TRPV1 mediation of local vasoconstrictor reflexes in spinal cord injured humans

TRPV1 介导脊髓损伤人体局部血管收缩反射

• 批准号: 8570431
• 负责人: DEAN L KELLOGG
• 金额: $ 6.3万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8570431
• 关键词: Acids; Address; Adrenergic Agents; Animal Model; Attenuated; Axon; Baroreflex; Biopsy; Blood Pressure; Blood Vessels; Blood flow; C Fiber; Clinical; Dependency; Development; Economic Inflation; Efferent Pathways; Forearm; Functional disorder; Goals; Health; Human; Individual; Injury; Laser-Doppler Flowmetry; Limb structure; Local anesthesia; Mediating; Mediation; Microdialysis; Nerve Fibers; Neurons; Neuropeptides; Orthostasis; Orthostatic Hypotension; Paraplegia; Pathway interactions; Peripheral; Persons; Physiological; Pilot Projects; Production; Publishing; Reflex action; Resistance; Sensory; Severities; Site; Skin; Smooth Muscle Myocytes; Spinal; Spinal Cord; Spinal cord injury; Stretch Receptors; TRPV1 gene; Testing; Therapeutic Intervention; Tissues; Vascular System; Vasoconstrictor Agents; Vasomotor; Veins; Venous Pressure level; adrenergic; afferent nerve; attenuation; base; blood pressure regulation; capsaicin receptor; capsazepine; experience; hemodynamics; improved; in vivo; insight; pressure; public health relevance; receptor; receptor density; relating to nervous system; response; vascular bed; vasoconstriction

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.

描述（由申请人提供）：小动脉肌源性反应和静脉反射（VAR）是局部血管收缩剂对涉及局部感觉传入的血管内压力增加的血管收缩反应。最近的证据表明，这些反应涉及激活神经元香草素受体，TRPV1在引起局部去极化和神经肽释放的C纤维上的激活和局部血管收缩的影响。当静脉压增加超过25mmHg并导致伸展受体的扩张导致血液流量减少时，发生VAR发生，从而导致“上游”大动脉血管收缩通过非肾上腺肾上腺素能局部神经元机制，这些机制也可能涉及TRPV1。这些局部血管收缩反应发生在健全的人中，但在维持脊髓损伤后血液动力学稳定性（SCI）中至关重要，而在脊髓损伤（SCI）中丧失了aroreflex介导的交感神经血管收缩；确实，这些血管收缩反应甚至可能在SCI中得到增强。该试点项目将检验以下假设：TRPV1受体通过人类的肌源性反应和静脉反射参与局部介导的血管收缩。此外，我们假设增强的局部血管收缩反应发现SCI损伤水平是由于TRPV1介导的局部神经血管反射的增强所致。我们在体内检验人类假设的特定目的是：1。在SCI中，TRPV1受体比在身体健全的个体中更普遍？ 2。封锁TRPV1受体是否会衰减SCI和健全的个体中的肌源性反应，并且组之间的衰减是否有所不同？ 3。封锁TRPV1受体是否会在SCI和健全的个体中衰减静脉反射，并且这种衰减在组之间是否有所不同？在皮肤健康的身体健美和SCI受试者中，目标将解决，因为这是一种易于访问的组织，既表现出肌源性反应和VAR。来自AIM 1的SCI人的身体活检以及SCI患者的感官和敏感的皮肤的皮肤活检将在AIM 1中测试TRPV1受体密度。AIM 2和3将通过比较局部麻醉和TRPV1受体拮抗作用对肌动力反应以及在LIMB依赖性和Limb Cuff cuff cuff Alteryation中的局部麻醉和TRPV1受体拮抗作用来测试。局部麻醉将通过辣椒粉的局部给药，由EMLA和TRPV1受体阻断。响应将由激光多普勒流量计记录。