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.
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