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.

自主性逆转录病毒（AD）是宫颈和高胸腔的潜在威胁生命的后果（以上 T6）脊髓损伤（SCI），其特征是血压突然高升高。 刺激低于伤害水平。 1,2除了血压急性升高引起的潜在发病率外， 较长时期的复发广告与导致CVD的血管结构变化有关 3,4和免疫功能受损，其中5个都是SCI患者死亡的主要原因。 6时 外围小动脉血管收缩（VC）记录在AD期间发音为7,8 该VC的病理生理机制尚未很好地定义。提出的一些机制包括：1） 去甲肾上腺素（NE）和共晶剂（CT）的神经元释放的增加； 2）骨后α受体 超敏反应； 3）NE和/或4的再摄取受损，循环儿茶酚胺的增加（肾上腺素> NE）来自肾上腺刺激。2,9这些机制均未得到充分证明或被广泛接受。 此外，没有已知的有效预防或靶向治疗 AD的病理生理学，因为机制尚不清楚。当前使用药理学AD的临床护理 疗法并非没有潜在的副作用。药理治疗包括短作用抗 高血压（例如；硝酸甘油和硝苯地平），可能导致全身性低血压。没有知道的 靶向AD的基础动脉血管收缩机制的处理，因为它们尚不清楚。 阐明潜在的病理生理学将促进靶向治疗的发展 没有明显的不良副作用的广告。我们的建议旨在迈出下一步 AD期间VC的基础病理生理学。我们旨在使用小说来测试提出的机制之一 非侵入性技术从未用于研究AD期间VC病理学的研究。具体我们将测试 以下假设：1）NE和CT的突触前神经酶的阻塞将废除皮肤VC 在AD和2）合成后肾上腺肾上腺肾上腺素受体的盖子将减少但不能完全废除VC 在广告期间。皮肤的小动脉很容易接触以检验这些假设。我们将使用小说和非 局部离子噬菌体递送药物的侵入性技术与皮肤血流结合 通过激光多普勒流量金属（LDF）和平均血压（MAP）监测监测以定义 基础病理生理学。10特定目标1将比较交感神经阻塞的影响 代理（甲酸= bt;阻止NE和co射手从交感神经能神经中释放））））） 在BT处理和对照（con）的AD发作期间，皮肤血管电导（CVC = LDF/MAP） 前臂和后小腿上的位置。 CVC将在基线= bl时在正常时进行比较，然后每20个 膀胱打击乐刺激的AD中的几秒钟。如果增加的小动脉血管收缩是由于 NE和CT的神经元释放增加，然后用BT处理的位点显示相对较少 血管收缩。具体目标2将评估非选择性α-肾上腺素能受体阻滞的影响 （苯丙胺 - PT）在AD期间的CVC上。在AD期间使用PT之前，最佳PT剂量可以阻止α 受体将通过使用pt的α1和2个激动剂来确定。总计需要PT剂量后 确定α-肾上腺封锁，类似于AIM 1，CVC将在PT处理和邻近的PT下进行测量 未经处理的cON位点。如果增加的小动脉血管收缩是由于NE释放，则CVC改变 PT和CON位点的不同。 最终，阐明此信息将为1）指导治疗和潜在的预防，以更好地针对 AD期间VC的基础病理生理学，具有较少的系统性副作用，2）有助于防止血管 有可能对CVD造成CVD和通过复发性AD的免疫损害的适应 可能会增加死亡率。