HYPERHOMOCYST(E)INEMIA INDUCED BY METHIONINE LOADING

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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.