Ischemic brain injury is one of the most common pathophysiological processes affecting more than 400,000 people per year in the US in the form of stroke. Restoration of blood flow following short periods of ischemia has been shown to benefit the brain, however, experimental and clinical evidence indicates that reperfusion following longer periods of ischemia may worsen brain injury. While the effects of ischemia and reperfusion have been extensively studied in neuronal injury, little information regarding these effects on cerebral arteries, and how this dysfunction affects stroke outcome, is available. This study investigates the ischemic and reperfusion effects on cerebral artery function, focusing on myogenic tone and reactivity to pressure, both important components of vascular resistance and autoregulation of cerebral blood flow. The intraluminal suture model of focal cerebral ischemia in rats will be used to induce controlled ischemia and reperfusion in middle cerebral arteries. The arteries will then be dissected from the occluded side of the brain and studied in vitro in a system that allows control of intravascular pressure and continuous measurement of lumen diameter. Arteries will be studied under variable periods of ischemia and reperfusion to determine the threshold duration of ischemia and reperfusion that arteries can still maintain viable myogenic responses (Aim 1). Since preliminary experiments determined that 2 hours of ischemia followed by 24 hours of reperfusion results in significantly diminished reactivity to pressure and abnormal basal tone of middle cerebral arteries, we will investigate alterations in cerebral artery structure (e.g., actin cytoskeleton) and function (e.g., myogenic behavior) that may contribute to the loss of function. In addition, inhibitors of compounds known to be detrimental during ischemia and reperfusion (e.g., nitric oxide, superoxide radical) will be used to determine if cerebral artery function can be preserved during reperfusion (Aim 2). Lastly, one promising therapeutic approach involves thrombolysis to restore blood flow to ischemic regions of the brain; however, the use of thrombolytic agents carries the risk of edema formation and hemorrhage. One mechanism that may contribute to these processes during thrombolysis is an effect of the agents themselves on cerebral artery myogenic behavior. Normal cerebrovascular resistance is important during reperfusion and during treatment with thrombolytic agents if vascular integrity is to be maintained and tissue damage minimized. Therefore, Aim 3 will investigate the effects of two types of thrombolytic agents (tissue-type and urokinase) on cerebral artery function, including myogenic processes.
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