Our overall aim is to define the role of adenosine, a purine nucleoside and potent vasodilator, in cerebral blood flow (CBF) regulation and to test the hypothesis that adenosine is serving as a chemical link between brain metabolism and CBF. In order to investigate this hypothesis, we will use a multi-faceted approach which will allow us to study the cerebrovascular physiology and metabolism of adenosine in whole brain, CSF, and on in situ pial vessels.
Our specific aims are: 1) to determine if increases in cerebral adenosine concentration and CBF are temporally related during post-hypoxic reactive hyperemia; 2) to determine: a) the concentration of adenosine in cerebrospinal fluid (CSF) during sustained hypoxia and b) the effects of CSF (with and without exogenous adenosine deaminase) from hypoxic animals on pial arteriole diameter in normoxic animals; 3) to determine if the changes in CBF during arterial infusion of theophylline and dipyridamole, drugs which affect adenosine activity and metabolism, are associated with a change in brain and CSF adenosine concentrations; 4) to determine the change in brain tissue adenosine concentration during short-lasting hypotension; 5) to measure the vasodilatory action of adenosine on in situ pial arterioles in the rat; 6) to further define the metabolism of adenosine and its metabolites in brain. Brain metabolites will be measured by both enzymatic and HPLC techniques. CBF measurements will be determined by both outflow and tracer methods. Radioisotopes will also be employed in metabolic studies. Further investigation of adenosine in brain will help define the possible role of adenosine in metabolic regulation of CBF. A comprehensive understanding of the control of CBF will allow a more rational treatment of alterations in CBF in disease states.
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