Examination of a novel potential therapy for autonomic dysreflexia

项目摘要/摘要 自主神经反射障碍(AD)是一种潜在威胁生命的高血压危象 主要影响脊髓损伤(SCI)在T6以上的个人。广告可以是 特发性地或由盆腔内脏器官的扩张或操作引起的， 尤其是膀胱和肠道，可通过导尿术和排泄物发生。 排空程序是管理膀胱和肠道排空所必需的。 来自盆腔内脏的感觉刺激激活心血管交感神经 节前神经元通过节间脊髓反射触发AD。 目前，还没有被批准用于预防AD的药物。 一种潜在的新的治疗方法可能是使用一种拮抗剂来抑制 受体(即解剖学、生理学、药理学和临床上的 与脊髓对内脏和心血管功能的控制有关 负责AD的反射通路)来预防AD的发生。 我们的初步数据表明，阻止一种特定的内源性 使用选择性受体拮抗剂的神经递质抑制结直肠扩张 急性脊髓损伤麻醉大鼠(CRD)诱导的高血压。我们假设 这种受体的选择性拮抗剂也可以减少或消除高血压。 CRD在慢性脊髓损伤大鼠中的作用，慢性损伤后的影响可能更大 由于L6背角和L6背角的突触可塑性的变化和纤维的发芽 骶骨副交感神经核。这一假设将通过检验能力来检验 选择性拮抗剂阻断CRD诱导的AD和自发性AD事件 慢性脊髓损伤大鼠。在具体目标1中，我们将检查拮抗剂对 慢性脊髓损伤雄性和雌性大鼠CRD诱导的高血压。 在特定的目标2中，我们将从目标1中选择最有效的拮抗剂来确定 SC每日给药1周对静息血压和血压的影响 慢性脊髓损伤大鼠的自发性AD事件。 由于几种选择性拮抗剂在美国被批准用于临床，这是合理的 期待预防阿尔茨海默病的概念验证临床试验即将开始 在从这项提案中获得支持数据后。

PROJECT SUMMARY/ABSTRACT Autonomic dysreflexia (AD) is a potentially life-threatening hypertensive crisis that predominantly affects individuals with a spinal cord injury (SCI) above T6. AD can be triggered idiopathically or by distention or manipulation of pelvic visceral organs, especially the bladder and bowel, which can occur with catheterization and fecal evacuation procedures that are necessary to manage bladder and bowel emptying. Sensory stimuli arising from the pelvic viscera activate cardiovascular sympathetic preganglionic neurons through an intersegmental spinal reflex that triggers AD. Currently, there are no pharmaceutical agents approved for the prevention of AD. A potential novel therapeutic approach may be to use an antagonist that inhibits a receptor (that is anatomically, physiologically, pharmacologically, and clinically implicated in the spinal control of visceral and cardiovascular function at various points in the reflex pathways responsible for AD) to prevent the occurrence of AD. Our preliminary data indicate that blocking the actions of a specific endogenous neurotransmitter using a selective receptor antagonist inhibits colorectal distension (CRD)-induced hypertension in anesthetized rats with acute SCI. We hypothesize that selective antagonists of this receptor will also reduce or eliminate hypertension induced by CRD in rats with chronic SCI, and that the effect may be greater after a chronic injury because of synaptic plasticity changes and sprouting of fibers in the L6 dorsal horn and sacral parasympathetic nucleus. This hypothesis will be tested by examining the ability of selective antagonists to block AD induced by CRD, and spontaneous AD events, in rats with chronic SCI. In Specific Aim 1, we will examine the effects of antagonists on CRD-induced hypertension in male and female rats with chronic SCI. In Specific Aim 2, we will select the most efficacious antagonist from Aim 1 to determine the effect of daily SC administration for 1 week on resting blood pressure and spontaneous AD events in rats with chronic SCI. As several selective antagonists are approved for clinical use in the US, it is reasonable to expect that a proof of concept clinical trial for the prevention of AD could begin soon after obtaining supportive data from this proposal.