PRECONDITIONING MECHANISMS REGULATING ISCHEMIA

这些研究的最终目标是描绘细胞的 心脏预适应的机制。实验性短暂性缺血和 临床心绞痛既促进心肌活力， 对持续缺血/再灌注的反应。可以预见的是， 利用心肌缺血作为保护性“预处理” 刺激已被证明是心脏病学家/外科医生的诅咒。几种激素 和药理学试剂已经出现， 防止持续的缺血性损伤。所有的几百个 每年进行的数千例心脏外科手术依赖于寒冷 高钾心肌保护技术。缺乏机械性 熟悉心脏“预处理”延迟了 这种生理现象进入目前的治疗。 肌细胞酸中毒可通过以下方式减轻：1）减少代谢质子 生产，2）细胞内缓冲和3）膜质子交换。 质子泵挤出可以强制膜钠交换， 序列可能会被撞出细胞，以换取增加 胞内钙细胞内高钠血症和 高钙血症可引起舒张期和收缩期心肌细胞 功能障碍缺血/激素/药理学“心脏预处理” 与多种异构体的易位（激活）有关， 蛋白激酶C拟议的一系列研究将澄清假定的 临床上有吸引力的激素/药物之间的联系，具体 PKC异构体与心脏预适应抗酸中毒机制 以及随后的持续心脏缺血/再灌注。的潜在 这些观察结果最初应用于所有计划的心脏 外科手术，并最终经皮血管成形术和 因此，心肌缺血的药物治疗应 相当可观

The ultimate goals of these investigations are to delineate the cellular mechanisms of cardiac preconditioning. Experimental transient ischemia and clinical angina both promote myocardial viability and mechanical function in response to sustained ischemia/reperfusion. Predictably, therapeutic utilization of myocardial ischemia as a protective "preconditioning" stimulus has proven anathema to cardiologists/surgeons. Several hormones and pharmacologic agents have surfaced that appear to reproduce cardiac protection against a sustained ischemic insult. All of the several hundred thousand cardiac surgical procedures performed each year rely upon cold hyperkalemic myocardial preservation techniques. Lack of mechanistic familiarity with cardiac "preconditioning" has delayed incorporation of this physiologic phenomenon into current therapy.Cardiac ischemia induces myocyte acidosis that can be attenuated by: 1) reduced metabolic proton production, 2) intracellular buffering and 3) membrane proton exchange. Proton pump extrusion may mandate membrane sodium exchange which in sequence may be bumped out of the cell in return for an increase in intracellular calcium. Both the intracellular hypernatremia and hypercalcemia could provoke both diastolic and systolic myocellular dysfunction. Ischemic/hormonal/pharmacologic "cardiac preconditioning" has been associated with a translocation (activation) of multiple isomers of protein kinase C. The proposed series of studies will clarify the putative link between clinically attractive hormone/pharmacologic agents, specific PKC isomers and mechanisms of antiacidosis during cardiac preconditioning and subsequent sustained cardiac ischemia/reperfusion. The potential application of these observations initially to all scheduled cardiac surgical procedures and ultimately to both percutaneous angioplasty and subsequently the medical therapy of myocardial ischemia should be substantial.