This proposal is based on our observations in neonatal animals that prostanoids and neurotransmitters individually are important modulators of the cerebral circulation, and our intriguing new data which provide the first direct evidence that there is an interaction between these two systems. The proposed studies are designed to address the overall hypothesis that prostanoids (prostaglandins and thromboxane) are intrinsic modulators of neural stimuli in the newborn cerebral circulation. Further, we hypothesize that this relationship is altered by cerebral perturbations that occur with intracranial hemorrhage and its aftermath, which are serious clinical problems in the neonate. To test these hypotheses, three specific aims will be addressed using newborn pigs: 1) characterization of the relationship between neurotransmitters and cerebral hemodynamics; 2) investigation of the contribution of prostanoids to the responses of cerebral arteries to neurotransmitters; and 3) determination of the effects of intracranial blood on the relationship between neurotransmitters and cerebral hemodynamics. The specific neurotransmitters to be studied are serotonin, 1-glutamate, vasoactive intestinal polypeptide, and calcitonin gene-related peptide. We will use the """"""""closed"""""""" cranial window method extensively in our experiments. This method allows us to: 1) directly observe and measure diameters of cerebral resistance vessels; 2) perivascularly apply exogenous neurotransmitters and other drugs; and 3) sample periarachnoid cerebrospinal fluid from the area between the vessels and window and measure prostanoid levels using radioimmunoassay. To complement the window experiments, we also will characterize the relationship between neural stimuli and prostanoids in isolated cerebral resistance vessels. This investigation will explore control mechanisms in neonatal animals during normal and pathological conditions and will provide new information in an area where little data are available. We hope our findings will be of clinical relevance and lead to therapies that improve outcome in stressed babies.
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