Role of Serotonin in Smypathetic Function

血清素在交感神经功能中的作用

基本信息

批准号：
8197458
负责人：
KARIE E SCROGIN
金额：
$ 25.99万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197458
关键词：
Acidosis Acute Address Adjuvant Age Agonist Animals Antihypertensive Agents Attenuated Bilateral Blood Blood Pressure Brain region Buffers Cardiac Cardiac Output Cardiovascular system Cause of Death Chemoreceptors Development Electric Capacitance Emergency Medicine Environmental air flow Financial compensation Health Hemorrhage Hemorrhagic Shock Hypercapnia Hypotension Hypovolemia Hypovolemic Shock Hypovolemics Individual Infusion procedures Injury Investigation Knockout Mice Lesion Maintenance Mediating Metabolic acidosis Methods Molecular Monitor Mus Nerve Neuraxis Neurons Norepinephrine Outcome Pathway interactions Patients Perfusion Plasma Process Rattus Receptor Activation Recovery Reperfusion Injury Respiratory Acidosis Resuscitation Role Serotonin Serotonin Receptor 5-HT1A Shock Splanchnic Nerves Techniques Testing Tissues Vasoconstrictor Agents Venous constriction extracellular hemodynamics hindbrain in vivo injured mouse model neuroregulation novel pre-clinical prevent receptor relating to nervous system research study respiratory response sensor serotonin receptor translational study vascular bed

项目摘要

DESCRIPTION (provided by applicant): This project will help to characterize the central nervous system mechanisms that regulate autonomic and respiratory compensation following hypovolemic hypotension and circulatory shock. Experiments will be conducted to test the hypothesis that caudal hindbrain serotonergic neurons activated by acidosis, stimulate 5-HT1A receptors to promote sympathetic-mediated venoconstriction of the splanchnic vascular bed during hypovolemia. It is further proposed that the preferential constriction of the venous vasculature induced by 5-HT1A receptor activation will produce less reperfusion injury during resuscitation from hypovolemic shock than clinically used vasoconstrictor agents which tend to constrict arterial vascular beds. Aim 1 will determine whether caudal hindbrain serotonin is critical for maintenance or recovery of sympathetic-mediated whole body venous tone and venous return following severe blood loss. Aim 2 will determine whether the acidemia associated with hypovolemia or respiratory and metabolic acidosis per se contribute to activation of caudal hindbrain serotonin neural activation and subsequent respiratory and autonomic responses. Further studies will assess with acidosis contributes to the maintenance of blood pressure through a preferential venoconstriction. Aim 3 will determine whether serotonin acts on 5-HT1A receptors to mediate compensatory responses to hypovolemia and whether this endogenous pathway can be exploited to produce a more favorable hemodynamic response during resuscitation from hypovolemic shock. These studies will rely heavily on a carefully developed in vivo rat and mouse models of hypotensive hemorrhage and hypovolemic shock. State of the art techniques for continuous monitoring of hemodynamic parameters, sympathetic nerve activity and central respiratory drive in unanesthetized animals will be used to assess cardiovascular parameters after pharmacological and molecular manipulation of serotonin and serotonin receptor levels. In addition, newly developed techniques for the recording of sympathetic activity in the unanesthetized mouse will enable use of genetically altered mice for investigation of the receptors involved in the compensatory responses to blood loss. Furthermore, novel molecular techniques to more acutely alter serotonin levels in discrete brain regions will be utilized to dissect regions important in the neural control of the circulatory responses to blood loss. Finally, pre-clinical, translational studies will address the potential utility of using 5-HT1A receptor agonists as adjuvants in resuscitation from circulatory shock. PUBLIC HEALTH RELEVANCE: Despite recent advances in emergency medicine, traumatic blood loss is currently one of the leading causes of death of individuals under 40 in the US. Patients typically succumb to severe blood loss either because of too little tissue perfusion or because of tissue injury incurred during the resuscitation process. Our studies will attempt to validate a new, promising therapy that may help patients recover from circulatory shock without further injuring tissue during the resuscitation process.

描述（由申请人提供）：该项目将有助于表征在低血肿低血压和循环休克后调节自主和呼吸补偿的中枢神经系统机制。将进行实验，以检验以下假设：酸中毒激活的尾脑后脑血清素能神经元刺激5-HT1A受体，以促进低血外血症期间诊断性血管床的交感神经介导的venoctiction。进一步提出，与临床使用的血管收缩剂相比，在复苏期间，由5-HT1A受体激活诱导的静脉血管的优先收缩将产生更少的再灌注损伤，而血管收缩剂倾向于收缩动脉血管床。 AIM 1将确定尾骨后脑5-羟色胺对于维持或恢复交感神经介导的全身静脉音调和严重失血后的静脉回流至关重要。 AIM 2将确定与低血容量或呼吸道和代谢性酸中毒相关的酸血症本身是否有助于激活尾骨后脑5-羟色胺神经激活以及随后的呼吸道和自主神经反应。进一步的研究将通过酸中毒评估有助于通过优先静脉收缩来维持血压。 AIM 3将确定5-羟色胺是否作用于5-HT1A受体来介导对血容量的补偿性反应，以及是否可以利用这种内源性途径来产生低伏击休克复苏期间更有利的血液动力学反应。这些研究将在很大程度上依赖于精心发达的体内大鼠和低血压性休克的小鼠模型。用于连续监测血液动力学参数，交感神经活性和无动物中央呼吸驱动的最先进技术将用于评估血清素和5-羟色胺受体水平的药理和分子操纵后的心血管参数。此外，新开发的技术用于记录未经麻醉小鼠中的交感神经活动，将有助于使用遗传改变的小鼠来研究与失血损失补偿性反应有关的受体。此外，将利用新型的分子技术来更严重地改变离散大脑区域中的5-羟色胺水平，以剖析对循环反应对失血的神经控制重要的区域。最后，临床前的转化研究将解决使用5-HT1A受体激动剂作为循环休克复苏的佐剂的潜在效用。公共卫生相关性：尽管急诊医学的最新进展，但创伤性失血目前是美国40岁以下个人死亡的主要原因之一。患者通常是由于组织灌注太少，或者是由于复苏过程中发生的组织损伤而屈服于严重失血。我们的研究将尝试验证一种新的，有希望的疗法，该疗法可能有助于患者在复苏过程中无需进一步伤害组织而从循环冲击中恢复。