This proposal is based upon our intriguing observation in piglets that oxygen free radicals are responsible for attenuated cerebrovascular responses to N-Methyl-D-Aspartate (NMDA), a substance which dilates by a mechanism involving enhanced nitric oxide (NO) production by cortical neurons. However, precise details concerning mechanisms of action of oxygen radicals are unclear. Based upon our findings and those int eh literature we propose the following hypotheses: a) Oxygen radicals alter cortical NMDA receptor characteristics; B) Oxygen radicals cause generalized """"""""stunning"""""""" of neurons and thus impaired synthesis of NO; C) Oxygen radicals inhibit activation of NO synthase (NOS); D) Continued oxygen radical production inactivates NO before it can reach vascular smooth muscle; E) Oxygen radicals inhibit function of receptors for calcitonin gene-related peptide; F) Oxygen radicals inhibit vascular responses dependent on guanylate cyclase; and G) Attenuated responsiveness to NMDA or glutamate occurs in other areas such as cerebellum. To test these hypotheses, two specific aims will be addressed using newborn pigs; 1. CHARACTERIZATION OF ASPHYXIA/REVENTILATION-INDUCED CHANGES IN CEREBROVASCULAR RESPONSIVENESS; AND 2. DETERMINATION OF MECHANISMS OF ASPHYXIA/REVENTILATION-INDUCED CHANGES IN CEREBROVASCULAR RESPONSIVENESS. We will use a number of complimentary methods for characterizing vascular and neuronal responses. These include the closed cranial window and intravital microscopy for characterization of responses of individual arteries and arterioles, the 14C-deoxyglucose method for determination of brain glucose utilization, in vitro measurement of NOS activity by L- arginine to L-citrulline conversion, measurement of cortical NO production by microdialysis, determination of superoxide anion production using the superoxide dismutase-inhibitable nitroblue tetrazolium method, and receptor binding determinations for numbers and affinities of NMDA receptors. This investigation will explore control mechanisms in neonatal animals during normal and pathophysiological conditions. We hope that our findings will be of clinical relevance and lead to therapies that improve outcome in stressed babies.

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National Heart, Lung, and Blood Institute (NHLBI)
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Experimental Cardiovascular Sciences Study Section (ECS)
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Wake Forest University Health Sciences
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Dutta, Somhrita; Rutkai, Ibolya; Katakam, Prasad V G et al. (2015) The mechanistic target of rapamycin (mTOR) pathway and S6 Kinase mediate diazoxide preconditioning in primary rat cortical neurons. J Neurochem 134:845-56
Rutkai, Ibolya; Katakam, Prasad V G; Dutta, Somhrita et al. (2014) Sustained mitochondrial functioning in cerebral arteries after transient ischemic stress in the rat: a potential target for therapies. Am J Physiol Heart Circ Physiol 307:H958-66
Katakam, Prasad V G; Gordon, Angellica O; Sure, Venkata N L R et al. (2014) Diversity of mitochondria-dependent dilator mechanisms in vascular smooth muscle of cerebral arteries from normal and insulin-resistant rats. Am J Physiol Heart Circ Physiol 307:H493-503
Busija, David W; Katakam, Prasad V (2014) Mitochondrial mechanisms in cerebral vascular control: shared signaling pathways with preconditioning. J Vasc Res 51:175-89
Carvalho, Cristina; Katz, Paige S; Dutta, Somhrita et al. (2014) Increased susceptibility to amyloid-? toxicity in rat brain microvascular endothelial cells under hyperglycemic conditions. J Alzheimers Dis 38:75-83
Katakam, Prasad V G; Wappler, Edina A; Katz, Paige S et al. (2013) Depolarization of mitochondria in endothelial cells promotes cerebral artery vasodilation by activation of nitric oxide synthase. Arterioscler Thromb Vasc Biol 33:752-9
Wappler, Edina A; Institoris, Adam; Dutta, Somhrita et al. (2013) Mitochondrial dynamics associated with oxygen-glucose deprivation in rat primary neuronal cultures. PLoS One 8:e63206
Nautiyal, Manisha; Katakam, Prasad V G; Busija, David W et al. (2012) Differences in oxidative stress status and expression of MKP-1 in dorsal medulla of transgenic rats with altered brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 303:R799-806
Institoris, Adam; Lenti, Laura; Domoki, Ferenc et al. (2012) Cerebral microcirculatory responses of insulin-resistant rats are preserved to physiological and pharmacological stimuli. Microcirculation 19:749-56
Katakam, Prasad V G; Snipes, James A; Steed, Mesia M et al. (2012) Insulin-induced generation of reactive oxygen species and uncoupling of nitric oxide synthase underlie the cerebrovascular insulin resistance in obese rats. J Cereb Blood Flow Metab 32:792-804

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