HYPERHOMOCYST(E)INEMIA INDUCED BY METHIONINE LOADING

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。高同型球蛋白(E)血症已被发现与早发性动脉和静脉血栓形成有关，并且是冠心病和脑血管疾病的危险因素。然而，它采取行动的机制尚不清楚。N-甲基-D-天冬氨酸(NMDA)受体是脑干、脊髓和自主神经系统兴奋性神经递质的受体。刺激NMDA受体可能会引起神经毒性。Homcyst(E)ine具有神经毒性作用，在实验动物中诱导癫痫发作和行为改变，这是由于NMDA受体的刺激以及通过产生自由基。它还具有血管效应，通过激活VSMC中的NMDA相关受体，导致神经沟来源的血管平滑肌细胞(VSMC)DNA合成增加和细胞增殖。脑干和脊髓中的NMDA受体和兴奋性神经递质在交感神经活动的维持和调节以及中枢心血管调节中发挥着重要作用。它们介导脑桥和延髓的血管加压反应、延髓和脊髓的压力反射功能、交感心脏反射和躯体交感反射。考虑到同型半胱氨酸对NMDA受体的刺激作用，以及NMDA受体在交感神经流出调节中的重要作用，高同型半胱氨酸血症可能通过激活NMDA受体而增加交感神经的活性。因此，这项研究将检验一种假设，即由蛋氨酸负荷引起的实验性高同型球蛋白(E)血症会增加健康人的肌交感神经活动。肌交感神经活动将通过使用显微神经成像技术的直接神经内记录来评估。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hyperhomocyst(e)inemia has been found to be associated with early onset arterial and venous thrombosis, and as a risk factor for coronary artery disease and cerebrovascular disease. However, the mechanisms through which it acts is unclear. N-Methyl D-aspartate (NMDA) receptors are receptors for excitatory neurotransmitters in the brain stem, spinal cord and autonomic nervous system. NMDA receptor stimulation may cause neurotoxicity. Homocyst(e)ine has neurotoxic actions, inducing seizures and behavioral changes in experimental animals, which are due to NMDA receptor stimulation as well as by producing free radicals. It also has vascular effects, causing increased DNA synthesis and cell proliferation in neural crest-derived vascular smooth muscle cells (VSMC), through activation of a NMDA-related receptor in VSMC. NMDA receptors and excitatory neurotransmitters in the brain stem and spinal cord play an important role in the maintenance and regulation of sympathetic nerve activity and central cardiovascular regulation. They mediate vasopressor responses of the pons and medulla, baroreflex functions of the medulla and spinal cord, reflex sympathetic heart effects and somatosympathetic reflexes. Considering the stimulation by homocyst(e)ine of NMDA receptors, and the importance of NMDA receptors on regulation of sympathetic outflow, it is possible that hyperhomocyst(e)inemia may increase sympathetic nerve activity through NMDA receptor activation. This study will, therefore, test the hypothesis that experimental hyperhomocyst(e)inemia, induced by methionine loading, increases muscle sympathetic nerve activity in healthy humans. Muscle sympathetic nerve activity will be assessed by direct intraneural recordings using microneurography techniques.