Elucidating sympathetic vasoconstrictor mechanisms of autonomic dysreflexia in persons with spinal cord injury

阐明脊髓损伤患者自主神经反射异常的交感血管收缩机制

• 批准号: 10257978
• 负责人: DEAN L KELLOGG
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10257978
• 关键词: Acute; Address; Adrenal Glands; Adrenergic alpha-Antagonists; Agonist; Antihypertensive Agents; Attenuated; Autonomic Dysreflexia; Baroreflex; Bladder; Blood Pressure; Blood Pressure Monitors; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Catecholamines; Cause of Death; Cervical; Chest; Clinical Trials; Clonidine; Cutaneous; Data; Development; Dose; Epinephrine; Forearm; Functional disorder; Future; Goals; Guide prevention; Hypersensitivity; Hypotension; Immune System Diseases; Immunity; Impairment; Incidence; Infection; Injury; Intervention; Intracranial Hemorrhages; Iontophoresis; Laser-Doppler Flowmetry; Lead; Lesion; Life; Measures; Methods; Modeling; Monitor; Morbidity - disease rate; Myocardial Infarction; Nerve; Neurons; Nifedipine; Nitroglycerin; Norepinephrine; Pathology; Percussion; Peripheral; Persons; Pharmacological Treatment; Pharmacology; Phentolamine; Phenylephrine; Prevention; Preventive treatment; Prophylactic treatment; Recurrence; Role; Seizures; Site; Skin; Spinal; Spinal cord injury; Stimulus; Structure; Synapses; Synaptic Receptors; Techniques; Testing; Therapeutic Intervention; Vascular resistance; Vasoconstrictor Agents; Vasomotor; alpha 2 agonist; alpha-adrenergic receptor; arteriole; blood pressure regulation; clinical care; comparative; design; fighting; immune function; mortality; mortality risk; neuropeptide Y; noradrenergic; novel; presynaptic; prevent; preventive intervention; receptor; relating to nervous system; response; reuptake; side effect; targeted treatment; theories; uptake; vasoconstriction

Autonomic dysreflexia (AD) is a potentially life-threatening consequence of cervical and high thoracic (above T6) spinal cord injury (SCI) characterized by abruptly high elevations in blood pressure in response to noxious stimuli below the injury level. 1,2 In addition to the potential morbidity caused by acute rise in blood pressure, recurrent AD over a longer period has been associated with changes in vascular structure that lead to CVD 3,4and impaired immune function, 5 which are both leading causes of mortality in persons with SCI. 6 While peripheral arteriolar vasoconstriction (VC) is documented to be pronounced during AD,7,8 The pathophysiological mechanisms of this VC are not well defined. A few proposed mechanisms include: 1) increase in neuronal release of norepinephrine (NE) and co-transmitters (CT); 2) post-junctional alpha-receptor hypersensitivity; 3) impaired reuptake of NE and/or 4) increases in circulating catecholamines (Epinephrine > NE) from adrenal stimulation.2,9 None of these mechanisms has been fully proven or is widely accepted. Furthermore, there are no known effective preventative or targeted treatment of the underlying pathophysiology of the AD, as the mechanisms are unknown. Current clinical care of AD with pharmacologic therapies is not without potential for significant side effects. Pharmacologic treatment includes short acting anti- hypertensives (e.g.; nitroglycerin and nifedipine), which can cause systemic hypotension. There is no known treatment targeting the underlying arteriolar vasoconstriction mechanisms of AD since they are unknown. Elucidating the underlying pathophysiology will facilitate the development of targeted treatment(s) to attenuate AD without significant adverse side effects. Our proposal aims to take the next step in elucidating the underlying pathophysiology of VC during AD. We aim to test one of the proposed mechanisms using a novel non-invasive technique never before used in studies testing VC pathology during AD. Specifically we will test following hypotheses: 1) Blockade of pre-synaptic neural release of NE and CT will abolish cutaneous VC during AD and 2) blockade of post synaptic alpha adrenergic receptors will decrease but not fully abolish VC during AD. Arterioles of the skin are easily accessible to test these hypotheses. We will use a novel and non- invasive technique of local iontophoretic delivery of pharmacologic agents combined with skin blood flow monitoring by laser Doppler flowmetry (LDF) and mean blood pressure (MAP) monitoring to define the underlying pathophysiology.10 Specific AIM 1 will compare the impact of a sympathetic neuronal blocking agent (bretylium = BT; blocks release of NE and co-transmitters from sympathetic noradrenergic nerves)) on cutaneous vascular conductance (CVC=LDF/MAP) during an AD episode at BT treated and control (CON) sites on a forearm and posterior calf. CVC will be compared at baseline = BL at normotension then every 20 seconds during AD stimulated by bladder percussion. If the increased arteriolar vasoconstriction is due to increased neuronal release of NE and CT then the sites treated with BT will demonstrate comparatively less vasoconstriction. Specific AIM 2 will evaluate the impact of non-selective alpha-adrenergic receptor blockade (phentolamine – PT) on CVC during AD. Before using PT during AD, the optimal PT dose to block alpha receptors will be determined by utilizing alpha 1 and 2 agonists with PT. After the PT dose required for total alpha –adrenergic blockade is determined, similar to AIM 1, CVC will be measured at PT treated and adjacent untreated CON sites. If the increased arteriolar vasoconstriction is due to NE release, then the CVC changes of PT and CON sites will differ. Ultimately, elucidating this information will 1) guide treatment, and potentially prophylaxis, to better target the underlying pathophysiology of VC during AD, with less systemic side effects and 2) help prevent the vascular adaptations with potential to contribute to CVD and impaired immunity associated with recurrent AD that both may increase mortality.

