It is thought that a decrease in release or increase in destruction of nitric oxide accounts for impaired endothelium-dependent relaxations (EDR) in hypercholesterolemia. Preliminary studies from the applicant's laboratory indicate that inhibition of NO accelerates growth of the atherosclerotic neointima giving weight to the hypothesis that abnormal NO function is important in atherogenesis. For poorly understood reasons, atherosclerosis shows a predilection for the thoracic aorta, appearing later in the abdominal aorta and common carotid arteries. Observations from this group suggest that differences in endothelial cell release, susceptibility to destruction, and mechanism of action of nitric oxide in the thoracic aorta compared with the common carotid artery might partially explain differences in susceptibility to atherosclerosis. The carotid artery releases more NO, and NO activity appears to be less susceptible to inhibition by NO synthase inhibitors and oxidative stress in the carotid artery than in the thoracic aorta. The principal investigator's studies also indicate that there are two distinct mechanisms by which NO controls smooth muscle cell relaxation, one via cGMP and protein kinase G and a second via hyperpolarization via activation of a KCa channel in the smooth muscle. In the carotid artery, endothelium-dependent vascular relaxation is less affected because of persistent activation of a KCa channel by nitric oxide. The principal aim of this proposal is therefore to determine the importance of these two mechanisms of action of NO in regulating vascular smooth muscle intracellular Ca2+, endothelium-dependent vascular relaxation, and atherogenesis in the carotid artery and thoracic aorta of hypercholesterolemic rabbits. In explaining differences in the susceptibility of these two arteries to atherosclerosis, new insights into the pathogenesis and therapy of atherosclerosis will be gained.
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