5-HT1A-agonist mediated recovery in hypovolemic shock

5-HT1A 激动剂介导低血容量休克的恢复

• 批准号: 6844325
• 负责人: KARIE E SCROGIN
• 金额: $ 29.6万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844325
• 关键词: alpha adrenergic receptor; angiotensin receptor; blood pressure; buspirone; cardiac output; cardiovascular disorder chemotherapy; disease /disorder model; hemorrhage; hypovolemia; laboratory rat; neurotransmitter agonist; nonhuman therapy evaluation; serotonin inhibitor; serotonin receptor; shock; solitary tract nucleus; sympathetic nervous system

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.

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）。大多数创伤死亡要么是由于失血过多导致组织灌注不足，要么是复苏后出现炎症、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快速输注晶体液来提高心输出量。现在人们认识到，过量的容量复苏可能会增加失血和再灌注损伤，从而导致低血容量性休克的发病率。因此，开发治疗创伤性失血的替代策略对于改善低血容量休克后患者的预后至关重要；进行性出血会产生双相反应。心率和交感神经活动的增加将血压维持在初始代偿阶段。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，激活血清素 5-HTIA 受体的药物可以迅速逆转清醒大鼠对出血的低血压和交感神经抑制反应。 5-HTIA 受体激动剂的中枢和全身给药均可在急性或持续失血后有效升高血压。 这些结果表明 5-HTIA 激动剂可以为低血容量性休克提供有希望的治疗方法。然而，尚不清楚 5-HTIA 受体激活如何增加动脉压，也不知道对激动剂给药的血流动力学反应是否对组织灌注产生有益影响。更重要的是，尚不清楚 5-HTIA 受体的激活是否可以延迟从低血容量休克到循环衰竭的转变。该项目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-HT1A 激动剂延迟从低血容量休克到循环衰竭转变的能力。