Clinically, hypomagnesemia is observed in the general population, particularly in women and the elderly, and very frequently in patients with cardiovascular disease. The long term objective of this proposal is to understand the pathobiology of magnesium-deficiency, particularly the enhanced susceptibility to injury due to ischemia/reperfusion of the heart. Our initial findings using rats point to a relevant inability of Mg-deficient hearts to tolerate oxidant stress, such as that induced by ischemia/reperfusion or by exogenously administered oxidants. Our research plan proposes to quantify the endogenous antioxidant status (eg. glutathione, vitamin E, ascorbate) and the endogenous pro-oxidant status (eg. transition metals, peroxidized lipids) with progression of the Mg-deficiency state. ESR-spin trapping will be used extensively to confirm increased production of primary and secondary radical species in ischemic/reperfused hearts, and the suppression, by antioxidant therapy, of impaired contractility and free radical production. The morphological endpoints will enable quantification of cardiomyopathic lesions and localization of enhanced cytokine production, particularly in vascular tissue. Immunochemical and molecular biological techniques include some that have been developed in our laboratory for highly sensitive detection of cytokines at the cellular and genomic levels in small tissue samples. Another novel technique employs the Meridian ACAS cytometer to detect peroxidation products in single endothelial cells, enabling quantification of the cellular susceptibility to oxidant stress in vitro. We submit that the combined research strategies utilizing biophysical, biochemical, immunological and molecular biological techniques should provide significant new information about the mechanisms of cardiac and cellular injury in Mg-deficiency. We hope that this research will lead to a better understanding of Mg-deficiency in man and potentially to better modalities for diagnosing and treating clinical Mg-deficiency.
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