The goal is to further define the role of adenosine, a purine nucleoside and potent cerebral vasodilator, in the regulation of cerebral blood flow (CBF) and to test the hypothesis that adenosine is serving as a chemical link between brain metabolism and CBF. Previous studies were designed to correlate the changes in brain adenosine concentrations in whole brain during changes in global CBF. We now plan to extend these findings to the level of the microcirculation and its components: the pial vessels in situ, intraparenchymal penetrating vessels in vitro, and cerebrovascular endothelial cells in culture. We will begin studies designed to determine the possible cellular source and location for adenosine in the brain and mechanisms involved in adenosine mediated vasodilation.
Our specific aims are: 1) to test the hypothesis that adenosine is involved in vasodilation in sensory cortex during contralateral sciatic nerve stimulation; 2) to further define the role of adenosine in hypoxic vasodilation and hypocarbic vasoconstriction; 3) to determine whether adenosine is involved in the regulation of CBF during normoxia by measuring simultaneously regional glucose utilization and CBF; 4) to investigate the metabolism of adenosine in cultured cells; 5) to determine if to intracerebral penetrating rat arterioles in vitro dilate in response to hypoxia and whether this action is mediated by adenosine. Furthermore, we will determine the influence of CSF from in vivo hypoxic animals on these in vitro vessels; 6) to define the receptor involved in adenosine mediated vasodilation of brain. All studies will be performed in the rat. We will use a multifaceted approach to study cerebrovascular physiology and metabolism using the following techniques: closed cranial windows; radioautography; in vitro microvessel analyses; cell culture; and metabolic analysis by HPLC. Further investigation of adenosine in brain will define the role of adenosine in metabolic regulation of CBF. A more thorough understanding of the control of CBF will allow a more rational approach to the treatment of stroke and other disorders of cerebrovasculature.
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