About 1.5 million myocardial infarctions occur annually in the United States with half of these patients sustaining cardiac arrest before they reach a hospital. Of approximately 70,000 successful cardiac resuscitations, only about 10% recover sufficiently to be able to resume their former life styles. A significant part of tissue damage occurring during reperfusion results from chain peroxidation of membrane lipids, mediated by low molecular weight chelates of iron (LMCW). Thus, cardiac resuscitation should be accompanied by therapy directed against lipid peroxidation. I (initiator) + PUFAH = IH + PUFA. (initiation) (1) PUFA. + 02 = PUFA-02. (propagation) (2) PUFA-02. + PUFAH = PUFA-OOH + PUFA. (propagation) (3) Fe (II) L + PUFA-OOH + Fe (III)L+PUFA-0.+H)- (secondary initiation)(4) PUFA.= PUFA-PUFA (termination). (5) The principal objectives of the proposed research are to better understand the iron-mediated reactions which contribute to post- ischemic reperfusion tissue damage following cardiac arrest, and to find chelators of iron which might be used to block these reactions in vivo. Tissue damage could be minimized via alternate chelation of the LMWC to give ferrous chelates unable to initiate peroxidation via reactions 1 and 4, and which react with H202 and 02 to give products incapable of initiating peroxidation. Chelates to be evaluated include ethylenediaminetetraacetate (EDTA) analogs, hydroxybenzoic acid analogs, N1,N8-bis(2,3-dihydroxybenzoyl) spermidine analogs, and a series of hydroxamic acids. Rates and mechanism of reaction of the ferrous chelates with H202 and 02 will be determined via stopped-flow spectrophotometry, H202 analyses, and scavenging experiments. Reactivity of the ferrous chelates and of the iron-oxo species produced by reaction of the chelates with H202 or 02 with bovine brain phospholipid liposomes and with detergent-solubilized lipids will be determined via the thiobarbiturate assay and high-performance liquid chromatography. Reactivities with lipid hydroperoxides (reaction 4) will be evaluated using partially peroxidized lipid materials, and the thiobarbiturate assay.
