The object of this project is to explain mechanistically, the preliminary observation of arterial wall supersensitivity to norepinephrine (NE) which was observed in nonatherosclerotic arteries obtained from dietary hypercholesterolemic-atherosclerotic Dutch Belt rabbits and from normal arteries acutely exposed to high cholesterol levels. The preliminary studies strongly implicated cholesterol as the agent inducing supersensitivity to NE, which appeared to result from a change in calcium permiability of the vascular smooth muscle (VSM) cells during adrenergic stimulation. These findings are significant since they provide evidence that: 1) the disease entity """"""""atherosclerosis"""""""" may involve alterations of the smaller nonatherosclerotic arteries as well; 2) increased exposure of arteries to cholesterol tends to bias the arterial wall toward enhanced vasoconstriction and hence may contribute to the development of a form of arterial vasospasm which has a dietary and/or metabolic component, and 3) hypertension associated with hypercholesterolemia, common in humans, may involve cholesterol induced increases in the sensitivity of resistance arterioles. Using an in-vitro arterial perfusion preparation, physiologic, pharmacologic and biochemical studies will be performed to answer the following specific aims: 1. To determine the minimum time required on a high fat diet to induce NE supersensitivity in rabbits. 2. To determine the mechanism by which cholesterol induces NE supersensitivity by evaluating a) whether changes in the arterial cell membrane cholesterol/phospholipid ratio (index of membrane """"""""fluidity"""""""") correlates with NE sensitivity, whether b) oxysterols or c) membrane Na+-K+ ATPase contribute to the development of cholesterol induced NE supersensitivity, and d) whether the arterial endothelium plays a role in this phenomenon. 3. To determine the susceptibility of resistance arterioles to cholesterol induced NE supersensitivity. 4. To compare lipoproteins from normal and hypercholesterolemic serum for their ability to induce NE supersensitivity. 5. To determine the reversibility of cholesterol-induced NE supersensitivity. The long term goals of this study are to evaluate the potential for cholesterol induced changes in arterial reactivity to contribute to various cardiovascular disorders including a) certain forms of arterial vasospasm and b) hypertension associated with hypercholesterolemia.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Experimental Cardiovascular Sciences Study Section (ECS)
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Allegheny University of Health Sciences
Schools of Medicine
United States
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Levitan, I; Christian, A E; Tulenko, T N et al. (2000) Membrane cholesterol content modulates activation of volume-regulated anion current in bovine endothelial cells. J Gen Physiol 115:405-16
Laury-Kleintop, L D; Gleason, M; Tulenko, T N (1999) Expression of the heterogenous nuclear ribonucleoprotein complex K protein and the prolyl-4-hydroxylase alpha-subunit in atherosclerotic arterial smooth muscle cells. Biochem Biophys Res Commun 260:382-9
Golden, G A; Mason, R P; Tulenko, T N et al. (1999) Rapid and opposite effects of cortisol and estradiol on human erythrocyte Na+,K+-ATPase activity: relationship to steroid intercalation into the cell membrane. Life Sci 65:1247-55
Tulenko, T N; Chen, M; Mason, P E et al. (1998) Physical effects of cholesterol on arterial smooth muscle membranes: evidence of immiscible cholesterol domains and alterations in bilayer width during atherogenesis. J Lipid Res 39:947-56
Cox, R H; Zhou, Z; Tulenko, T N (1998) Voltage-gated sodium channels in human aortic smooth muscle cells. J Vasc Res 35:310-7
Tulenko, T N; Laury-Kleintop, L; Walter, M F et al. (1997) Cholesterol, calcium and atherosclerosis: is there a role for calcium channel blockers in atheroprotection? Int J Cardiol 62 Suppl 2:S55-66
Cox, R H; Tulenko, T N (1995) Altered contractile and ion channel function in rabbit portal vein with dietary atherosclerosis. Am J Physiol 268:H2522-30
Chen, M; Mason, R P; Tulenko, T N (1995) Atherosclerosis alters the composition, structure and function of arterial smooth muscle cell plasma membranes. Biochim Biophys Acta 1272:101-12
Izzo Jr, N J; Tulenko, T N; Colucci, W S (1994) Phorbol esters and norepinephrine destabilize alpha 1B-adrenergic receptor mRNA in vascular smooth muscle cells. J Biol Chem 269:1705-10
Stepp, D W; Tulenko, T N (1994) Alterations in basal and serotonin-stimulated calcium permeability and vasoconstriction in atherosclerotic aorta. Arterioscler Thromb 14:1854-9

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