ROLE OF ADENOSINE IN CEREBRAL BLOOD FLOW REGULATION

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The broad, long-term objective of the proposed research is to further our understanding of cerebral blood flow (CBF) regulation. Specifically, the goal of the experiments described in this proposal is to elucidate the role of adenosine in the local metabolic regulation of CBF. Fundamental to the adenosine hypothesis for regulation of CBF is the prediction that cerebral interstitial fluid (ISF) serves as the medium which couples the adenosine released by brain cells to the site of action on the cerebral vasculature. Despite the recognized importance of cerebral ISF to our understanding of the role of adenosine in the regulation of CBF, progress in this area has been limited by the practical difficulty of gaining access to the cerebral ISF compartment in order to determine its composition. However, with the use of the recently developed brain dialysis technique, cerebral ISF composition can be determined. The proposed experiments will test the adenosine hypothesis for regulation of CBF using a modification of the brain dialysis technique to monitor changes in local CBF and cerebral ISF adenosine concentration. The specific aims of the proposed research are: 1) to develop pharmacological regimens by which the adenosine hypothesis can be tested with the brain dialysis technique; 2) to determine the role of adenosine in CBF regulation-during pharmacologically- induced changes in local metabolic activity and local CBF; 3) to determine the role of adenosine in CBF regulation during hypoxia; 4) to develop the brain dialysis technique in a conscious rat model; 5) to determine the role of adenosine in CBF regulation during and after cerebral ischemia in the conscious rat, and; 6) to determine the role of adenosine in CBF regulation during physiological activation of specific brain regions in the conscious rat. The significance of the proposed research is twofold: 1) by the application of the brain dialysis technique to the study of the cerebral circulation, new information will be gained as to the basic mechanisms by which metabolic regulation of CBF is achieved, specifically as to the role of adenosine in CBF regulation, and; 2) the fundamental insights attained from the proposed research may lead to therapeutic regimens by which pathologies associated with seizures, hypoxia, and cerebral ischemia can be treated.