Much of the recent research interest on myocardial ischemia has been aimed at the preservation of myocardial cellular function and viability, while little attention has been directed toward coronary vascular function and reactivity. It should be apparent, and was indeed confirmed by recent electron microscopic studies, that ischemic damages following transient coronary occlusion occur not only in myocardial cells but also in coronary vasculatures. In particular, coronary endothelium has been shown to be highly sensitive to ischemic injury. The functional significance of these coronary vascular derangements on the maintenance of coronary blood flow during coronary reperfusion is not well understood. Recently, it has been reported that, in addition to its role in the regulation of capillary transport, endothelial cells also possess metabolic and enzymatic activities, such as synthesis and release of prostaglandins and adenine nucleotides, as well as play an obligatory role in the vasodilatation induced by several vasoactive agents. More significantly, in a recent preliminary study, we have reported that thrombin, a naturally occurring blood-borne factor which is readily activated during vascular injury, produced a potent vasodilatation in normal coronary artery with intact endothelium, while it produced a potent, dose-related vasoconstriction in the ischemically injured arteries or in mechanically endothelium-denuded coronary arteries. These findings strongly suggest that coronary intimal endothelium plays a far more important role in the regulation of coronary blood flow than has been thought previously and that an altered response to vasoactive agents in coronary arteries with either ischemically and/or mechanically injured endothelium may contribute to, or be responsible for, the development of coronary vasospasm in ischemic heart disease. Therefore, the primary objective as well as long term goal of the present proposal is to examine the pathophysiological role of intimal endothelial cells in coronary vascular responses to circulating vasoactive factors. Specifically, attempts will be made 1) determine the role of endothelial cells in coronary vascular response to various circulating factors, such as thrombin, acetylcholine and adenine nucleotides, and 2) to determine the mechanism(s) of thrombin-induced coronary vasconstriction and its role in the development of coronary vasospasm. In addition, attempts will also be made to identify conditions and/or pharmacologic agents which may protect the coronary endothelium from ischemic injury and thus minimize the incidences of coronary vasospasm.
