NMR STUDIES OF THE MECHANISMS OF CELL INJURY

现在已经证实，离子的功能是细胞内的信使。 离子转运和离子动态平衡也变得非常明显。 信号转导的重要方面。这项研究的目标是 对这些途径是如何改变的理解的发展 在病理条件下，即离子动态平衡和离子转运 改变，从而导致细胞功能改变和疾病。 以前，我们已经证明胞浆游离钙的增加是 与细胞损伤有关。为了了解负责的机制，我们 已经调查了减少伤害的干预措施。它已经被证明了 这种短暂的间歇性应激(预适应)可以减少 由随后更严重的无应力性坏死造成的损伤， 更好地保存离子动态平衡，减缓ATP周转。我们有 我一直在研究各种可能的预适应介质 腺苷拮抗剂不能阻断 大鼠心脏的预适应。对格列本脲敏感的激活作用 钾通道也被认为参与了预适应。 然而，我们发现格列本脲并不能阻断这种保护作用。 预适应对降低脑缺血再灌注时血管紧张素转换酶活性升高的影响 改善回流过程中的收缩性能。我们最近也开始 研究磷酸酶在预适应中的作用。我们发现 磷酸酶抑制剂微囊藻毒素阻断预适应；在 微囊藻毒素的存在在脑缺血和脑缺血恢复过程中的作用 预适应不能改善对回流的作用。我们的工作 假说是，预适应可以刺激一种磷酸酶 结果观察到了有益的效果。我们目前正在 研究花生四烯酸代谢物是否能激活 磷酸酶与中介预适应。我们发现，阻止 去甲二氢愈创木酸(NDGA)阻断脂氧合酶途径 预适应对脑缺血时钙离子浓度升高的保护作用 改善了复流时的功能恢复。另外，我们发现， 吲哚美辛抑制环氧合酶途径不阻断 预适应的有益效果。

It is now established that ions function as intracellular messengers. It has also become clear that ion transport and ion homeostasis are very important aspects of signal transduction. The goal of this research is the development of an understanding of how these pathways are altered under pathologic conditions, i.e., how ion homeostasis and ion transport are altered and thereby lead to altered cell function and disease. Previously, we have shown that an increase in cytosolic free calcium is associated with cell injury. To understand mechanisms responsible, we have investigated interventions which reduce injury. It has been shown that brief intermittent exposure to stress (preconditioning) reduces injury resulting from a subsequent, more severe stress - less necrosis, better preservation of ion homeostasis, slower ATP turnover. We have been investigating various potential mediators of preconditioning adenosine antagonists do not block the protective effect of preconditioning in rat heart. Activation of the glybenclamide sensitive potassium channel was also suggested to be involved in preconditioning, however we found that glybenclamide did not block the protective effects of preconditioning on reducing the rise in Cai during ischemia or improving contractility during reflow. We have also recently begun investigating the role of phosphatases in preconditioning. We find that the phosphatase inhibitor microcystin blocks proconditioning; in the presence of microcystin the rise in Cai during ischemia and recovery of function on reflow are not improved by preconditioning. Our working hypothesis is that preconditioning may stimulate a phosphatase which results in the beneficial effects observed. We are currently investigating whether an arachidonic acid metabolite could activate a phosphatase and mediate preconditioning. We find that blocking the lipoxygenase pathway with nordihydroguaiaretic acid (NDGA) blocks the beneficial effects of preconditioning on the rise in Cai during ischemia and improved recovery of function on reflow. In addition, we find that inhibiting the cyclooxygenase pathway with indomethacin does not block the beneficial effects of preconditioning.