The major objective of my proposal is to investigate the interaction of eicosanoids, specifically the cyclooxygenase (COX)-prostanoid system, with the heme oxygenase (HO)-carbon monoxide (CO) system in the regulation of cerebral vasodilation. 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 nitric oxide (NO) synthase inhibitor L-nitro-Nw-arginine;and c) 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 central hypothesis of my proposal is that prostaglandins produced in cerebral blood vessels through NO and 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 and reactive oxygen species to AA- and PGE2-induced vasodilation in newborn pigs;2) examine the role of NO in CO-mediated AA- and PGE2- induced cerebral vasodilation;3) Investigate the contributions of cAMP and cGMP in AA- and PGE2-induced cerebral vasodilation;and 4) examine the involvement of BKCa and KATP channels in cerebral vasodilation produced by AA and PGE2. To pursue these aims, I will use cranial windows and observe changes in pial arteriolar diameters and collect periarachnoid fluid to measure biological makers (CO, NO, cAMP, cGMP), before and after topical application of agonists, inhibitors, and precursors. I also will determine the contribution of astrocytes to AA and PGE2 -induced cerebral vasodilation. 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.
|Jennings, Brett L; Moore, Joseph A; Pingili, Ajeeth K et al. (2015) Disruption of the cytochrome P-450 1B1 gene exacerbates renal dysfunction and damage associated with angiotensin II-induced hypertension in female mice. Am J Physiol Renal Physiol 308:F981-92|
|Jennings, Brett L; Montanez, David E; May Jr, Michael E et al. (2014) Cytochrome P450 1B1 contributes to increased blood pressure and cardiovascular and renal dysfunction in spontaneously hypertensive rats. Cardiovasc Drugs Ther 28:145-61|