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
基本信息
- 批准号:8655188
- 负责人:
- 金额:$ 6.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-01 至 2017-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcidsAddressAdrenergic AgentsAnimal ModelAttenuatedAxonBaroreflexBiopsyBlood PressureBlood VesselsBlood flowC FiberClinicalDependencyDevelopmentEconomic InflationEfferent PathwaysForearmFunctional disorderGoalsHealthHumanIndividualInjuryLaser-Doppler FlowmetryLimb structureLocal anesthesiaMediatingMediationMicrodialysisNerve FibersNeuronsNeuropeptidesOrthostasisOrthostatic HypotensionParaplegiaPathway interactionsPeripheralPersonsPhysiologicalPilot ProjectsProductionPublishingReflex actionResistanceSensorySeveritiesSiteSkinSmooth Muscle MyocytesSpinalSpinal CordSpinal cord injuryStretch ReceptorsTRPV1 geneTestingTherapeutic InterventionTissuesVascular SystemVasoconstrictor AgentsVasomotorVeinsVenous Pressure leveladrenergicafferent nerveattenuationbaseblood pressure regulationcapsaicin receptorcapsazepineexperiencehemodynamicsimprovedin vivoinsightpressurepublic health relevancereceptorreceptor densityrelating to nervous systemresponsevascular bedvasoconstriction
项目摘要
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小动脉反射(VAR)是对血管内压力增加的局部血管收缩反应,涉及局部感觉传入。最近的证据表明,这些反应涉及神经元香草酸受体、C 纤维上的 TRPV1 的激活,导致局部去极化和神经肽释放影响局部血管收缩。当静脉压增加超过 25mmHg 时,VAR 就会发生,并可能通过牵张感受器扩张导致血流量减少,从而通过非肾上腺素能局部神经机制(也可能涉及 TRPV1)导致“上游”小动脉血管收缩。这些局部血管收缩反应发生在身体健全的人身上,但对于脊髓损伤(SCI)后维持血流动力学稳定性特别重要,因为脊髓损伤(SCI)导致压力感受反射介导的交感血管收缩丧失。事实上,这些血管收缩反应甚至可能在 SCI 中增强。该试点项目将测试 TRPV1 受体通过人类生肌反应和静脉小动脉反射参与局部介导的血管收缩的假设。此外,我们假设 SCI 损伤尾部发现的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所致。我们在人体体内测试我们的假设的具体目标是: 1. TRPV1 受体在 SCI 中是否比在健全个体中更普遍? 2. TRPV1 受体的阻断是否会减弱 SCI 和健全个体的肌源性反应,并且这种减弱在各组之间是否存在差异? 3. TRPV1 受体的阻断是否会减弱 SCI 和健全个体的小静脉小动脉反射,并且这种减弱在各组之间是否存在差异?目标将在健康的身体健全和 SCI 受试者的皮肤中解决,因为这是一种易于接近的组织,表现出肌源性反应和 VAR。目标 1 中将测试来自健全人以及 SCI 人有感觉和无感觉皮肤的 TRPV1 受体密度的皮肤活检。目标 2 和 3 将在同一组中进行测试,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充气期间的肌源性反应和 VAR。局部麻醉将通过局部施用辣椒西平来阻断 EMLA 和 TRPV1 受体。反应将通过激光多普勒流量计记录。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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10257978 - 财政年份:2021
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Elucidating sympathetic vasoconstrictor mechanisms of autonomic dysreflexia in persons with spinal cord injury
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TRPV1 mediation of local vasoconstrictor reflexes in spinal cord injured humans
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