VASOACTIVE DRUGS AND NEONATAL CEREBROVASCULAR REACTIVITY

应聘者描述(由申请者提供)：应聘者在照顾患病新生儿方面有丰富的经验，将结合她的基础科学策略知识来检验血管活性药物，如消炎痛、多巴胺和多巴酚丁胺对新生儿脑血管反应性的影响。尽管这些药物有公认的立竿见影的心血管效应，但更微妙和更持久的影响仍未得到研究和了解。大脑循环尤其如此，与体循环相比，大脑循环往往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和受体机制仍处于成熟阶段的情况下，长期接触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，本提案探索了特定的假设，即未成熟的大脑动脉在新生期接触常用的血管活性药物会改变急性和长期的脑血管反应性。由于5-羟色胺是一种有效的脑动脉血管收缩因子，产生的收缩强度至少是去甲肾上腺素的100倍，因此拟议的研究将重点放在这些药物如何改变5-羟色胺诱导的张力上。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以下方面来影响5-羟色胺诱导的收缩张力：1)动脉形态和成分，2)内皮功能，3)5-羟色胺剂量-反应耦合，以及4)5-羟色胺和三磷酸肌醇亲和力和受体密度。 在完成这些研究后，候选人的目标是建立一个翻译研究中心，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，候选人正在与护士、新生儿医生、儿科神经学家和血管生理学家合作，启动对增加脑血管破裂和出血风险的变量的系统探索。为了实现这一目标，候选人计划从事一项研究，该研究将导致彻底了解影响脑血流和脑血管平滑肌功能的变量。完成这一目标所需的资源都可以在候选人所在的院校获得。由于该机构和赞助商致力于候选人的研究事业发展，候选人乐观地认为，她目前和未来的调查结果将导致治疗方法的改进和对危重新生儿的护理质量的提高。

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.