VASOACTIVE DRUGS AND NEONATAL CEREBROVASCULAR REACTIVITY

描述（由申请人提供）：候选人在照顾患病新生儿方面的广泛经验将与她的基础科学策略知识相结合，以检查血管活性药物如吲哚美辛，多巴胺和多巴酚丁胺对新生儿脑血管反应性的影响。虽然这些药物具有公认的直接心血管作用，但更微妙和持久的影响仍未被研究和未知。与体循环相比，脑循环对许多药物的反应往往表现出独特的模式，这一点尤其正确。最重要的是，在大脑血管周围神经支配和受体机制仍处于成熟阶段的时期，长期暴露于这些药物对脑血管的长期影响尚不清楚。利用通过人体器官和组织捐赠获得的组织，本提案探讨了在新生儿时期未成熟的大脑动脉暴露于常用的血管活性药物会改变急性和长期脑血管反应性的具体假设。由于血清素是一种有效的脑动脉血管收缩剂，产生的收缩比去甲肾上腺素产生的收缩至少强100倍，因此拟议的研究将重点放在这些药物如何改变血清素诱导的张力上。我们的假设有四个推论，每个推论都提出了一种机制，即暴露于这些药物可能通过改变来影响血清素诱导的收缩张力：1)动脉形态和组成，2)内皮功能，3)血清素剂量-反应耦合，4)血清素和三磷酸肌醇的亲和力和受体密度。

DESCRIPTION (provided by applicant): 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.