Role of Serotonin in Smypathetic Function

描述（由申请人提供）：本项目将有助于描述中枢神经系统在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机制。实验将验证酸中毒激活的尾侧后脑5-羟色胺能神经元在低血容量时刺激5-HT1A受体促进内脏血管床交感介导的静脉收缩的假设。进一步提出，5-HT1A受体激活诱导的静脉血管优先收缩在低血容量性休克复苏过程中产生的再灌注损伤比临床使用的血管收缩剂更小，血管收缩剂倾向于收缩动脉血管床。目的1将确定尾侧后脑血清素是否对维持或恢复严重失血后交感神经介导的全身静脉张力和静脉回流至关重要。目的2将确定与低血容量或呼吸和代谢性酸中毒相关的酸血症本身是否有助于尾部后脑血清素神经激活和随后的呼吸和自主神经反应的激活。进一步的研究将评估酸中毒有助于维持血压通过优先静脉收缩。目的3将确定血清素是否作用于5-HT1A受体介导低血容量血症的代偿反应，以及这种内源性途径是否可以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精心开发的体内大鼠和小鼠低血压出血和低血容量性休克模型。在未麻醉的动物中持续监测血液动力学参数、交感神经活动和中枢呼吸驱动的最新技术将用于评估5 -羟色胺和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，新开发的记录未麻醉小鼠交感神经活动的技术将使转基因小鼠能够用于研究与失血代偿反应有关的受体。此外，新的分子技术将更敏锐地改变离散脑区域的血清素水平，以解剖在血液流失循环反应的神经控制中重要的区域。最后，临床前，转化研究将解决使用5-HT1A受体激动剂作为辅助剂在循环休克复苏中的潜在效用。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，要么是因为组织灌注过少，要么是因为复苏过程中组织损伤。我们的研究将尝试验证一种新的，有希望的治疗方法，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.