application) The primary goal of this proposal is to investigate mechanisms that may be involved in the regulation of cytosolic free calcium concentration ([Ca2+]I) during ischemia and reperfusion and may be involved in the pathogenesis of stunning and lethal ischemic injury. The applicants initially reported and others have subsequently found that ischemic preconditioning (PC), produced by brief intermittent periods of ischemia and reperfusion prior to a sustained period of ischemia, minimizes ionic alterations, particularly the rise in [Ca2+]I, during the subsequent period of sustained ischemia, in parallel with a reduction in stunning in rat heart, if the sustained period of ischemia is 30 minutes or less, and less lethal injury if sustained ischemia is longer than 30 minutes. They have found that an effect of PC is stimulation of 12-lipoxygenase (12-LO) metabolism of arachidonic acid, and this appears to be of crucial importance for the protective effect of PC on stunning. The applicants have measured a two-fold increase in 12-LO metabolite content during PC, they have found that a variety of structurally unrelated lipoxygenase inhibitors which prevent the increase in 12-LO metabolites also block the protective effect of PC, and they have found that the 12-LO metabolite, 12 (S)-HpETE, can mimic the protective effect of PC on stunning. They also have preliminary data that inhibition of p38 MAP kinase blocks the protective effect of PC. In the first specific aim, they plan to investigate the relationships between 12-LO metabolism, p38 MAP kinase activation, PKC activation, and the rise in [Ca2+]I during ischemia, and how these mechanisms contribute to the protective effect of PC against stunning and against lethal ischemic injury. In the second specific aim, they will investigate whether 12-LO metabolism, p38 activation, PKC activation, and altered calcium homeostasis are involved in the protective effect of other cardioprotective agents. They have also developed methods to measure [Ca2+] in the sarcoplasmic reticulum (SR) and have found that, although there is no significant net release of SR calcium during ischemia, there is a marked decrease in the calcium gradient between SR and cytosol, which is out of proportion to the decrease in the free energy of ATP hydrolysis, which provides the driving force for the SR CaATPase; this decrease in SR calcium gradient is attenuated by PC. One interpretation of the decrease in the SR calcium gradient is increased calcium cycling between SR and cytosol during ischemia. In the third specific aim, the applicants plan to determine the importance of SR calcium cycling in ischemia, whether decreased SR calcium cycling plays a major role in PC, and whether 12-LO metabolites and p38 activation are involved.
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