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: 10404588
• 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/10404588
• 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）是颈部和高胸部（上图）的潜在危及生命的后果。 T6）脊髓损伤（SCI），其特征是响应于有害的 低于损伤水平的刺激。1.2除了血压急性升高引起的潜在发病率外， 长期复发的AD与导致CVD的血管结构变化有关 3，4和免疫功能受损，5这两者都是SCI患者死亡的主要原因。6虽然 外周小动脉血管收缩（VC）被证明在AD期间是明显的，7，8。 这种VC的病理生理机制尚未明确。一些拟议的机制包括： 去甲肾上腺素（NE）和共递质（CT）神经元释放增加; 2）连接后α受体 超敏反应; 3）NE的再摄取受损和/或4）循环中的儿茶酚胺增加（肾上腺素> NE）。2，9这些机制都没有得到充分证实或被广泛接受。 此外，没有已知的有效的预防性或靶向治疗的基础 AD的病理生理学，因为机制未知。AD的临床治疗现状 这些疗法并非没有潜在的显著副作用。药物治疗包括短效抗- 高血压患者（例如;硝酸甘油和硝苯地平），可引起全身性低血压。没有已知 针对AD的潜在小动脉血管收缩机制的治疗，因为它们是未知的。 阐明潜在的病理生理学将有助于开发靶向治疗，以减轻 AD无明显不良副作用。我们的建议旨在进一步阐明 AD期间VC的潜在病理生理学。我们的目标是使用一种新的方法来测试所提出的机制之一。 非侵入性技术以前从未用于AD期间VC病理学的研究。具体来说，我们将测试 以下假设：1）阻断NE和CT的突触前神经释放将消除皮肤VC 2）突触后α肾上腺素能受体的阻断将减少但不能完全消除VC 在AD期间。皮肤的小动脉很容易接近，以测试这些假设。我们将使用一个小说和非- 结合皮肤血流局部离子导入药物的侵入性技术 通过激光多普勒血流仪（LDF）和平均血压（MAP）监测来确定 潜在的病理生理学。10特定AIM 1将比较交感神经元阻滞的影响， 药剂（溴苄铵= BT;阻断交感去甲肾上腺素能神经释放NE和共递质）） BT治疗组和对照组（CON）AD发作期间的皮肤血管传导性（CVC=LDF/MAP） 前臂和小腿后侧的伤口将在基线时比较CVC =正常血压时的BL，然后每20分钟比较一次 在膀胱叩击刺激AD期间，如果小动脉血管收缩增加是由于 增加NE和CT的神经元释放，那么用BT处理的部位将表现出相对较少的 血管收缩特异性AIM 2将评估非选择性α-肾上腺素能受体阻滞剂的影响 （酚妥拉明- PT）对AD期间CVC的影响。在AD期间使用PT之前， 受体将通过使用α 1和α 2激动剂与PT来确定。总剂量所需的PT剂量后 确定α-肾上腺素能阻滞，类似于AIM 1，将在PT治疗和相邻治疗时测量CVC 未经处理的CON站点。如果增加的小动脉血管收缩是由于NE释放，那么CVC改变， 的PT和CON站点将不同。 最终，阐明这一信息将1）指导治疗，并可能预防，以更好地针对 AD期间VC的潜在病理生理学，全身副作用较少，2）有助于预防血管 适应可能导致CVD和与复发性AD相关的免疫力受损， 可能会增加死亡率。

项目成果

Mechanistic involvement of noradrenergic neuronal neurotransmitter release in cutaneous vasoconstriction during autonomic dysreflexia in persons with spinal cord injury.

脊髓损伤患者自主神经反射异常期间去甲肾上腺素能神经元神经递质释放参与皮肤血管收缩的机制。

• DOI: 10.1016/j.autneu.2024.103154
• 发表时间: 2024
• 期刊: Autonomic neuroscience : basic & clinical
• 作者: Trbovich,Michelle;Wu,Yubo;Romo,Terry;Koek,Wouker;Kellogg,Dean
• 通讯作者: Kellogg,Dean