5-HT1A-agonist mediated recovery in hypovolemic shock

描述(由申请人提供)： 创伤是美国年轻人的主要死因(每年15万人)。大多数创伤死亡要么是由于失血过多导致的组织灌流不足，要么是因为复苏后发生炎症、感染和终末器官损伤。目前低血容量性休克的治疗计划依赖于大量和快速的晶体液体输注来提高心输出量。现已认识到过多的容量复苏会增加失血和再灌注损伤，从而导致低血容量休克的发生。因此，开发治疗创伤性失血的替代策略对于改善低血容量性休克患者的预后至关重要；进行性失血会产生双相反应。心率和交感神经活动的增加在最初的代偿阶段维持血压。这些代偿反应在大量失血(20%-30%)后突然减弱，导致低血压、心动过缓和交感神经抑制。我们最近发现，激活5-HTIA受体的药物能迅速逆转清醒大鼠对出血的低血压和交感神经抑制反应。中枢和全身应用5-HTIA受体激动剂均可在急性或持续失血后有效地升高血压。这些结果表明，5-HTIA激动剂可以为低血容量性休克提供一种有前途的治疗方法。然而，目前尚不清楚5-HTIA受体激活是如何增加动脉压的，也不知道给予激动剂后的血流动力学反应是否对组织灌注量有有益的影响。更重要的是，激活5-HTIA受体是否能延缓低血容量性休克向循环衰竭的转变尚不清楚。本项目中提出的研究将确定选择性5-HTIA激动剂在持续低血压出血后的自主神经和血流动力学效应，以评估它们对血流灌流的影响。其他研究将评估失血时选择性5-HTIA激动剂升压作用的中枢神经系统机制。我们还将评估临床上可用的5-HT1A激动剂延缓从低血容量性休克到循环衰竭的转变的能力。

DESCRIPTION (provided by applicant): Trauma is the leading cause of death of young people in the U.S. (150,000/year). Most trauma deaths result either from insufficient tissue perfusion, due to excessive blood loss, or the development of inflammation, infection and end organ damage following resuscitation. Current treatment plans for hypovolemic shock rely on massive and rapid infusion of crystalloid fluids to raise cardiac output. It is now recognized that excessive volume resuscitation may increase blood loss and the reperfusion injury that contributes to the morbidity of hypovolemic shock. As such, the development of alternative strategies for the treatment of traumatic blood loss will be critical for the improvement of patient outcomes following hypovolemic shock; progressive hemorrhage produces a biphasic response. Increases in heart rate and sympathetic activity maintain blood pressure in the initial compensatory phase. These compensatory responses suddenly abate after significant blood loss (20-30%), resulting in hypotension, bradycardia and sympathoinhibition. We recently discovered that drugs that activate serotonin 5-HTIA receptors rapidly reverse the hypotensive and sympathoinhibitory responses to hemorrhage in conscious rats. Both central and systemic administration of 5-HTIA receptor agonists effectively raises blood pressure after either acute or sustained blood loss. These results indicate that 5-HTIA agonists could provide a promising therapy for hypovolemic shock. However, it is not known how 5-HTIA receptor activation increases arterial pressure or if the hemodynamic responses to agonist administration provide a beneficial effect on tissue perfusion. More importantly, it is not known if activation of 5-HTIA receptors can delay the transition from hypovolemic shock to circulatory collapse. Studies proposed in this project will determine the autonomic and hemodynamic effects of selective 5-HTIA agonists following sustained hypotensive hemorrhage to assess their impact on perfusion. Additional studies will assess the central nervous system mechanisms responsible for pressor effects of selective 5-HTIA agonists during hemorrhage. We will also assess the ability of clinically available 5-HT1A agonists to delay the transition from hypovolemic shock to circulatory collapse.