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

自主神经反射障碍(AD)是颈椎和上胸(上图)的一种潜在的危及生命的后果 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 损伤水平以下的刺激。1、2除了血压急剧上升可能导致的发病率外， 较长时间内复发的AD与血管结构改变有关，而血管结构改变会导致CVD 3、4和免疫功能受损，5这两个都是脊髓损伤患者死亡的主要原因。6同时 外周动脉血管收缩(VC)在AD期间被记录为明显的，7，8 该病的病理生理机制尚不清楚。一些拟议的机制包括：1) 神经元去甲肾上腺素(NE)和共递质(CT)释放的增加；2)连接后的α受体 超敏反应；3)NE再摄取受损和/或4)循环中儿茶酚胺(肾上腺素和GT； 2，9所有这些机制都没有得到充分的证明或被广泛接受。 此外，目前还没有已知的有效的预防性或靶向治疗潜在的 阿尔茨海默病的病理生理机制尚不清楚。阿尔茨海默病的药理学临床护理现状 治疗并不是没有潜在的显著副作用。药物治疗包括短效抗肿瘤药物 高血压(如硝酸甘油和硝苯地平)，可导致全身性低血压。目前尚无已知的 针对AD潜在的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机制将有助于发展靶向治疗(S)以减轻 AD无明显不良反应。我们的建议旨在采取下一步，澄清 阿尔茨海默病的基础病理生理学研究。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检测AD期间VC病理的研究。具体来说，我们将测试 以下假设：1)阻断NE和CT突触前神经的释放将取消皮肤VC 在AD期间和2)阻断突触后α-肾上腺素能受体将减少但不能完全消除VC 在AD期间。可以很容易地接触到皮肤的小动脉来检验这些假设。我们将使用一部小说和非 药物局部离子导入结合皮肤血流的侵入性技术 通过激光多普勒血流仪(LDF)和平均血压(MAP)监测来确定 基础病理生理学：10特定的AIM 1将比较交感神经元阻断的影响 药物(Bretylium=Bt；阻断交感去甲肾上腺素能神经的去甲肾上腺素和共同递质的释放) BT治疗组和对照组AD发作期间的皮肤血管传导(CVC=LDF/MAP)(CON) 前臂和小腿后部的部位。CVC将在常压下的基线=BL进行比较，然后每隔20 在AD期间，由膀胱冲击刺激的秒数。如果动脉血管收缩增加是由于 NE和CT的神经元释放增加，那么Bt治疗的部位显示的相对较少 血管收缩。特异性AIM 2将评估非选择性α-肾上腺素能受体阻断的影响 (酚妥拉明-PT)在AD期间的CVC。在AD期间使用PT之前，最佳PT剂量以阻断α 受体将通过使用α1和α2激动剂与PT一起确定。在总计所需的PT剂量之后 α-肾上腺素能阻断被确定，类似于AIM 1，将在PT治疗时及邻近测量CVC 未经处理的Con站点。如果小动脉血管收缩增加是由于NE的释放，那么CVC就会改变 PT和CON站点的百分比将有所不同。 最终，阐明这一信息将1)指导治疗，并可能指导预防，以更好地针对 AD期间VC的潜在病理生理学基础，全身副作用较少，2)有助于预防血管 可能导致CVD的适应和与复发性AD相关的免疫受损，两者都 可能会增加死亡率。

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.