时程缩短在调节预适应中的重要性。 这将通过确定腺苷、PCO或apd的效果来完成。 预适应前后。他们还将确定影响 将取消IKR受体阻滞剂的时程缩短效应 预适应等，对预适应。在AIM II中，他们将 确定PC产生的受体或信号转导途径 由局部缺氧引起。他们将确定PKC-α-1的作用 相互作用，cAMP(通过儿茶酚胺)，腺苷，最后如果KATP 是由PKC激活产生的末端效应器。这将使用以下工具完成 犬低氧缓冲时间(4x5分钟)。他们将使用多种激动剂 和KATP、腺苷、PKA、PKC的拮抗剂 重要性。在AIM III中，他们将确定腺苷是否增加 Release负责触发PC，如果KATP开关器起作用 通过促进腺苷的释放。这将使用低氧来完成 或其他AIMS中所描述的缺血。腺苷将被测量 使用微透析技术。在目标IV中，申请者将决定 如果KATP开放剂或腺苷激动剂降低PC阈值 腺苷或PKC或KATP介导记忆(PC多久后才能 保护措施？)。他们还将确定伊藤在 心脏记忆。他们将使用PKC抑制剂，KATP阻滞剂，腺苷 拮抗剂，4-氨基吡啶。

DESCRIPTION: This application for Dr. Gross and his research team is concerned with the determination of the mechanism of myocardial preconditioning. More specifically, the investigators will determine the role of KATP in mediating preconditioning and its interaction with other signaling pathways. Their first aim is to determine if preconditioning (PC) produced by ischemia, hypoxia, KATP openers or adenosine share common hemodynamic or electrophysiologic (EP) mechanisms. They will determine the effect of a nonselective blocker (glyburide), an ischemia selective blocker (5-HD), or a vascular selective blocker on preconditioning. They will also determine the effect of a putative pancreatic selective KATP blocker on preconditioning. They will determine the importance of APD shortening in mediating preconditioning. This will be done by determining the effect of adenosine or PCO or APD before and after preconditioning. They will also determine the effect of IKr blockers which will abolish the APD shortening effects of preconditioning, etc., on preconditioning. In aim II, they will determine the receptor or signal transduction pathways for PC produced by regional hypoxia. They will determine the role of PKC-alpha-1 interactions, cAMP (via catecholamines), adenosine, and finally if KATP is the end effector produced by PKC activation. This will be done using hypoxic buffer (4X5 min) in dogs. They will use a variety of agonists and antagonists of KATP, adenosine, PKA, PKC to determine their importance. In aim III, they will determine if increased adenosine release is responsible for triggering PC and if KATP openers work through enhancing adenosine release. This will be done using hypoxia or ischemia as described in other aims. Adenosine will be measured using a microdialysis technique. In aim IV the applicant will determine if KATP openers or adenosine agonists lower PC threshold and if adenosine or PKC or KATP mediate memory (how long after PC can protection be seen?). They will also determine the role of Ito in cardiac memory. They will use PKC inhibitors, KATP blockers, adenosine antagonists, 4-aminopyridine.