TRPV1 mediation of local vasoconstrictor reflexes in spinal cord injured humans

描述（由申请方提供）：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，这些反应涉及激活神经元香草素受体，C-纤维上的TRPV 1引起局部去极化和神经肽释放效应局部血管收缩。当静脉压增加超过25 mmHg时发生VAR，并可能通过牵张受体的扩张导致血流减少，这导致“上游”小动脉血管收缩，这可能也涉及TRPV 1的非肾上腺素能局部神经元机制。这些局部血管收缩反应发生在身体健全的人中，但在脊髓损伤（SCI）后维持血流动力学稳定方面特别重要，脊髓损伤（SCI）中存在压力反射介导的交感血管收缩的损失;事实上，这些血管收缩反应甚至可能在SCI中增强。本试验项目将验证TRPV 1受体通过肌源性反应和静脉动脉反射参与人体局部介导的血管收缩的假设。此外，我们推测，增强的局部血管收缩反应发现尾部的损伤水平在SCI是由于增强TRPV 1介导的局部神经血管反射。我们的具体目标是在人体内测试我们的假设是：1。TRPV 1受体在SCI中比在健全个体中更普遍吗？2.阻断TRPV 1受体是否会减弱SCI和健全个体的肌源性反应，这种减弱在组间是否存在差异？3.阻断TRPV 1受体是否会减弱SCI和健全个体的静脉动脉反射，这种减弱在组间是否存在差异？目标将在健康健全和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。在目标1中，将测试来自健全人以及来自SCI人的有感觉皮肤和无感觉皮肤的皮肤活检的TRPV 1受体密度。通过比较局部麻醉和TRPV 1受体拮抗剂对肌源性反应和肢体依赖性和肢体袖带充气期间VAR的影响，在相同组中检验目的2和3。局部麻醉将通过EMLA和TRPV 1受体阻滞剂（通过辣椒平局部给药）进行。将通过激光多普勒血流仪记录反应。

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.