Carmichael Fellowship: The Role of Forebrain TRPV Channels in Salt-Sensitive Hypertension

The goal of this fellowship is to identify the role of TRPV1 channels on sodium osmosensitive neurons of the organum vasculosum of the lamina terminalis (OVLT) and its descending hypothalamic pathways in the control of sympathetic nerve activity and blood pressure in a model of rat salt-sensitive hypertension. My preliminary data indicate that electrical stimulation of OVLT neurons produces a sympathetically-mediated increase in arterial blood pressure that depends on the hypothalamic paraventricular nucleus (PVH). Our working hypothesis is that increases in plasma sodium (Le. hyperosmotic stimuli) activate TRPV1 channels to increase the tonic activity of OVLT neurons. Activated OVLT neurons projecting to the PVH excite sympathetic-regulatory within the PVH through local activation of excitatory amino acid (EM) or angiotensin II-type 1A receptors. In turn, PVH sympathetic neurons increase sympathetic outflow and arterial blood pressure through mono- and poly-synaptic pathways through the brainstem and spinal cord. Specific aim #1 will identify the synaptic mechanisms within the PVH that mediate sympathetic nerve activity and arterial blood pressure responses produced by OVLT stimulation. Specific aim #2 will identify the neurochemical phenotype of OVLT neurons projecting to the PVH responsive to changes in plasma sodium. Specific Aim #3 will identify the contribution of TRPV1 channel activation within the OVLT to elevated sympathetic nerve activity and arterial blood pressure in salt-sensitive hypertension (DOCA salt hypertensive rats). Experiments will involve identification of the specific neural pathways, neurotransmitters, receptors, and cellular mechanisms that contribute to salt-sensitive hypertension via increases in sympathetic outflow from the brain. This research encompasses the mission statement of the American Heart Association concerning the reduction in "disability and death from cardiovascular diseases and stroke". Investigation into the role of the central nervous system and its relationship with salt in the development of hypertension represents a poorly understood area of public health. The response of the brain to salt and related mechanisms involved in the control of blood pressure must be determined. Insight gained in this area will provide the framework for the development of specific drugs acting on the central nervous system for the treatment of salt-sensitive hypertension in humans.