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: 7002315
• 负责人: KARIE E SCROGIN
• 金额: $ 28.9万
• 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/7002315
• 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150,000）。大多数创伤死亡是由于失血过多而导致的组织灌注不足，或者复苏后炎症，感染和最终器官损伤的发展。当前的低血容量休克治疗计划依赖于大量和快速输注晶体液来提高心输出量。现在已经认识到，过量的量复苏可能会增加失血量和再灌注损伤，这导致低血容量减震的发病率。因此，开发治疗创伤性失血的替代策略对于改善低血容量减震后的患者结局至关重要。进行性出血产生双相反应。心率的增加和交感神经活动在初始补偿阶段保持血压。这些补偿性反应在大量失血后突然减轻（20-30％），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受体的药物迅速扭转了对有意识大鼠出血的降低和交感抑制反应。 5-HTIA受体激动剂的中央和全身给药可有效地升高急性或持续失血后的血压。 这些结果表明，5-HTIA激动剂可以为低血容量休克提供有希望的疗法。但是，尚不清楚5-HTIA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产生了有益的作用。更重要的是，尚不清楚5-HTIA受体的激活是否会延迟从低血容量休克到循环崩溃的过渡。该项目中提出的研究将确定持续性低血压出血后选择性5-HTIA激动剂的自主和血液动力学作用，以评估其对灌注的影响。其他研究将评估导致选择性5-HTIA激动剂在出血期间的施加效应的中枢神经系统机制。我们还将评估临床上可用的5-HT1A激动剂延迟从低血液性休克到循环崩溃的过渡的能力。