Role of Serotonin in Smypathetic Function

描述(由申请人提供)：该项目将有助于描述低血容量性低血压和循环休克后调节自主神经和呼吸代偿的中枢神经系统机制。实验将验证酸中毒激活后脑尾侧5-羟色胺能神经元，在低血容量时刺激5-HT1a受体促进交感神经介导的内脏血管床静脉收缩的假说。进一步提出，在低血容量性休克复苏过程中，5-HT1a受体激活引起的优先收缩的静脉血管比临床上使用的血管紧张剂对动脉血管床的收缩作用更小。目的1将确定在严重失血后，5-羟色胺对维持或恢复交感神经调节的全身静脉张力和静脉回流是否起关键作用。目的2将确定低血容量酸血症或呼吸和代谢性酸中毒本身是否有助于激活尾侧后脑5-羟色胺神经激活以及随后的呼吸和自主神经反应。进一步的研究将评估酸中毒通过优先收缩静脉有助于维持血压。目的3将确定5-羟色胺是否作用于5-HT1a受体来介导对低血容量的代偿反应，以及在低血容量休克复苏过程中是否可以利用这一内源性途径来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精心开发的低血压出血和低血容量性休克的在体大鼠和小鼠模型。在非麻醉动物中连续监测血流动力学参数、交感神经活动和中枢呼吸驱动的最先进技术将被用于评估在对5-羟色胺和5-羟色胺受体水平进行药物和分子操作后的心血管参数。此外，新开发的记录未麻醉小鼠交感神经活动的技术将使使用基因改变的小鼠来研究参与失血代偿反应的受体成为可能。此外，新的分子技术将被用来更敏锐地改变离散脑区的5-羟色胺水平，以解剖在神经控制对失血反应的循环反应中重要的区域。最后，临床前翻译研究将探讨使用5-HT1A受体激动剂作为循环休克复苏辅助剂的潜在效用。公共卫生相关性：尽管急救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。患者通常会死于严重的失血，要么是因为组织灌注量太少，要么是因为复苏过程中造成的组织损伤。我们的研究将尝试验证一种新的、有希望的治疗方法，该方法可能有助于患者从循环休克中恢复，而不会在复苏过程中进一步损伤组织。

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.