自主神经反射异常 (AD) 是颈椎和高胸椎（以上）可能危及生命的后果 T6) 脊髓损伤 (SCI)，其特征是对有害物质的反应导致血压突然升高 低于损伤水平的刺激 1,2 除了血压急剧升高引起的潜在发病率外， AD 长期复发与导致 CVD 的血管结构变化有关 3,4 和免疫功能受损，5 都是 SCI 患者死亡的主要原因 6。 据记录，外周小动脉血管收缩 (VC) 在 AD 期间明显，7,8 这种 VC 的病理生理机制尚未明确定义，一些提出的机制包括：1)。 去甲肾上腺素 (NE) 和共递质 (CT) 的神经元释放增加；2) 结后 α 受体 过敏；3) NE 再摄取受损和/或 4) 循环儿茶酚胺增加（肾上腺素 > NE）来自肾上腺刺激。2,9 这些机制都没有得到充分证明或被广泛接受。 此外，尚无已知的有效预防或针对性治疗方法 AD 的病理生理学，因为其机制尚不清楚，目前 AD 的临床治疗与药物治疗有关。 治疗并非没有潜在的显着副作用，药物治疗包括短效抗-。 高血压药物（例如硝酸甘油和硝苯地平），可能会导致全身性低血压。目前尚不清楚。 针对 AD 潜在小动脉血管收缩机制的治疗，因为这些机制尚不清楚。 阐明潜在的病理生理学将有助于开发有针对性的治疗方法以减轻 我们的提案旨在进一步阐明 AD 的不良副作用。 我们的目标是使用一种新颖的方法来测试所提出的机制之一。 以前从未在 AD 期间测试 VC 病理学的研究中使用过这种非侵入性技术。 以下假设：1) 阻断 NE 和 CT 的突触前神经释放将消除皮肤 VC AD 期间和 2) 突触后 α 肾上腺素受体的阻断会减少，但不会完全消除 VC 在 AD 期间，可以轻松访问皮肤小动脉来测试这些假设。 局部离子电渗疗法结合皮肤血流的有创技术 通过激光多普勒血流计 (LDF) 和平均血压 (MAP) 监测来定义 潜在的病理生理学。10 具体 AIM 1 将比较交感神经元阻断的影响 剂（溴乙铵 = BT；阻断交感去甲肾上腺素神经释放 NE 和共递质）） AD 发作期间 BT 治疗和对照 (CON) 的皮肤血管传导 (CVC=LDF/MAP) 前臂和小腿后部 CVC 上的位点将在基线 = BL 正常血压下进行比较，然后每 20 次进行比较。 如果小动脉血管收缩增加是由于膀胱叩击刺激，则在AD期间持续数秒。 NE 和 CT 的神经释放增加，然后用 BT 治疗的部位将表现出相对较少 特定 AIM 2 将评估非选择性 α-肾上腺素能受体阻断的影响。 AD 期间使用 CVC（酚妥拉明 – PT） 在 AD 期间使用 PT 之前，阻断 α 的最佳 PT 剂量。 受体将通过使用 PT 所需的 PT 剂量后的 α 1 和 2 激动剂来确定。 确定α-肾上腺素能阻断，与 AIM 1 类似，将在 PT 治疗处和邻近处测量 CVC 如果小动脉血管收缩增加是由于 NE 释放引起的，则 CVC 会发生变化。 PT 和 CON 站点的数量会有所不同。 最终，阐明这些信息将 1) 指导治疗和潜在的预防，以更好地针对 AD 期间 VC 的潜在病理生理学，具有较少的全身副作用，2) 有助于预防血管性 可能导致 CVD 和与复发性 AD 相关的免疫力受损的适应 可能会增加死亡率。