Role of Serotonin in Smypathetic Function

描述（由申请人提供）：该项目将有助于表征在低血容量性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：酸中毒激活的尾侧后脑多巴胺能神经元刺激5-HT 1A受体，以促进低血容量期间交感神经介导的内脏血管床的静脉收缩。进一步提出，在低血容量性休克复苏过程中，由5-HT 1A受体激活诱导的静脉血管系统的优先收缩将比临床上使用的倾向于收缩动脉血管床的血管收缩剂产生更少的再灌注损伤。目的1将确定尾侧后脑5-羟色胺是否对严重失血后交感神经介导的全身静脉张力和静脉回流的维持或恢复至关重要。目的2将确定是否酸血症与血容量不足或呼吸性和代谢性酸中毒本身有助于激活尾侧后脑5-羟色胺神经激活和随后的呼吸和自主反应。进一步的研究将评估酸中毒通过优先静脉收缩有助于维持血压。目的3将确定5-羟色胺是否作用于5-HT 1A受体介导对低血容量的代偿反应，以及是否可以利用这种内源性途径在低血容量性休克复苏期间产生更有利的血流动力学反应。这些研究将在很大程度上依赖于一个精心开发的体内大鼠和小鼠模型的肿胀出血和低血容量性休克。在对5-羟色胺和5-羟色胺受体水平进行药理学和分子操作后，将使用用于连续监测未麻醉动物的血流动力学参数、交感神经活动和中枢呼吸驱动的最新技术水平来评估心血管参数。此外，新开发的记录未麻醉小鼠交感神经活动的技术将使基因改变的小鼠用于研究参与失血补偿反应的受体成为可能。此外，新的分子技术，以更急性地改变血清素水平在离散的大脑区域将被用来解剖区域的重要性，在神经控制的循环反应失血。最后，临床前转化研究将解决使用5-HT 1A受体激动剂作为循环休克复苏中的佐剂的潜在效用。公共卫生相关性：尽管急诊医学最近取得了进展，但创伤性失血目前是美国40岁以下人群死亡的主要原因之一。患者通常死于严重失血，这是因为组织灌注太少或因为在复苏过程中发生的组织损伤。我们的研究将试图验证一种新的，有前途的治疗方法，可以帮助患者从循环休克中恢复，而不会在复苏过程中进一步伤害组织。

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.