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.
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