TRPV1 mediation of local vasoconstrictor reflexes in spinal cord injured humans

描述（由申请人提供）：小动脉生肌反应和小动脉反射（VAR）是局部血管收缩反应，涉及局部感觉传入的血管内压力增加。最近的证据表明，这些反应包括神经元香草样受体的激活，c纤维上的TRPV1引起局部去极化和神经肽释放影响局部血管收缩。当静脉压升高超过25mmHg时，可能由于拉伸受体的扩张导致血流减少，从而通过非肾上腺素能性局部神经元机制导致“上游”小动脉血管收缩，这也可能涉及TRPV1。这些局部血管收缩反应发生在健全的人身上，但在脊髓损伤（SCI）后维持血流动力学稳定性方面具有特别重要的意义，因为脊髓损伤失去了压力反射介导的交感血管收缩；事实上，这些血管收缩反应甚至可能在脊髓损伤中增强。该试点项目将验证TRPV1受体通过肌源性反应和静脉-小动脉反射参与人体局部介导的血管收缩的假设。此外，我们假设脊髓损伤尾侧局部血管收缩反应增强是由于trpv1介导的局部神经血管反射增强。我们在人体中验证我们的假设的具体目标是：1。TRPV1受体在脊髓损伤中是否比健康人更普遍？2. 阻断TRPV1受体是否会减弱脊髓损伤和健全个体的肌原性反应？这种减弱在组间是否有所不同？3. 阻断TRPV1受体是否会减弱脊髓损伤和健全个体的静脉小动脉反射？这种减弱在两组之间是否有所不同？目标将在健康的健全和脊髓损伤受试者的皮肤中进行，因为这是一种容易接近的组织，既表现出肌原性反应，也表现出VAR。在Aim 1中，对健全者的皮肤活检以及脊髓损伤患者的感觉和无感觉皮肤进行TRPV1受体密度测试。目的2和目的3将在同一组中通过比较局部麻醉和TRPV1受体拮抗剂对肢体依赖和肢体袖带膨胀期间肌源性反应和VAR的影响来进行测试。局部麻醉将由EMLA和TRPV1受体阻断，局部给药辣椒平。反应将由激光多普勒血流仪记录。

DESCRIPTION (provided by applicant): The arteriolar myogenic response and the venoarteriolar reflex (VAR) are local vasoconstrictor responses to increased intravascular pressure that involve local sensory afferents. Recent evidence suggests that these responses involve activation of the neuronal vanilloid receptor, TRPV1 on C-fibers causing local depolarization and neuropeptide release effects local vasoconstriction. The VAR occurs when venous pressure increases more than 25mmHg and causes a reduction in blood flow probably by distention of stretch receptors that results in an 'upstream' arteriolar vasoconstriction throug non-adrenergic local neuronal mechanisms that may also involve TRPV1. These local vasoconstrictor responses occur in able-bodied persons, but are of special importance in maintaining hemodynamic stability after spinal cord injury (SCI) where there is loss of baroreflex mediated sympathetic vasoconstriction; indeed, these vasoconstrictor responses may even be enhanced in SCI. This pilot project will test the hypothesis that TRPV1 receptors participate in the locally mediated vasoconstrictions by the myogenic response and venoarteriolar reflex in humans. In addition, we hypothesize that enhanced local vasoconstrictor responses found caudal to the level of injury in SCI is due to augmented TRPV1-mediated local neurovascular reflexes. Our specific aims to test our hypotheses in humans in vivo are: 1. Are TRPV1 receptors more prevalent in SCI than in able-bodied individuals? 2. Does blockade of TRPV1 receptors attenuate the myogenic response in SCI and able-bodied individuals and does this attenuation differ between groups? 3. Does blockade of TRPV1 receptors attenuate the venoarteriolar reflex in SCI and able-bodied individuals and does this attenuation differ between groups? Aims will be addressed in healthy able-bodied and SCI subjects in skin as this is a readily accessible tissue that manifests both the myogenic response and VAR. Skin biopsies from able-bodied persons and from sensate and insensate skin of SCI persons will be tested for TRPV1 receptor density in Aim 1. Aims 2 and 3 will be tested in the same groups by comparing the effects of local anesthesia and TRPV1 receptor antagonism on myogenic responses and the VAR during limb dependency and limb cuff inflation. Local anesthesia will be by EMLA and TRPV1 receptor blockade by local administration of capsazepine. Responses will be recorded by laser-Doppler flowmetry.