Participants in the regulation of vascular tone include remote influences (i.e., central nervous system, hormonal) and local factors (i.e., endothelium-derived relaxing and contracting factors). Recently, epoxyeicosatrienoic acids (EETs), cytochrome P-450- derived metabolites of arachidonic acid (AA), have been implicated as local participants in vasoregulation. EETs are produced by vascular endothelial cells and, in some studies, have been reported to relax blood vessels through activation of Kplus channels. By virtue of these properties, EETs are considered to be endothelium- deried hyperpolarizing factors. EETs have been suggested to contribute substantially to endothelium-dependent relaxation responses in epicardial coronary arteries and in the coronary microcirculation. However, no studies have been performed to directly examine responses to EETs in coronary microvessels. Moreover, little is known about the regulation of EET metabolism and uptake by blood vessels. Although vascular cells rapidly convert EETs to dihydroxyeicosatrienoic acids (DHETs) and rapidly incorporate EETs into cell lipids, the importance of these processes to the vascular actions of EETs is unknown. Preliminary studies from our laboratory indicate that 1) EETs are potent dilators of coronary microvessels, producing significant vasodilatation at picomolar concentrations 2) DHETs produce similar amounts of porcine coronary artery relaxation as EETs and 3) incubation of porcine coronary arteries with EETs to promote incorporation into cell lipids results in potentiation of relaxation to bradykinin, a compound which stimulates endothelial cell phospholipid hydrolysis. We hypothesize that EETs and DHETs contribute importantly to the physiologic and pathophysiologic vasoregulation of the coronary circulation. In order to elucidate the regulatory roles of EETs and DHETs in the coronary circulation, we propose to determine the mechanisms by which EETs relax coronary microvessels, define the contribution of DHETs to EET-mediated relaxation of coronary arteries, and investigate the mechanisms which regulate EET incorporation into and release from coronary artery endothelial cells.
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