VASOACTIVE DRUGS AND NEONATAL CEREBROVASCULAR REACTIVITY

描述（由申请人提供）：候选人在护理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。 虽然这些药物具有明确的心血管即时效应，但更微妙和持久的影响尚未研究和未知。 这对于脑循环尤其如此，当与体循环相比时，脑循环常常对许多药物表现出独特的反应模式。 最重要的是，在大脑的血管周围神经支配和受体机制仍在成熟的时候，长期暴露于这些药物的长期脑血管效应仍然未知。 利用通过人体器官和组织捐赠提供的组织，本提案探讨了新生儿期未成熟脑动脉暴露于常用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，产生的收缩至少比去甲肾上腺素产生的收缩强100倍，因此拟议的研究将集中在这些药物如何改变阿托伐他汀诱导的张力上。 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：1）动脉形态和组成，2）内皮功能，3）5-羟色胺剂量-反应偶联，4）5-羟色胺和三磷酸肌醇亲和力和受体密度来影响降钙素诱导的收缩张力。 完成这些研究后，候选人的目标是建立一个转化研究中心，其主要目的是检查可能影响新生儿长期脑血管和神经功能的临床过程。 更具体地说，该候选人与护士，儿科医生，儿科神经学家和血管生理学家合作，正在开始系统地探索增加脑血管破裂和出血风险的变量。 为了实现这一目标，候选人计划进行一系列研究，这将导致对影响脑血流和脑血管平滑肌功能的变量的透彻理解。 完成这一目标所需的资源都可以在候选人的机构。 由于该机构和申办者对候选人研究职业发展的承诺，候选人乐观地认为，她目前和未来的研究结果将导致治疗方法的改进和危重新生儿护理质量的提高。

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.