The African American population has high prevalence of DM and CAD. In disease states such as diabetes and atherosclerosis coronary dilation to endothelial derived nitric oxide is reduced. A widely recognized mechanism of this impairment involves heightened free-radical stress, largely due to superoxide. Dilator mechanisms operating through vascular smooth muscle hyperpolarization, including endothelial-derived hyperpolarization factor (EDHF) are exposed to the same oxidative stress in diabetes of vascular smooth muscle hyperpolarization by EDHF or by openers of K/ATP play a prominent role in vasodilation of human coronary resistance vessels. Our overall objective is to determine how superoxide influences human coronary arteriolar dilation mediated by smooth muscle hyperpolarization. This proposal is highly relevant to African American subjects since NO may play a less important role in vasodilation.
In aim 1 we examine the hypothesis that superoxide impairs vasodilation to activation of K/ATP but not BK/Ca (calcium-activated K+) channels.
In aim 2 we determine the effect of a pathophysiological relevant state of increased oxidative stress (atherosclerosis and diabetes) on K/ATP and K/Ca++ channel-mediated dilation and channel opening. Preliminary data suggest that coronary dilation mediated by K/ATP but not BK/Ca channels is impaired in patients with DM and CAD. This will be extended to hypoxic coronary dilation which is mediated by K/ATP channels in humans. Since hyperglycemia is associated with increased oxidant stress, in aim 3 we determine the effect of high glucose on hyperpolarization- mediated dilation of human coronary arterioles. Fresh human coronary arterioles isolated from myocardial tissue (during cardiopulmonary bypass) are mounted onto micropippettes and pressurized for diameter measurements using in vitro videomicroscopy. Isolated human coronary arteriolar smooth muscle cells will be prepared for patch-clamp analysis of potassium channel currents. This combination of pharmacological and electrophysiological assessment of vascular and cellular function provides a power mechanism for studying hyperpolarization-dependent regulatory processes in health and disease. These studies will have important implications for coronary vasomoter regulation. Arterioles responsible for regulating myocardial perfusion (between 50-150 microns in diabetes) will be studied. Results from the proposed experiments should identify in human subjects novel mechanisms of altered coronary vasoregulation with particular relevance to African Americans. The results could suggest new therapeutic approaches for the treatment of microvascular dysfunction in patients with diabetes and coronary disease.
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