5-HT1A-agonist mediated recovery in hypovolemic shock

描述（由申请人提供）： 创伤是美国年轻人死亡的主要原因（每年15万人）。大多数创伤死亡是由于组织灌注不足，失血过多，或复苏后炎症，感染和终末器官损伤的发展。目前低血容量性休克的治疗方案依赖于大量和快速输注晶体液以提高心输出量。现在认识到，过度的容量复苏可能会增加失血和再灌注损伤，导致低血容量性休克的发病率。因此，开发创伤性失血的替代治疗策略对于改善低血容量性休克后的患者结局至关重要;进行性出血产生双相反应。心率和交感神经活动的增加使血压维持在最初的代偿阶段。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-羟色胺5-HTIA受体的药物可以迅速逆转清醒大鼠对出血的兴奋和交感神经抑制反应。在急性或持续失血后，5-HT 1A受体激动剂的中枢和全身给药均有效地升高血压。 这些结果表明，5-HTIA激动剂可以提供一个有前途的治疗低血容量性休克。然而，目前尚不清楚5-HT 1A受体激活如何增加动脉压，或者对激动剂给药的血液动力学反应是否对组织灌注提供有益作用。更重要的是，尚不清楚5-HT 1A受体的激活是否可以延迟从低血容量性休克到循环衰竭的转变。本项目中提出的研究将确定持续性脑出血后选择性5-HTIA激动剂的自主神经和血流动力学效应，以评估其对灌注的影响。其他研究将评估出血期间选择性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-HT 1A激动剂延迟从低血容量性休克向循环衰竭转变的能力。

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.