The overall goal of this proposal is to test the hypothesis that adenosine (ADO) is involved in cerebral blood flow (CBF) regulation. In our initial years, we focused on the characterization of changes in whole brain during ischemia, hypoxia, hypotension and seizures. We subsequently designed studies to evaluate the role of ADO in the brain microcirculation and created an experimental paradigm to allow discrete activation of the sensory cortex by sciatic nerve stimulation (SNS). We then developed approaches to investigate the causal relationship between ADO and CBF. In the present proposal, we will focus on the cellular and molecular mechanisms involved in ADO's regulation of CBF and brain activity in physiologic and pathophysiologic states, as well as factors regulating endogenous ADO concentrations. We will use a comprehensive multidisciplinary approach involving whole animal studies, in vitro and in vivo vessel preparations, freshly dissociated vascular smooth muscle, radio immunoassay and electrophysiologic (patch clamp) techniques.
Specific Aims : (1) To define the specific mechanisms and adenosine receptors involved in pial vasodilation during SNS. (2) To test the hypothesis that diffusion and/or conduction mechanisms are involved in pial vasodilation during SNS. (3) To test the hypothesis that glutamate causes pial vasodilation by means of an ADO-related mechanism. (4) To test the hypothesis that in vascular smooth muscle (VSM), ADO causes vasodilation by either cAMP- or cGMP-mediated signal transduction pathways. We will also determine the ion channels involved. We will compare the responses in cerebral resistance vessels to that in larger conductance vessels (basilar) and non-cerebral vessels (mesenteric). (5) To define the ADO receptor subtypes that mediate the neuroprotective effects of ADO during hyperglycemic ischemia and reperfusion, and to test the hypothesis that alteration in ADO receptor activity will affect not only the degree of tissue injury but also the neurobehavioral outcome. Further investigations of ADO in the brain will define the role of ADO in metabolic regulation of CBF and allow a more rational treatment of stroke.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology A Study Section (NEUA)
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Jacobs, Tom P
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University of Washington
Schools of Medicine
United States
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Kulik, Tobias B; Aronhime, Shimon N; Echeverry, German et al. (2010) The relationship between oxygen and adenosine in astrocytic cultures. Glia 58:1335-44
Kusano, Yoshikazu; Echeverry, German; Miekisiak, Greg et al. (2010) Role of adenosine A2 receptors in regulation of cerebral blood flow during induced hypotension. J Cereb Blood Flow Metab 30:808-15
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Kulik, Tobias; Kusano, Yoshikazu; Aronhime, Shimon et al. (2008) Regulation of cerebral vasculature in normal and ischemic brain. Neuropharmacology 55:281-8
Miekisiak, Greg; Kulik, Tobias; Kusano, Yoshikazu et al. (2008) Cerebral blood flow response in adenosine 2a receptor knockout mice during transient hypoxic hypoxia. J Cereb Blood Flow Metab 28:1656-64
Haglund, Michael M; Meno, Joseph R; Hochman, Daryl W et al. (2008) Correlation of intrinsic optical signal, cerebral blood flow, and evoked potentials during activation of rat somatosensory cortex. J Neurosurg 109:654-63
Britz, Gavin W; Meno, Joseph R; Park, Ik-Seong et al. (2007) Time-dependent alterations in functional and pharmacological arteriolar reactivity after subarachnoid hemorrhage. Stroke 38:1329-35

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