Grant: $220,946 - National Institutes of Health - Jul. 15, 2009
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Award Description: Previous studies from our laboratory and those from other investigators have shown that prostanoids generated in cerebral blood vessels contribute to cerebral vasodilation produced by hypotension. Recently, we reported that arachidonic acid (AA)-induced cerebrovasodilation is mediated by COX products, mainly prostaglandin E2 (PGE2), and that AA and PGE2 stimulate CO production. My preliminary experiments indicate that AA- and PGE2-induced increases in cerebral vasodilation are inhibited by: a) the HO inhibitor chromium mesoporphyrin; b) the adenylyl cyclase-cAMP and guanylyl cyclase-cGMP inhibitors SQ 22536 and ODQ, respectively. Moreover, it has been shown that BkCa and KATP channel blockers, iberiotoxin and glibenclamide respectively attenuate the PGE2-induced increase in cerebral blood flow. Therefore, on the basis of these observations, the present proposal is to examine this possibility by addressing the unifying hypothesis that prostaglandins produced in cerebral blood vessels through CO stimulate cAMP and cGMP and produce cerebral vasodilation by activating BKCa and KATP channels. To test this hypothesis, I will address the following specific aims: 1) investigate the contribution of CO in AA- and PGE2-induced vasodilation in newborn pigs and 2) examine the contribution of cAMP and cGMP in AA- and PGE2-induced cerebral vasodilation. To pursue these aims, I will use cranial windows and observe changes in pial arteriolar diameters, collect periarachnoid fluid to measure biological makers (CO, cAMP, cGMP), before and after topical application of agonists, inhibitors, and precursors. These studies should advance our knowledge of cerebral blood flow regulation and identify targets for the development of new techniques as well as therapeutic agents for the long-term treatment of cerebrovascular disorders in newborns.
Project Description: As described in Award Description field.
Jobs Summary: Job Title: Instructor Job Desc: Performs research using the neonatal piglet cranial window model on interactions among the heme oxygenase/carbon monoxide, cyclooxygenase/prostanoid, and nitric oxide synthase/nitric oxide systems in control of neonatal cerebral circulation. (Total jobs reported: 1)
Project Status: Less Than 50% Completed
This award's data was last updated on Jul. 15, 2009. Help expand these official descriptions using the wiki below.