Brief periods of coronary artery occlusion, approximately 10-20 minutes, have been shown to cause prolonged functional impairment of myocardial contraction, i.e., myocardial stunning. Although ischemia is a vascular phenomenon, little attention has focused on the role of the endothelial vascular reactivity with brief periods of ischemia, although many prior studies have utilized longer periods of ischemia and have observed impaired endothelial function. Preliminary data, collected by the applicant and his sponsor using a conscious animal model, found that following a 10 min period of ischemia a significant increase in endothelial function occurred beginning 6 hours after reperfusion with a maximum response appearing 102 days later. Accordingly, the overall goal of the proposal is to investigate the mechanism of this previously unobserved phenomenon. An important aspect of the experimental design is to identify the role of endothelial control by using selective intracoronary infusion of vasooactive drugs in chronically instrumented conscious dogs. This approach avoids the pronounced systemic hemodynamic responses caused by intravenous administration of these drugs, since alterations of hemodynamic factors cause concurrent changes in myocardial oxygen demand and activation of neural and hormonal reflexes. Furthermore, using biochemical, morphological, and immunological techniques, this proposal will also investigate the cellular mechanism of altered endothelial regulation in coronary arteries. The hypothesis of this study is that brief periods of myocardial ischemia induce delayed and prolonged enhanced endothelial function. This may be a mechanism by which myocardial blood flow can be preserved int he presence of chronic coronary artery disease.
