The long-term objectives of this research project are to understand the relation of the adrenal cortex to the production of coronary artery disease and to determine whether changes in the phospholipid content of leukocyte membranes found to occur in patients with coronary artery disease (CAD) are the result of increased adrenal secretion. An increase in the phosphatidylcholine to sphingomyelin ratio (PC/Sph) has been found in membranes isolated from human polymorphonuclear leukocytes obtained from patients receiving corticosteroids, patients with Cushing's syndrome, and patients who have proven coronary artery disease. Studies are to be carried out in a larger group of patients to confirm the observed changes in PC/Sph in patients with CAD and determine if these lipid changes occur in lymphocytes and monocytes. Polymorphonuclear leukocytes are isolated from 20 ml blood samples drawn at 8 a.m. from fasting subjects. Viability of the cells is assured by using only those which attach to glass Petri dishes following the initial isolation on Ficoll-Hypaque. These cells are scraped from the plates, lipids are extracted by the procedure of Bligh and Dyer, applied to silica coated chromarods, separated by thin layer chromatography, and quantified by flame ionization in a latroscan. Patients used in this study initially will be those undergoing coronary angiography to determine the presence of coronary artery disease. Those found to have greater than 70% occlusion of one or more arteries are considered to have CAD while those with less than 25% occlusion make up the control group. Determination of adrenal secretion and responsivity to ACTH in a control group and a group of patients with proven CAD will also be performed. Previous studies have demonstrated increased responsivity of the adrenal gland and higher than normal ACTH levels in patients with CAD. Estimation of leukocyte membrane PC/Sph and adrenal studies will be carried out to determine if there is a correlation between these two findings in patients with CAD. In addition, plasma corticoids will be increased by administration of cortisol or ACTH for a few hours each day to determine whether this is sufficient to produce the changes in membrane lipids noted in patients receiving more prolonged corticoids or in those with proven CAD. If this is found to be true, it will be consistent with patients who are found to have therapeutic effects from corticosteroids given intermittently as in alternate day therapy.
| Murray, D K; Hill, M E; Nelson, D H (1990) Inhibitory action of sphingosine, sphinganine and dexamethasone on glucose uptake: studies with hydrogen peroxide and phorbol ester. Life Sci 46:1843-9 |
| Nelson, D H; Murray, D K (1988) Dexamethasone and sphingolipids inhibit concanavalin A stimulated glucose uptake in 3T3-L1 fibroblasts. Endocr Res 14:305-18 |
| Sorenson, D K; Kelly, T M; Murray, D K et al. (1988) Corticosteroids stimulate an increase in phospholipase A2 inhibitor in human serum. J Steroid Biochem 29:271-3 |
| Nelson, D H; Murray, D K (1987) Dexamethasone inhibition of hydrogen peroxide-stimulated glucose transport. Endocrinology 120:156-9 |
