The candidate's broad experience with the care of sick neonates will be combined with her knowledge of basic science strategies to examine the effects of vasoactive pharmaceuticals such as indomethacin, dopamine and dobutamine on neonatal cerebrovascular reactivity. Although these drugs have well-established immediate cardiovascular effects, the more subtle and long lasting effects remain unstudied and unknown. This is particularly true for the cerebral circulation which when compared to the systemic circulation often exhibits unique patterns of responsiveness to many drugs. Most importantly, the long-term cerebrovascular effect of prolonged exposure to these medications during a time when the brain's perivascular innervation and receptor mechanisms are still maturing remains unknown. Utilizing tissues made available through human organ and tissue donation, the present proposal explores the specific hypothesis that exposure of immature cerebral arteries to commonly administered vasoactive pharmaceuticals during the neonatal period alters acute and long-term cerebrovascular reactivity. Because serotonin is a potent vasoconstrictor of cerebral arteries and produces contractions that are at least 100 times stronger than those produced by norepinephrine, the proposed studies will focus on how these pharmaceutical agents alter serotonin-induced tone. Our hypothesis has four corollaries each of which proposes a mechanism whereby exposure to these drugs may be influencing serotonin-induced contractile tone by altering: 1) artery morphology and composition, 2) endothelial function, 3) serotonin dose-response coupling, and 4) serotonin and inositol triphosphate affinity and receptor densities. Upon completion of these studies, the candidate's goal is to establish a translational research center whose main purpose is to examine clinical processes that may influence a neonate's long-term cerebrovascular and neurological function. More specifically, the candidate, in collaboration with nurses, neonatologists, pediatric neurologists and vascular physiologists is initiating a systematic exploration of variables that increase risk for cerebrovascular rupture and hemorrhage. To achieve this goal, the candidate plans to pursue a line of study that will lead to a thorough understanding of variables affecting cerebral blood flow and cerebrovascular smooth muscle function. Resources needed to complete this goal are all available in the candidate's institution. With the institution's and sponsor's commitment to the research career development of the candidate, the candidate is optimistic that results from her current and future investigations will lead to modification in therapies and an improvement in the quality of care given to critically ill neonates.
| Angeles, Danilyn M; Ashwal, Stephen; Wycliffe, Nathaniel D et al. (2007) Relationship between opioid therapy, tissue-damaging procedures, and brain metabolites as measured by proton MRS in asphyxiated term neonates. Pediatr Res 61:614-21 |
